ArticleLiterature Review

Role of nitric oxide in the regulation of monoaminergic neurotransmission

September 2000
Brain Research Bulletin 52(6):459-66

September 2000
52(6):459-66

DOI:10.1016/S0361-9230(00)00282-3

Source
PubMed

Authors:

Janos P Kiss

Kinepict Health Ltd

Data accumulated in the last decade indicate that nitric oxide (NO) participates in the regulation of neurotransmission in the central nervous system. Due to its physicochemical properties, NO is an ideal mediator of nonsynaptic interactions. The importance of monoaminergic systems in the function of the brain is clearly shown by the number of severe neuropsychiatric diseases (e.g. depression, Parkinson's disease) caused by the impairment of monoaminergic neurotransmission. Because of their neuroanatomical characteristic, monoaminergic systems participate mainly in nonsynaptic interactions. Since NO is a potential nonsynaptic modulator, it may have an important role in the regulation of monoaminergic systems. The aim of the present review is to survey the literature on the effect of NO on dopaminergic, noradrenergic and serotonergic neurotransmission. The potential mechanisms of action are summarized. Since there is no agreement in the literature on the nature of the effect of NO exerted on monoaminergic neurotransmission, and there are contradictory data concerning the mechanisms involved, the possible reasons for this unusual inconsistency are also discussed.

Role of nitric oxide in the induction of the behavioral and cellular changes produced by a common aversive stimulus in Aplysia

Article

Dec 2018
BEHAV BRAIN RES

Although it is well documented that exposure to aversive stimuli induces modulation of neural circuits and subsequent behavioral changes, the means by which an aversive stimulus concomitantly alters behaviors of different natures (e.g., defensive and appetitive) remains unclear. Here, we addressed this issue by using the learning-induced concurrent modulation of defensive and appetitive behaviors that occurs when the mollusk Aplysia is exposed to aversive stimuli. In Aplysia, aversive stimuli concomitantly enhance withdrawal reflexes (i.e., sensitization) and suppress feeding. Sensitization and feeding suppression, which are expressed in the short term and long term, depending on the training protocol, are accompanied by increased excitability of the tail sensory neurons (TSNs) controlling the withdrawal reflexes, and by decreased excitability of feeding decision-making neuron B51, respectively. Serotonin (5-HT) has been shown to mediate sensitization, but not feeding suppression. In this study, we examined which other neurotransmitter might be responsible for feeding suppression and its underlying cellular changes. Our results indicate that nitric oxide (NO) contributes to both short-term and long-term feeding suppression, as well as to the underlying decreased B51 excitability. NO was also necessary for the induction of long-term sensitization and for the expression of short-term increased TSN excitability in vitro, revealing a previously undocumented interaction between 5-HT and NO signaling cascades in sensitization. Overall, these results revealed a scenario in which multiple modulators contribute to the widespread changes induced by sensitizing stimuli in Aplysia.

Differential behavioral and glial responses induced by dopaminergic mechanisms in the iNOS knockout mice

Article

May 2018
BEHAV BRAIN RES

The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system provides new avenues to the development of pharmacological tools for the pathophysiological conditions of the dopaminergic system. Our aim was to investigate the influences of dopamine-induced effects in inducible NOS knockout (iNOS KO) mice. In order to characterize iNOS KO mice phenotype, the animals were submitted to the basal analyses of motor, sensorimotor and sensorial abilities. Pharmacological challenging of the dopaminergic system included the investigation of amphetamine-induced prepulse inhibition (PPI) disruption, haloperidol-induced catalepsy, reserpine-induced oral involuntary movements and hyperlocomotion induced by amphetamine in reserpine treated mice. The iNOS KO mice showed significant reduction of spontaneous motor activity, but there was no significant difference in sensorimotor or sensorial responses of iNOS KO mice compared to wild type (WT). Regarding the dopaminergic system, iNOS KO mice showed a significant increase of haloperidol-induced catalepsy. This effect was confirmed through an iNOS pharmacological inhibitor (1400 W) in WT mice. In addition, iNOS KO reserpine treated mice showed reduced oral involuntary movements and amphetamine-induced hyperlocomotion. Knowing that iNOS is mainly expressed in glial cells we analyzed the immunoreactivity (ir) for GFAP (astrocyte marker) and IBA-1 (microglial marker) in the striatum, an area enrolled in motor planning among other functions. iNOS KO presented reduced GFAP-ir and IBA-1-ir compared with WT. Reserpine treatment increased GFAP-ir and only IBA-1-ir microglia with reactive phenotype in both WT and iNOS KO. However, these effects were slighter in iNOS KO. Our results further demonstrated that the absence of iNOS interfered with dopamine-mediated behavioral and molecular responses. These results increase the understanding of the dopamine and NO system interaction, which is useful for the management of the dopamine-related pathologies.

Novel enhancement mechanism of tyrosine hydroxylase enzymatic activity by nitric oxide through S-nitrosylation

Article

Full-text available

Mar 2017

Tyrosine hydroxylase (TH) is a rate-limiting step enzyme in the synthesis of catecholamines. Catecholamines function both as hormone and neurotransmitters in the peripheral and central nervous systems, therefore TH’s expression and enzymatic activity is tightly regulated by various mechanisms. Several post-translational modifications have been shown to regulate TH’s enzymatic activity such as phosphorylation, nitration and S-glutathionylation. While phosphorylation at N-terminal of TH can activate its enzymatic activity, nitration and S-glutathionylation can inactivate TH. In this study, we found that TH can also be S-nitrosylated by nitric oxide (NO). S-nitrosylation is a reversible modification of cysteine (cys) residue in protein and is known to be an emerging signaling mechanism mediated by NO. We found that TH can be S-nitrosylated at cys 279 and TH S-nitrosylation enhances its enzymatic activity both in vitro and in vivo. These results provide a novel mechanism of how NO can modulate TH’s enzymatic activity through S-nitrosylation.

NO Reactions Inside Crystals

Article

Full-text available

Jul 2023
EUR J INORG CHEM

Reactions of chemisorbed reagents inside the crystalline molecular solid state are rare but offer unexploited methods for selective solvent‐free chemical synthesis. Here we show that the greenhouse gas precursor, nitric oxide (NO) is chemisorbed by crystals of the hexafluorophosphate salts of complexes containing dicobalt sites. On NO sorption a cascade of reactions results in the in‐crystal synthesis of nitrite and other gaseous NOx. Recrystallization enabled structural elucidation of the mixed valent {[(bpbp)Co2(μ‐(η¹‐O : η¹‐N)‐ONO)]2(bdc)}⁴⁺ (bpbp=2,6‐bis(N,N‐bis(2‐pyridylmethyl)aminomethyl)‐4‐tert‐butylphenolato, bdc=1,4‐benzenedicarboxylato) cation. Overlapping signals in the solid‐state EPR spectra confirm the CoIICoIII oxidation state and the presence of NO2 trapped inside the unrecrystallised solid products (br. g=4, triplet g=2 (340 mT), A(N)=73 MHz), despite three cycles of vacuum and N2 flushing. Consistently, νN−O bands appear in the Raman and IR spectra that are due to the coordinated nitrate and the trapped NO2 that were synthesized in‐crystal. The latter is expelled by heating the solid to 160 °C or by recrystallization. Dimetallic cooperativity is proposed for the NO transformations in these rare examples of selective, chemisorptive substrate reactions in the solid‐state.

Dietary N-carbamylglutamate supplementation improves ammonia tolerance of juvenile yellow catfish Pelteobagrus fulvidraco

Article

Full-text available

Apr 2023

Introduction: Ammonia has been of concern for its high toxicity to animals. N -carbamylglutamate (NCG) can reduce blood ammonia levels in mammals, but studies on ammonia tolerance in fish are insufficient. Methods: Juvenile yellow catfish were fed two levels of NCG (0.00% and 0.05%) for 84 days under three ammonia levels (0.00, 0.08, and 0.16 mg/L NH 3 ). Results and Discussion: The results showed that survival rate (SUR), final body weight (FBW), weight gain (WG), and serum total protein (TP), triglycerides (TG), glucose (Glu), ornithine (Orn), citrulline (Cit) contents, and liver superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), arginase (ARG), ornithine transcarbamylase (OTC) activities decreased with the increase of ammonia levels, on the contrary, feed conversion ratio (FCR), hepatosomatic index (HSI), and serum ammonia, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamine (Gln), arginine (Arg) contents, and liver malondialdehyde (MDA), tumor necrosis factor (TNF), interleukin (IL) 1, IL 8 contents, and mRNA expressions of cu/zn sod , cat , gpx , gr , tnf ɑ , il 1 , and il 8 were significantly increased. Dietary 0.05% NCG supplementation had higher SUR, FBW, WG, feed intake (FI), whole-body protein, and serum TP, total cholesterol (TC), Glu, citrulline (Cit) contents, and liver SOD, GPx, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), inducible nitric oxide synthase (iNOS) activities compared to 0.00% NCG group, but had lower serum ammonia, urea, ALT, AST, Gln, Arg contents, and liver MDA, TNF, IL 1, IL 8 contents, and neuronal nitric oxide synthase activity. At the end of bacterial challenge, cumulative mortality (CM) increased with ammonia levels increased, but serum antibody titer (AT), lysozyme (LYZ) activity, 50% hemolytic complement, immunoglobulin (Ig) contents, respiratory burst (RB), phagocytic indices decreased with ammonia levels increased. CM in 0.05% NCG group was lower than that in 0.00% NCG group, but serum AT, LYZ activity, Ig content, RB in 0.05% NCG group were significantly higher. The correlation analysis found that iNOS was positively correlated with ASS activity. This study indicates that dietary NCG supplementation can improve the ammonia tolerance of yellow catfish, and ASS may also be the target of NCG to activate the urea cycle.

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

Article

Full-text available

Feb 2023
J NEURAL TRANSM

The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.

Cytomorphological Analysis and Interpretation of Nitric Oxide-Mediated Neurotoxicity in Sleep-Deprived Mice Model

Article

Full-text available

Feb 2022

Background Sleep deprivation (SD) is a biological stress condition for the brain, and the pathogenesis of SD is closely related to elevated oxidative stress, mitochondrial dysfunction, a major cause of neurodegeneration. This oxidative stress-mediated cell death is attributed to rise in calcium ion influx which further excites or alters the neurotransmitters level by activating neuronal nitric oxide (NO) synthase (nNOS) release of NO in mouse SD model. This study indicates that the nitrergic neurons are possible therapeutic targets for the amelioration of SD-induced cognitive dysfunction and behavioral alterations. Purpose SD is considered as a risk factor for various neurodegenerative diseases. SD leads to biochemical, behavioral, and neurochemical alterations in animals. This study was designed to explore the possible involvement of a nitrergic neuron system in six days SD-induced morphological and neurodegenerative changes in mice. Methods Using nNOS immunohistochemistry, we have investigated the effects of SD on nNOS positive neurons. Immunohistochemical study for the distribution of nNOS positive neuronal cell bodies was carried out in the hippocampus, prefrontal cortex (PFC), and amygdaloid nuclei of mice brain. Results Sleep-deprived animals showed a significantly increased number of nNOS positive neurons and altered neuronal cytomorphology as compared with the control group. Conclusion These results indicate that total SD may induce morphological changes in nNOS positive neurons in the brain, thus increasing NO synthesis, which is implicated in SD-induced neuronal cell death.

Does the food processing contaminant acrylamide cause developmental neurotoxicity? A review and identification of knowledge gaps

Article

Full-text available

Feb 2021
REPROD TOXICOL

There is a worldwide concern on adverse health effects of dietary exposure to acrylamide (AA) due to its presence in commonly consumed foods. AA is formed when carbohydrate rich foods containing asparagine and reducing sugars are prepared at high temperatures and low moisture conditions. Upon oral intake, AA is rapidly absorbed and distributed to all organs. AA is a known human neurotoxicant that can reach the developing foetus via placental transfer and breast milk. Although adverse neurodevelopmental effects have been observed after prenatal AA exposure in rodents, adverse effects of AA on the developing brain has so far not been studied in humans. However, epidemiological studies indicate that gestational exposure to AA impair foetal growth and AA exposure has been associated with reduced head circumference of the neonate. Thus, there is an urgent need for further research to elucidate whether pre- and perinatal AA exposure in humans might impair neurodevelopment and adversely affect neuronal function postnatally. Here, we review the literature with emphasis on the identification of critical knowledge gaps in relation to neurodevelopmental toxicity of AA and its mode of action and we suggest research strategies to close these gaps to better protect the unborn child.

Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish

Article

Full-text available

Dec 2020
PLOS ONE

Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish ( Danio rerio ) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2–4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18–19%), and its precursor, glutamine (17–22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.

Tetrahydrobiopterin deficiency in schizophrenia as a new target for personalized medicine

Article

Full-text available

Dec 2020

Tetrahydrobiopterin (BH4) is an important cofactor, that involved in the synthesis of dopamine, norepinephrine, and serotonin, as well as affecting the production of nitric oxide (NO) and regulating the activity of the glutamatergic system. A few foreign studies have shown, that patients with schizophrenia had a markedly reduced level of BH4 compared to the healthy population. The aim of this work was to study the association of BH4 deficiency with the risk of schizophrenia among Russian patients by comparison with a group of healthy volunteers. Materials and methods: 50 patients with schizophrenia and 36 healthy volunteerswere randomly selected and underwent a biochemical study of the BH4 level using the method of competitive enzyme immunoassay (ELISA) on a spectrophotometer (Sunrise, Tecan) with a set of CEG421Ge (CloudClone Corp). Results: it was found that the BH4 level was significantly lower in patients than in the controlgroup (3684.75 [1283.00; 4815.00] versus 4260.60 [4057.40; 5236.85] pmol / l, respectively, p = 0 , 0016). The proportion of patients with a BH4 level below the lower limit of the interquartile range in healthy volunteers (4057.40 pmol / l) is 30/50 (60%), the proportion of healthy volunteers with a BH4 level below this border is 9/36 (25%), the difference is statistically significant, χ2 = 10.35; p = 0.002; OR = 4.5; 95% CI [1.75; 11.56](CI — confidence interval). The correlation of BH4 level with the duration of the disease, gender, age of the subjects is very weak and not statistically significant. Conclusion: further interdisciplinary studies are required to identify the causes and molecular mechanisms for the development of BH4 deficiency in schizophrenia and to develop approaches to personalized pharmacological intervention.

The role of nitric oxide and neuronal nitric oxide synthase in zebrafish (Danio rerio) shoaling.

Article

Full-text available

Sep 2020

Nitric oxide (NO)—the product of arginine metabolism catalyzed by nitric oxide synthases (NOS)—is a well-known neurotransmitter which plays an important role in metabolism and amino acid transportation in the nervous system. In particular, it can inhibit monoamine neurotransmitter transportation which affects animal behavior, especially social behavior. Shoaling—is a one kind of social behavior. It is a behavior that individual fish choose to join with their group within two factors; food and predation risk. Shoaling fish has quickly responded to predator and increased the change in feeding competition. In addition, shoaling also effect to stress response on stock density of aquaculture system. The effect of NO molecular signaling on the dopamine pathway was investigated using zebrafish (Danio rerio) as a model organism. Our aim was to understand the role of NOS and NO in shoaling behavior, which is typical of zebrafish. The concentration of NO in the zebrafish brain was modulated using a knockout for the neuronal NOS gene, and NO production was induced through treatment with L-arginine. The existence of NO in the zebrafish brain was confirmed by using a fluorescent probe. Dopamine concentration in the brain was measured by UPLC tandem mass spectrometer. We measured shoaling cohesion of all individual fish of D. rerio, using average distance between all pairs of fish (nearest neighbor distance) and analyzed tracking by Zebralab ViewPoint software. Collectively, our results suggest that a lower level of NO was associated with a higher level of dopamine, which in turn leads to the shoaling behavior.

Direct dopamine terminal regulation by local striatal microcircuitry

Article

Full-text available

Jun 2020
J NEUROCHEM

Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward‐related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms—such as presynaptic dopamine autoreceptors and dopamine transporters ‐ as well heterosynaptic mechanisms such as retrograde signaling from postsynaptic cholinergic and dynorphin systems, among others. Additionally, modulation of dopamine release via diffusible messengers, such as nitric oxide and hydrogen peroxide, allows for various metabolic factors to quickly and efficiently regulate dopamine release and subsequent signaling. Here we review how these mechanisms work in concert to influence the timing and magnitude of striatal dopamine signaling, independent of action potential activity at the level of dopaminergic cell bodies in the midbrain, thereby providing a parallel pathway by which dopamine can be modulated. Understanding the complexities of local regulation of dopamine signaling is required for building comprehensive frameworks of how activity throughout the dopamine system is integrated to drive signaling and control behavior. image

Developmental and behavioural toxicity induced by acrylamide exposure and amelioration using phytochemicals in Drosophila melanogaster

Article

Mar 2020
J HAZARD MATER

Acrylamide, an environmental pollutant, is known to occur in food substances cooked at high temperatures. Studies on various models indicate acrylamide to cause several physiological conditions such as neuro- and reproductive toxicity, and carcinogenesis. In our study, exposure of Drosophila melanogaster (Oregon K strain) to acrylamide via their diet resulted in a concentration and time-dependent mortality, while the surviving flies exhibited significant locomotor deficits, most likely due to oxidative stress-induced neuronal damage. Also, Drosophila embryos exhibited signs of developmental toxicity as evidenced by the alteration in the migration of border cells and cluster cells during the developmental stages, concomitant to modulation in expression of gurken and oskar genes. Curcumin, a known antioxidant has been widely studied for its neuroprotective effects against acrylamide; however; very few studies focus on thymoquinone for its role against food toxicant. Our research focuses on the toxicity elicited by acrylamide and the ability of the antioxidants: thymoquinone, curcumin and combination of thereof, in reversing the same.

Cannabinoids, TRPV and nitric oxide: the three ring circus of neuronal excitability

Article

Full-text available

Jan 2020
BRAIN STRUCT FUNCT

Endocannabinoid system is considered a relevant player in the regulation of neuronal excitability, since it contributes to maintaining the balance of the synaptic ionic milieu. Perturbations to bioelectric conductances have been implicated in the pathophysiological processes leading to hyperexcitability and epileptic seizures. Cannabinoid influence on neurosignalling is exerted on classic receptor-mediated mechanisms or on further molecular targets. Among these, transient receptor potential vanilloid (TRPV) are ionic channels modulated by cannabinoids that are involved in the transduction of a plethora of stimuli and trigger fundamental downstream pathways in the post-synaptic site. In this review, we aim at providing a brief summary of the most recent data about the cross-talk between cannabinoid system and TRPV channels, drawing attention on their role on neuronal hyperexcitability. Then, we aim to unveil a plausible point of interaction between these neural signalling systems taking into consideration nitric oxide, a gaseous molecule inducing profound modifications to neural performances. From this novel perspective, we struggle to propose innovative cellular mechanisms in the regulation of hyperexcitability phenomena, with the goal of exploring plausible CB-related mechanisms underpinning epileptic seizures.

Striatal dopaminergic dysregulation and dystonia-like movements induced by sensorimotor stress in a pharmacological mouse model of rapid-onset dystonia-parkinsonism

Article

Full-text available

Nov 2019

Rapid-onset dystonia-parkinsonism (RDP) is a rare form of hereditary dystonia caused by loss-of-function mutations of the Na+/K+-ATPase α3 isoform (ATP1α3). An acute onset of generalized dystonia and parkinsonism after exposure to stress and an incomplete disease penetrance is described in RDP, thereby suggesting a gene-environmental interaction in individuals with a genetic predisposition for dystonia development. Dystonia is considered a central motor network disease and in line with this concept, alterations in cerebellar neuronal firing have been described in RDP mouse models, but the pathogenic role of the basal ganglia remains unclear. We have mimicked RDP pharmacologically by simultaneous perfusion of the selective ATP1α3-blocker ouabain into the striatum and cerebellum of mice, followed by repeated exposure to mild motor stress. Ouabain-perfused RDP mice developed dystonia-like movements, which were exacerbated by exposure to sensorimotor stress. Compared to control mice, ouabain perfusion of the striatum led to dendritic spine loss of medium spiny neurons in addition to loss of cholinergic and GABAergic interneurons in the striatum. High-pressure liquid chromatography analyses revealed significant dopamine (DA) depletion and increased DA and serotonergic turnover, while qPCR analyses displayed reduction of glutamatergic receptors. Adding stress to the ouabain-predisposed brain, however, resulted in an elevation of the striatal DA metabolism back to the level of control animals. Our results indicate an ouabain-induced basal ganglia and cerebellar motor network dysfunction characterized by structural and neurochemical alterations of striatal dopaminergic, cholinergic and glutamatergic pathways that represent a motor endophenotype of RDP mutation carriers. Challenging the motor circuit by sensorimotor stress causes exacerbation of dystonia-like movements tightly linked to a hyperdopaminergic state in the striatum. Our observations support a gene-environment interaction or "second-hit" hypothesis in the symptomatogenesis of RDP.

Antidepressant‐like effect of anacardic acid in mice via the L‐arginine–nitric oxide–serotonergic system

Article

Feb 2019

Depression, a multifactorial neuronal disorder with high morbidity/mortality, is associated with psychological, psychosocial, hereditary, and environmental etiologies, where reactive species exert pathophysiological functions. Anacardic acid (AA), a natural compound obtained from cashew nut liquid, has several pharmacological activities, including antioxidant and anticonvulsant. The aim of the present study was to evaluate the antidepressant‐like effect of AA and the involvement of serotonergic, noradrenergic, and L‐arginine–nitric oxide (NO) in tail suspension and forced swim tests and, more so, to investigate its antioxidant effect in Saccharomyces cerevisiae and in male Swiss mice (n = 8). In order to identify the antidepressant mechanisms, AA (10, 25, or 50 mg/kg, p.o.) was given 30 min before clonidine (2‐adrenergic receptor agonist), L‐arginine (NO precursor), propranolol (β‐adrenergic receptor antagonist), and several other agonists or antagonists used. On the other hand, clonidine, noradrenoreceptor, noradrenaline, and L‐arginine were used to identify the antidepressant mechanisms. Results suggest that AA exerts antidepressant‐like activity, especially at higher doses, possibly by inhibiting serotonin and 5HT‐1A reuptake receptors and by inhibiting NO synthetase and guanylyl cyclase enzymes. Additionally, AA exhibited antioxidant effect in S. cerevisiae. This antioxidant capacity may be linked to its antidepressant‐like effect but does not interact with α‐ and β‐adrenoceptor receptors. In conclusion, AA may be used as a promising agent to treat depression, especially which arises from oxidative stress.

Understanding zebrafish aggressive behavior

Article

Nov 2018
BEHAV PROCESS

Aggression is a common agonistic behavior affecting social life and wellbeing of humans and animals. However, the underlying mechanisms of aggression remain poorly understood. For decades, studies of aggression have mostly focused on laboratory rodents. The growing importance of evolutionarily relevant, cross-species disease modeling necessitates novel model organisms to study aggression and its pathobiology. The zebrafish (Danio rerio) is rapidly becoming a new experimental model organism in neurobehavioral research. Zebrafish demonstrate high genetic and physiological homology with mammals, fully sequenced genome, ease of husbandry and testing, and robust behavioral repertoire. As zebrafish present overt aggressive behaviors, here we focus on their behavioral models and discuss their utility in probing aggression neurobiology and its genetic, pharmacological and environmental modulation. We argue that zebrafish-based models represent an excellent translational tool to understand aggressive behaviors and related pathobiological brain mechanisms.

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures

Article

Full-text available

Jul 2018
INT J MOL SCI

An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression

Article

Full-text available

Nov 2017

Background Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. Objective The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. Methods Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). Results Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. Conclusion The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals

Article

Aug 2017

Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model

Article

Full-text available

Jan 2017
INT J MOL SCI

Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS-/⁻ knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS-/⁻ mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS-/⁻ mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation.

NO Exchange for a Water Molecule Favorably Changes Iontophoretic Release of Ruthenium Complexes to the Skin

Article

Full-text available

Jan 2017
MOLECULES

Ruthenium (Ru) complexes have been studied as promising anticancer agents. Ru nitrosyl complex (Ru‐NO) is one which acts as a pro‐drug for the release of nitric oxide (NO). The Ru‐ aqueous complex formed by the exchange of NO for a water molecule after NO release could also possess therapeutic effects. This study evaluates the influence of iontophoresis on enhancing the skin penetration of Ru‐NO and Ru‐aqueous and assesses its applicability as a tool in treating diverse skin diseases. Passive and iontophoretic (0.5 mA • cm −2) skin permeation of the complexes were performed for 4 h. The amount of Ru and NO in the stratum corneum (SC), viable epidermis (VE), and receptor solution was quantified while the influence of iontophoresis and irradiation on NO release from Ru‐NO complex was also evaluated. Iontophoresis increased the amount of Ru‐NO and Ru‐aqueous recovered from the receptor solution by 15 and 400 times, respectively, as compared to passive permeation. Iontophoresis produced a higher accumulation of Ru‐aqueous in the skin layers as compared to Ru‐NO. At least 50% of Ru‐NO penetrated the SC was stable after 4 h. The presence of Ru‐NO in this skin layer suggests that further controlled release of NO can be achieved by photo‐stimulation after iontophoresis.

Review Paper: Role of Nitric Oxide on Dopamine Release and Morphine-Dependency

Article

Oct 2016

Basic and Clinical Neuroscience (IUMS

The catastrophic effects of opioids use on public health and the economy are documented clearly in numerous studies. Repeated morphine administration can lead to either a decrease (tolerance) or an increase (sensitization) in its behavioral and rewarding effects. Morphine-induced sensitization is a major problem and plays an important role in abuse of the opioid drugs. Studies reported that morphine may exert its effects by the release of nitric oxide (NO). NO is a potent neuromodulator, which is produced by nitric oxide synthase (NOS). However, the exact role of NO in the opioid-induced sensitization is unknown. In this study, we reviewed the role of NO on opioid-induced sensitization in 2 important, rewarding regions of the brain: nucleus accumbens and ventral tegmentum. In addition, we focused on the contribution of NO on opioid-induced sensitization in the limbic system.

Review Paper: Role of Nitric Oxide on Dopamine Release and Morphine-Dependency

Article

Full-text available

Oct 2016

Neuron-astrocyte interactions in spinal cord dorsal horn in neuropathic pain development and docosahexaenoic acid therapy

Article

Jul 2016
J NEUROIMMUNOL

The analgesic activity of docosahexaenoic acid (DHA, 22:6 n − 3) was studied using a chronic constriction injury (CCI) rat model. Animals were subcutaneously injected with DHA emulsion at a dose of 4.5 mg/kg (125 mМ/kg) daily during 2 weeks after surgery. We characterized the dynamics of GFAP-positive astrocyte, substance P (SP) and nNOS-positive neurons activity in the spinal cord dorsal horn (SCDH) superficial lamina. We found that DHA treatment decrease the intensity and duration of neurogenic pain syndrome, results in earlier stabilization of weight distribution, prevents the cold allodynia and dystrophic changings in denervated limb tissue. DHA treatment reduced the reactive astrocyte number, decrease SP-immunopositive fibers and nNOS-positive neurons number in the SCDH in neuropathic pain.

Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal Stress

Article

Full-text available

Jan 2016
Neural Plast

The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1 β , IL-18, IL-6, TNF- α , CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain.

A study on the possible therapeutic role of panax ginseng extract against a rat model of Parkinson’s disease induced by intrastriatal rotenone injection

Article

Full-text available

Feb 2016

The neuroprotective effects of Panax ginseng were extensively studied. However, the therapeutic role of Panax ginseng in rat model of Parkinson’s disease (PD) has not been studied enough. In the present study, rats were divided into three groups; control, rat model of PD induced by intrastriatal injection of rotenone and rat model of PD treated daily with Panax ginseng extract (100 mg/kg for 2 weeks). Forelimb wire hanging and the traction tests scored a significant decrease in PD model rats. In ginseng extract-treated group, these behavioral parameters changed to non significant values from the control rats. In the midbrain of rat model, a state of oxidative stress was observed as indicated from the significant increase in lipid peroxidation, nitric oxide and tumor necrosis factor-α and the decrease in reduced glutathione in comparison to control. This was accompanied by a significant decrease in dopamine and a significant increase in acetylcholinesterase activity. In the striatum, an increase in lipid peroxidation and a decrease in nitric oxide, dopamine content and acetylcholinesterase were recorded. Panax ginseng treatment improved all the midbrain and striatal changes induced by rotenone except nitric oxide. However, this improvement was partial since the measured parameters in ginseng-treated group were not significant from the rat model of PD except tumor necrosis factor-α. From the present findings, it could be concluded that Panax ginseng extract administration for 2 weeks showed a partial ameliorative effect against the rat model of PD induced by the intrastriatal injection of rotenone. © 2016, International Journal of Clinical and Experimental Medicine. All right reserved.

A behaviorally related developmental switch in nitrergic modulation of locomotor rhythmogenesis in larval Xenopus tadpoles

Article

Full-text available

Jan 2016
J NEUROPHYSIOL

Locomotor control requires functional flexibility to support an animal's full behavioural repertoire. This flexibility is partly endowed by neuromodulators, allowing neural networks to generate a range of motor output configurations. In hatchling Xenopus tadpoles, before the onset of free swimming behaviour, the gaseous modulator nitric oxide (NO) inhibits locomotor output, shortening swim episodes and decreasing swim cycle frequency. While populations of nitrergic neurons are already present in the tadpole's brainstem at hatching, neurons positive for the NO-synthetic enzyme, NOS, subsequently appear in the spinal cord suggesting additional as yet unidentified roles for NO during larval development. Here, we first describe the expression of locomotor behaviour during the animal's change from an early sessile to a later free-swimming lifestyle and then compare the effects of NO throughout tadpole development. We identify a discrete switch in nitrergic modulation from net inhibition to overall excitation, coincident with the transition to free-swimming locomotion. Additionally, we show in isolated brainstem-spinal cord preparations of older larvae that NO's excitatory effects are manifest as an increase in the probability of spontaneous swim episode occurrence, as found previously for the neurotransmitter dopamine (DA), but that these effects are mediated within the brainstem. Moreover, while the effects of NO and DA are similar, the two modulators act in parallel rather than NO operating serially by modulating dopaminergic signalling. Finally, NO's activation of neurons in the brainstem also leads to the release of NO in the spinal cord that subsequently contributes to NO's facilitation of swimming.

Functionalized Mesoporous Silica via an Aminosilane Surfactant Ion Exchange Reaction: Controlled Scaffold Design and Nitric Oxide Release

Article

Dec 2015
ACS APPL MATER INTER

Nitric oxide-releasing mesoporous silica nanoparticles (MSNs) were prepared using an aminosilane-template surfactant ion exchange reaction. Initially, bare silica particles were synthesized under basic conditions in the presence of cetyltrimethylammonium bromide (CTAB). These particles were functionalized with nitric oxide (NO) donor precursors via the addition of aminosilane directly to the particle sol and a commensurate ion exchange reaction between the cationic aminosilanes and CTAB. N-diazeniumdiolate NO donors were formed at the secondary amines to yield NO-releasing silica MSNs. Tuning of the ion exchange-based MSN modification approach allowed for the preparation of monodisperse particles ranging from 30 to 1100 nm. Regardless of size, the MSNs stored appreciable levels of NO (0.4-1.5 µmol mg-1) with tunable NO-release durations (1-33 h) dependent on the aminosilane modification. Independent control of NO-release properties and particle size was achieved, demonstrating the flexibility of this novel MSN synthesis over conventional co-condensation and surface grafting strategies.

Evaluation of the potential role of glutamatergic, cholinergic, and nitrergic systems in the dopamine release induced by the pesticide glyphosate in rat striatum

Article

Jun 2024
J APPL TOXICOL

Glyphosate (GLY) is a pesticide that severely alters nigrostriatal dopaminergic neurotransmission, inducing great increases in dopamine release from rat dorsal striatum. This GLY‐induced striatal dopamine overflow occurs through mechanisms not yet fully understood, hence the interest in evaluating the role of other neurotransmitter systems in such effects. So, the main objective of this mechanistic study was to evaluate the possible mediation of the glutamatergic, cholinergic, and nitrergic systems in the GLY‐induced in vivo dopamine release from rat dorsal striatum. The extracellular dopamine levels were measured by cerebral microdialysis and HPLC with electrochemical detection. Intrastriatal administration of GLY (5 mmol/L) significantly increased the dopamine release (1102%). Pretreatment with MK‐801 (50 or 400 μmol/L), a non‐competitive antagonist of NMDA receptors, significantly decreased the effect of GLY (by 70% and 74%, respectively), whereas AP‐5 (400 μmol/L), a competitive antagonist of NMDA receptors, or CNQX (500 μmol/L), an AMPA/kainate receptor antagonist, had no significant effect. Administration of the nitric oxide synthase inhibitors, L‐nitroarginine (L‐NAME, 100 μmol/L) or 7‐nitroindazole (7‐NI, 100 μmol/L), also did not alter the effect of GLY on dopamine release. Finally, pretreatment of the animals with mecamylamine, an antagonist of nicotinic receptors, decreased the effect of GLY on dopamine release by 49%, whereas atropine, a muscarinic antagonist, had no significant effect. These results indicate that GLY‐induced dopamine release largely depends on the activation of NMDA and nicotinic receptors in rat dorsal striatum. Future research is needed to determine the effects of this pesticide at environmentally relevant concentrations.

From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease

Article

Full-text available

Oct 2023

Current research has described improving multisystem disease and organ function through dietary nitrate (DN) supplementation. They have provided some evidence that these floras with nitrate (NO3⁻) reductase are mediators of the underlying mechanism. Symbiotic bacteria with nitrate reductase activity (NRA) are found in the human digestive tract, including the mouth, esophagus and gastrointestinal tract (GT). Nitrate in food can be converted to nitrite under the tongue or in the stomach by these symbiotic bacteria. Then, nitrite is transformed to nitric oxide (NO) by non-enzymatic synthesis. NO is currently recognized as a potent bioactive agent with biological activities, such as vasodilation, regulation of cardiomyocyte function, neurotransmission, suppression of platelet agglutination, and prevention of vascular smooth muscle cell proliferation. NO also can be produced through the conventional l-arginine–NO synthase (l-NOS) pathway, whereas endogenous NO production by l-arginine is inhibited under hypoxia–ischemia or disease conditions. In contrast, exogenous NO3⁻/NO2⁻/NO activity is enhanced and becomes a practical supplemental pathway for NO in the body, playing an essential role in various physiological activities. Moreover, many diseases (such as metabolic or geriatric diseases) are primarily associated with disorders of endogenous NO synthesis, and NO generation from the exogenous NO3⁻/NO2⁻/NO route can partially alleviate the disease progression. The imbalance of NO in the body may be one of the potential mechanisms of disease development. Therefore, the impact of these floras with nitrate reductase on host systemic health through exogenous NO3⁻/NO2⁻/NO pathway production of NO or direct regulation of floras ecological balance is essential (e.g., regulation of body homeostasis, amelioration of diseases, etc.). This review summarizes the bacteria with nitrate reductase in humans, emphasizing the relationship between the metabolic processes of this microflora and host systemic health and disease. The potential effects of nitrate reduction bacteria on human health and disease were also highlighted in disease models from different human systems, including digestive, cardiovascular, endocrine, nervous, respiratory, and urinary systems, providing innovative ideas for future disease diagnosis and treatment based on nitrate reduction bacteria.

Inclusion Complexation of S -Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Article

Dec 2022

S-Nitrosoglutathione (GSNO) is a nontoxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host-guest chemistry-based strategy to modulate the GSNO reactivity and NO release kinetics for the design of anti-infective catheters and hydrogels. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host-guest complexation reduces the decomposition reactivity of GSNO in the order of αCD > γCD > hydroxypropyl βCD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37 °C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in αCD undergoes a conformational change that significantly reduces the S-NO bond distance and increases its stability. The calculated S-NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-αCD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains, including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

The argininosuccinate synthetase can differentially regulate nitric oxide synthase in yellow catfish Pelteobagrus fulvidraco

Article

Jul 2022
FISH SHELLFISH IMMUN

Fish are at high risk of exposure to ammonia in aquaculture systems. When ammonia stress occurs, fish are more prone to disease outbreaks, but the mechanism is not very clear. The argininosuccinate synthetase (ASS) plays an important role in the regulation of urea synthesis and nitric oxide synthesis. We speculated that there must be some relationship between ASS expression and disease outbreak. In this study, ASS was cloned from the yellow catfish. The full-length cDNAs of ASS was 1558 bp, with open reading frames of 1236 bp. The mRNA expression of ASS gene was the highest in liver, kidney and brain. This study consists of two parts: 1) For ammonia challenge in vivo, yellow catfish (15.00 ± 1.50 g) were divided into control group, low ammonia group (1/10 96 h LC50), and high ammonia group (1/2 96 h LC50). The experiment continued for 192 h. The results showed that ammonia stress elevated serum ammonia content, and inhibited urea synthesis enzymes activities but up-regulated the expression levels of related genes except ARG, and induced arginine accumulation and nitric oxide synthase (nNOS and iNOS) different expression, and decreased resistance to Aeromonas hydrophage; 2) For ammonia challenge in vitro, the primary culture of liver cell was divided into four groups: control group, BPP group (Bj-BPP-10c was added as ASS activator), Amm group (96 h LC50), and Amm + BPP group. The experiment continued for 96 h. The results showed that the Bj-BPP-10c can inhibit nNOS activity and improve cell survival rate, and enhance iNOS activity and immune response (lysozyme, complement, respiratory burst, and phagocytic index) by activate ASS when ammonia stress occurred. Our results indicated that targeted regulation of ASS can improve iNOS activity, and enhance the immune response of yellow catfish under ammonia stress.

Tetrahydrobiopterin deficiency in schizophrenia: Biochemical and clinical aspects

Article

Sep 2022
J PSYCHIATR RES

It was reported that the levels of tetrahydrobiopterin (BH4) are reduced in schizophrenia. However, mechanisms of BH4 deficiency in schizophrenia had not been studied precisely. Objective: the search of the association between BH4 deficiency in schizophrenia and a range of biochemical and clinical parameters for the evaluation of the possible mechanisms of BH4 loss and its role in the development of the symptoms. Methods: 93 patients with schizophrenia and 60 healthy volunteers were randomly selected and evaluated with a biochemical examination of BH4, folate, cobalamin (B12), homocysteine, C-reactive protein (CRP), reduced glutathione (GSH) levels in the blood serum.Patients underwent standardized psychopathological examination. Results: In patients, the levels of BH4 and folate were lower (p = 0.001 and p = 0.054, respectively), and the levels of homocysteine were higher (p = 0.012) compared to the control group. BH4 levels directly moderately correlated with folate (ρ = 0.43; p = 0.0029) and B12 levels (ρ = 0.43; p = 0.0020) and inversely moderately correlated with homocysteine levels (ρ = -0.54; p = 0.00015) in patients. Cluster analysis identified schizophrenia biotype characterized by a deficiency of BH4, folate, B12, and hyperhomocysteinemia. The clinical characteristics of this biotype were not specific. CRP and GSH were higher in patients compared to controls, but their association with serum BH4 was not confirmed.

The role of estrogens on the immune response against parasitic infections and parasite physiology: focus on estradiol.

Chapter

Full-text available

Nov 2021

Parasitic infections rank amongst the most significant causes of morbidity and mortality worldwide, yet economic and other factors have contributed to a lack of innovation in treating these maladies. Thus, understanding all biological factors associated to susceptibility and resistance have become highly relevant. The existence of sexual dichotomy has been well described in several parasites of medical relevance. Intriguingly, regulation of specific immune responses against parasites have been associated with sex hormones, particularly estradiol. Moreover, sex hormones can directly affect parasites, which in turn have developed different trans-regulatory mechanisms to exploit the hormonal microenvironment of its host. This interaction occurs via expression of membranal components similar to the hormonal receptors present in mammals. Interaction of host hormones with the parasitic membranal components impacts directly on growth, reproduction, viability, and infectivity of different parasites. In this chapter we will discuss specifically the role of estradiol in the regulation of the immune response of the host during parasitic infections and how estradiol affects parasite physiology. The chapter will focus mainly on parasites medically relevant in human health.

Analgesic Activity of Synaptamide in a Rat Sciatic Nerve Chronic Constriction Injury Model

Article

Sep 2021

At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA), or synaptamide, an endogenous metabolite of docosahexaenoic acid, is a promising compound with anti-inflammatory activity. The results of this study demonstrate that synaptamide, when administered subcutaneously (4 mg/kg/day, 35 days), promotes a decrease in cold allodynia and mechanical hyperalgesia in a rat sciatic nerve chronic constriction injury (CCI) model. After CCI, synaptamide treatment enhanced the remyelination process in the site of sciatic nerve injury (33.4 ± 1.1% in the CCI+Syn group, compared to 28.4 ± 0.9% in the CCI group). Further, synaptamide suppressed the CCI-induced increase in the activity of microglia (13.1 ± 0.5% in CCI+Syn, compared to 15.3 ± 0.7% in the CCI group) and the number of nitric oxide synthase-positive neurons (58,307 ± 5,206 cells/mm3 in CCI+Syn, compared to 80,288 ± 4,287 cells/mm3 in the CCI group) in the dorsal horns of the spinal cord, and also reduced the concentration of interleukin 1 beta in the spinal cord (169.3 ± 4 pg/mg of protein in CCI+Syn, compared to 236.9 ± 9.3 pg/mg of protein in CCI group) 35 days after surgery. Synaptamide treatment resulted in decrease of reactive astrogliosis in the spinal cord dorsal horns to 20.8 ± 1.3%, which occurred simultaneously with a decrease in the substance P (SP) level (9.8 ± 0.5%) compared to vehicle-treated animals (30.2 ± 2.2% and 13.4 ± 0.9% of astroglia and SP staining area, respectively). In addition, synaptamide increased superoxide dismutase activity up to 68.6 ± 0.8% (control 50.6 ± 0.9%) in astrocyte culture. Thus, synaptamide provides anti-inflammatory and neuroprotective effects in both peripheral and central nervous system after sciatic nerve injury.

Expired air nitric oxide in patients with bronchial asthma and chronic obstructive pulmonary disease with different disease course

Article

Dec 2013

Expired air nitric oxide was measured in 113 subjects (26 healthy controls, 64 bronchial asthma (BA) patients and 23 COPD patients. In BA patients 10 had mild course of the disease. In 50 the course was estimated as moderate, 4 patients had severe course of the disease. In 20 patients BA was associated with COPD. The results revealed the dependence of FeNO on following factors: severity of the disease: in severe and moderate BA course FeNO was significantly higher than in mild BA; on phase of the disease: in exacerbation FeNO was significantly higher than in remission; on control of the disease: in patients, in whom it was difficult to reach the disease control, FeNO was higher than in others. In COPD patients FeNO was significantly lower than in BA ones. Even in subjects with marked airways inflammation manifested by high sputum cellularity FeNO was low.

Nitric oxide modulates tapentadol antinociceptive tolerance and physical dependence

Article

Jun 2021
EUR J PHARMACOL

Tapentadol, an analgesic with a dual mechanism of action, involving both μ-opioid receptor agonism and noradrenaline reuptake inhibition (MOP-NRI), was designed for the treatment of moderate to severe pain. However, the widely acknowledged risk of analgesic tolerance and development of physical dependence following sustained opioid use may hinder their effectiveness. One of the possible mechanisms behind these phenomena are alterations in nitric oxide synthase (NOS) system activity. The aim of the study was to investigate the tolerance and dependence potential of tapentadol in rodent models and to evaluate the possible role of nitric oxide (NO) in these processes. Our study showed that chronic tapentadol treatment resulted in tolerance to its antinociceptive effects to an extent similar to tramadol, but much less than morphine. A single injection of a non-selective NOS inhibitor, NG-nitro-L-arginine (L-NOArg), reversed the tapentadol tolerance. In dependence studies, repeated administration of L-NOArg attenuated naloxone-precipitated withdrawal in tapentadol-treated mice, whereas a single injection of L-NOArg was ineffective. Biochemical analysis revealed that tapentadol decreased nNOS protein levels in the dorsal root ganglia of rats following 31 days of treatment, while no significant changes were found in iNOS and eNOS protein expression. Moreover, pre-treatment with L-NOArg augmented tapentadol antinociception in an opioid- and α2-adrenoceptor-dependent manner. In conclusion, our data suggest that the NOS system plays an important role in the attenuation of tapentadol-induced tolerance and withdrawal. Thus, inhibition of NOS activity can serve as a promising treatment option for long-term tapentadol use by extending its effectiveness and improving the side-effects profile.

Scientific Opinion on acrylamide in food

Article

Jun 2015

EFSA Panel on Contaminants in the Food Chain (CONTAM

EFSA was asked to deliver a scientific opinion on acrylamide (AA) in food. AA has widespread uses as an industrial chemical. It is also formed when certain foods are prepared at temperatures above 120 °C and low moisture, especially in foods containing asparagine and reducing sugars. The CONTAM Panel evaluated 43 419 analytical results from food commodities. AA was found at the highest levels in solid coffee substitutes and coffee, and in potato fried products. Mean and 95th percentile dietary AA exposures across surveys and age groups were estimated at 0.4 to 1.9 µg/kg body weight (b.w.) per day and 0.6 to 3.4 µg/kg b.w. per day, respectively. The main contributor to total dietary exposure was generally the category ‘Potato fried products (except potato crisps and snacks)’. Preferences in home-cooking can have a substantial impact on human dietary AA exposure. Upon oral intake, AA is absorbed from the gastrointestinal tract and distributed to all organs. AA is extensively metabolised, mostly by conjugation with glutathione but also by epoxidation to glycidamide (GA). Formation of GA is considered to represent the route underlying the genotoxicity and carcinogenicity of AA. Neurotoxicity, adverse effects on male reproduction, developmental toxicity and carcinogenicity were identified as possible critical endpoints for AA toxicity from experimental animal studies. The data from human studies were inadequate for dose-response assessment. The CONTAM Panel selected BMDL10 values of 0.43 mg/kg b.w. per day for peripheral neuropathy in rats and of 0.17 mg/kg b.w. per day for neoplastic effects in mice. The Panel concluded that the current levels of dietary exposure to AA are not of concern with respect to non-neoplastic effects. However, although the epidemiological associations have not demonstrated AA to be a human carcinogen, the margins of exposure (MOEs) indicate a concern for neoplastic effects based on animal evidence.

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

Preprint

Full-text available

Sep 2020

Introduction Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish ( Danio rerio ) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function. Methods Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed. Results Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter γ-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior. Conclusion Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.

Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

Article

Aug 2019

In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine‐restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH4) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH4‐responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH4‐responsive and BH4‐unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH4 might directly influence neurocognitive functioning in PKU having passed the blood‐brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH4 treatment in PKU may improve neuropsychological outcome and mental health in both BH4‐responsive and BH4‐unresponsive PKU patients. This article is protected by copyright. All rights reserved.

Mechanisms of Soft and Hard Electrophile Toxicities

Article

Feb 2019
TOXICOLOGY

Electron-deficient chemicals (electrophiles) react with compounds that have one or more unshared valence electron pairs (nucleophiles). The resulting covalent reactions between electrophiles and nucleophiles (e.g., Michael addition, S N 2 reactions) are important, not only to Organic Chemistry, but also to the fields of Molecular Biology and Toxicology. Specifically, covalent bond formation is the operational basis of many critically important cellular processes; e.g., enzyme function, neurotransmitter release, and membrane-vesicle fusion. Given this context it is understandable that these reactions are also relevant to Toxicology, since a significant number of xenobiotic chemicals are toxic electrophiles that can react with endogenous nucleophilic residues. Therefore, the purpose of this Review is to discuss electrophile-nucleophile chemistry as it pertains to cell injury and resulting organ toxicity. Our discussion will involve an introduction to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson. The HSAB concept provides a framework for calculation of quantum chemical parameters that classify the electrophile and nucleophile covalent components according to their respective electronic nature (softness/hardness) and reactivity (electrophilicity/nucleophilicity). The calculated quantum indices in conjunction with corroborative in vivo, in chemico (cell free) and in vitro research can offer an illuminating approach to mechanistic discovery. Accordingly, we will provide examples that demonstrate how this approach has been used to discern mechanisms and sites of electrophile action.

Assessment the effect of NO inhibition on hippocampal normetanephrine level in stress and non-stress conditions in adult male rats

Article

Full-text available

Mar 2016

Background: Nitric oxide (NO) has a role in the regulation of neurotransmitters release such as norepinephrine, in the hippocampus.Normetanephrine (NMN) is a metabolite of norepinephrine created by action of catechol-O-methyl transferase (COMT) on norepinephrine. Several studies have shown that various stresses increased release of norepinephrine and its metabolites. Therefore in the present study, the role of Nitric oxide in regulation of norepinephrine release and its metabolism was investigated by administration of L-NAME (NO synthase inhibitor) in stressed and non-stressed rats. Materials and Methods: For this purpose, 50 adult rats were divided into 10 groups, of which 5 groups were exposed to restraint stress while another 5 groups were without stress. These two set of groups included intact, saline and L-NAME (20, 40, 80 mg/kg). Thirty minutes after intraperituneal injection of L-NAME, brains removed, the hippocampus dissected, weighed, homogenized and centrifuged then amount of NMN measured by ELISA kit. Results: The results showed that in non-stressed condition amount of NMN were significantly increased in group that received L-NAME (80 mg/kg) in comparison with other groups but in stress condition, amount of NMN was significantly decreased in groups that received L-NAME (20,40,80 mg/kg), in comparison with control and saline groups. Comparison between stress and non-stressed groups showed that stress alone cause an increase in amount of NMN in control and saline groups. Conclusion: In conclusion, NO synthesis inhibition produced opposite responses with respect to NMN amount in the presence or absence of stress, and probably L-NAME preventing the effect of stress on increasing NMN levels mediated by nitrergic pathway.

13 C-phenylalanine breath test and serum biopterin in schizophrenia, bipolar disorder and major depressive disorder

Article

Feb 2018
J PSYCHIATR RES

Phenylalanine is required for the synthesis of the neurotransmitters dopamine, noradrenaline, and adrenaline. The rate-limiting step for phenylalanine metabolism is catalyzed by phenylalanine hydroxylase (PAH) and its cofactor tetrahydrobiopterin. We aimed to detect altered phenylalanine metabolism in major psychiatric disorders using the l-[1-13C]phenylalanine breath test (13C-PBT) and serum biopterin levels. We also investigated association of PAH mutations with schizophrenia and phenylalanine metabolism.13C-phenylalanine (100 mg) was orally administered, and the breath13CO2/12CO2ratio was monitored for 120 min in four groups: 103 patients with schizophrenia (DSM-IV), 39 with bipolar disorder, 116 with major depressive disorder (MDD), and 241 healthy controls. Serum biopterin levels were measured by high performance liquid chromatography. Mutation screening of PAH exons was performed by direct sequencing in 46 schizophrenia patients. Association analysis was performed using six tag single nucleotide polymorphisms and the PAH Arg53His mutation by TaqMan assays in 616 schizophrenia patients and 1194 healthy controls. Analyses of covariance controlling for age, sex, and body weight showed that the index for the amount of exhaled13CO2was significantly lower in the schizophrenia group than in the other three groups (all p < 0.05). Biopterin levels in schizophrenia and MDD were significantly lower than those in controls. Biopterin levels correlated with13C-PBT indices in controls. PAH polymorphisms were not associated with schizophrenia or13C-PBT indices.13C-PBT revealed reduced phenylalanine metabolism in schizophrenia, though we obtained no evidence of involvement of PAH polymorphism. Serum biopterin levels were lower in schizophrenia and MDD, warranting further investigation.

Systemic and local anti-nociceptive effects of simvastatin in the rat formalin assay: Role of peroxisome proliferator-activated receptor γ and nitric oxide: Role of NO and PPARγ in Simvastatin Antinociception

Article

Apr 2017
J NEUROSCI RES

This study aimed to determine the potential systemic and local anti-nociceptive effects of simvastatin (SIM) and the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide (NO) pathways using a formalin assay in rats. After allocation, rats were intraplantarly (i.pl.) treated with formalin solution (2.5%) and the flinching behaviors were recorded for 5 min (phase 1) and 15-60 min (phase 2). SIM was given intraperitoneally (i.p.) and i.pl. 30 and 20 min before test, respectively. Intraperitoneal administration of SIM attenuated the flinching number during both phases of the test. This effect of i.p. SIM was significantly reduced by L -NAME (NO synthase blocker, i.p.), but was augmented by L -arginine (NO precursor, i.p.) during both phases of the formalin assay. Moreover, the antinociception caused by i.p. SIM was blocked by GW-9662 (PPARγ antagonist) at dose 2 mg/kg (i.p.). In another experiment, concurrent ip administration of non-effective dose of simvastatin (5 mg/kg) with pioglitazone (PPARγ agonist; 10, 20 mg/kg) produced antinociception. However, pre-treatment with i.p. GW-9662 inhibited the enhanced antinociceptive effect of pioglitazone on SIM during the phase 2 of formalin assay. Results also showed that i.pl. SIM alone had no anti-nociceptive effects. However, significant anti-nociception was observed when SIM (i.pl.) co-administered with non-effective dose of pioglitazone. Moreover, the enhanced effect was antagonized by pre-treatment with i.pl. GW-9662. Our data suggest that SIM produced antinociception through systemic but not local route of administration in rats. Moreover, the antinociceptive effect of SIM is partly mediated through PPARγ receptors and NO pathway. © 2017 Wiley Periodicals, Inc.

Neuronal Nitric Oxide Synthase-Immunoreactive Neurons In the Hamster Visual Cortex: Lack of Co-localization with Parvalbumin

Article

Jun 2005

Nitric oxide (NO) and calcium-binding proteins occur in various types of cells in the central nervous system. They are important signaling and calcium buffering molecules, respectively. In the present study, using immunocytochemistry we examined the distribution and the co-localization pattern of neurons containing neuronal nitric oxide synthase (nNOS) and parvalbumin in the visual cortex of hamster. The overall number of parvalbumin-immunoreactive (IR) neurons was 17 times higher than that of the nNOS-IR neurons in the hamster visual cortex. The highest differences were found in layer V, where parvalbumin-IR neurons were 54.7 times more abundant than nNOS-IR neurons. Many nNOS- and parvalbumin-IR neurons were similar in size, shape, and manner of distribution in the visual cortex. However, two-color immunofluorescence revealed that no neurons in the hamster visual cortex expressed both nNOS and parvalbumin. The present results indicate that there are subtle species differences in the co-localization pattern between nNOS and calcium-binding proteins. The present results also suggest not only the heterogeneity and functional diversity of nNOS-IRneurons in the visual cortex, but also the importance of understanding animal diversity

Pharmacological evidence for systemic and peripheral antinociceptive activities of pioglitazone in the rat formalin test: Role of PPARγ and nitric oxide

Article

Mar 2017

Nitric oxide (NO) is involved in numerous physiological processes of the central and peripheral nervous system. This study aimed to evaluate the involvement of PPARγ and NO pathway in the systemic and peripheral antinociceptive effect pioglitazone (Pio) using formalin test in rats. After allocation, rats were injected with 2.5% formalin solution and the flinching behaviors were recorded for 5 min (phase 1) and 15–60 min (phase 2). pioglitazone was administered intraperitoneally (i.p.) at doses (10–50 mg/kg) and intraplantarly (i.pl.) at doses (10–30 μg/paw) 60 and 20 min before test, respectively. To investigate the mechanism involved, rats were given GW-9662 (a PPARγ antagonist), L-NAME (NO synthase inhibitor), L-arginine (NO precursor), or L-NAME + GW-9662 along with pioglitazone. Results showed that both of i.p. and i.pl. routes of pioglitazone administration produced antinociception in both phases of formalin-induced pain. Antinociception caused by i.p. and i.pl. pioglitazone was blocked by GW-9662 at doses 2 mg/kg (i.p.) and 3 μg/paw (i.pl.) in both phases of the test, respectively. The antinociceptive effects of i.p. and i.pl. pioglitazone were significantly reduced by L-arginine, but were augmented by L-NAME in second phase of test. However, pre-treatment with GW-9662 inhibited the enhanced antinociceptive effect of L-NAME on pioglitazone in second phase of formalin test during i.p. and i.pl. administration. Furthermore, the antinociceptive effect of systemic pioglitazone was antagonized by i.pl. administration of GW-9662 (3 μg/paw). Our data suggest that local and systemic antinociceptive activity of pioglitazone is mediated partly through PPARγ in collaboration with NO pathway. Moreover, the cumulative results suggest a close link of interaction between PPARγ and NO.

Novel Targets in the Glutamate and Nitric Oxide Neurotransmitter Systems for the Treatment of Depression

Chapter

Dec 2016

The N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine has repeatedly shown rapid and sustained antidepressant effects following a single dose in a number of clinical studies. Since the adverse effects associated with ketamine limit its wider use in the clinic, investigations are instead aimed at developing “cleaner” ketamine compounds that could demonstrate a fast onset of action and sustained efficacy without incurring adverse effects. In this regard, targets located downstream of the NMDA-R, such as nitric oxide synthase (NOS), may represent novel avenues for treating neuropsychiatric disorders. Since nNOS couples to the NMDA-R via the postsynaptic protein PSD-95, strategies that target the PSD-95/nNOS interaction may also represent an interesting locus for the treatment of neuropsychiatric disorders. Here, we review the rationale for the development of glutamate and nitric oxide (NO)-modulating drugs for treating depression and highlight findings in the field, which provide a basis for ongoing drug development.

Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test

Article

Aug 2004
EUR NEUROPSYCHOPHARM

The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor N-G-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.

Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant-like effect of Wuling mycelia powder in rat

Article

Mar 2016
BIOMED PHARMACOTHER

Context: Wuling mycelia powder is the dry powder of rare a fungi Xyla ria sp., Carbon species, with a long history of medicinal use in Chinese medicine. Recently it has shown a powerful antidepressant activity in clinic. Objective: The present study explores the antidepressant activity of Wuling mycelia powder in chronic unpredictable mild stress (CUMS) rats and its possible involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway. Materials and methods: Experiments were performed in the rat CUMS model. CUMS rats were treated with Wuling mycelia powder (0.5, 1.0 or 2.0 g/kg, i.g.) to test behavioral changes including the sucrose preference, the crossing number and food consumption. Further, L-arginine (substrate for nitric oxide) (750 mg/kg), 7-nitroindazole (a specific neuronal nitric oxide synthase inhibitor) (25 mg/kg), sildenafil (phosphodiesterase 5 inhibitor) (5 mg/kg) and methylene blue (direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase) (10 mg/kg) were treated for 60 min before each test to detect the possible mechanism of antidepressant-like effect of Wuling mycelia powder. Results: After 4 weeks of administration, both 1.0 or 2.0 g/kg Wuling mycelia powder suppressed the behavioral changes including the sucrose preference [F(3, 31)=50.87, p<0.001], the crossing number [F(3, 31)=68.98, p<0.05], and food consumption [F(3, 31)=19.04, p<0.05] in the CUMS rats. The antidepressant-like effect of Wuling mycelia powder was prevented by pretreatment with l-arginine and sildenafil. Pretreatment of rats with 7-nitroindazole and methylene blue potentiated the effect of Wulin mycelia powder. Discussion and conclusion: Our findings demonstrate that Wuling mycelia powder has an antidepressant-like effect in the CUMS rats, and possible involvement of L-arginine-nitric oxide-cyclic GMP signaling pathway in its antidepressant effect.

The NO Hypothesis: Possible Effects of a Short-Lived, Rapidly Diffusible Signal in the Development and Function of the Nervous System

Article

Full-text available

Jun 1990

Several observations suggest that the Ca2(+)-dependent postsynaptic release of nitric oxide (NO) may be important in the formation and function of the vertebrate nervous system. We explore here the hypothesis that the release of NO and its subsequent diffusion may be critically related to three aspects of nervous system function: (i) synaptic plasticity and long-term potentiation in certain regions of the adult nervous system, (ii) the control of cerebral blood flow in such regions, and (iii) the establishment and activity-dependent refinement of axonal projections during the later stages of development. In this paper, we detail and analyze the basic assumptions underlying this NO hypothesis and describe a computer simulation of a minimal version of the hypothesis. In the simulation, a 3-dimensional volume of neuropil is presented with patterned afferent input; NO is produced, diffuses, and is destroyed; and synaptic strengths are determined by a set of synaptic rules based on the correlation of synaptic depolarization and NO levels. According to the hypothesis, voltage-dependent postsynaptic release of this rapidly diffusing substance links the activities of neurons in a local volume of tissue, regardless of whether the neurons are directly connected by synapses. This property is demonstrated in the simulation, and it is this property that is exploited in the hypothesis to account for certain aspects of long-term potentiation and activity-dependent sharpening of axonal arbors.

Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat

Article

Full-text available

Dec 1995

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.

Nitric Oxide and Synaptic Function

Article

Full-text available

Feb 1994

The free radical gas nitric oxide (NO) is a recently identified neuronal messenger that carries out diverse signaling tasks in both the central and peripheral nervous systems. Whereas most neurotransmitters are packaged in synaptic vesicles and secreted in a Ca2+-dependent manner from specialized nerve endings, NO is an unconventional transmitter which is not packaged in vesicles, but rather diffuses from its site of production in the absence of any specialized release machinery. The lack of a requirement for release apparatus raises the possibility that NO can be released from both pre- and postsynaptic neuronal elements. In addition, because NO is gaseous and extremely membrane permeant, it can bypass normal signal transduction routes involving interactions with synaptic membrane receptors. Although the targets of NO have not yet been completely described, it is known that NO can bind to the iron contained in heine groups, leading to conformational changes in associated proteins, such as guanylyl cyclase.

Nitric Oxide Synthases: Properties and Catalytic Mechanism

Article

Full-text available

Feb 1995

Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57: 683-706

Article

Full-text available

Feb 1995

Modulation of In Vivo Striatal Transmitter Release by Nitric Oxide and Cyclic GMP

Article

Full-text available

Mar 1994

The effects of nitric oxide (NO) and cyclic GMP on in vivo transmitter release in the rat striatum were investigated using microdialysis sampling in urethane-anaesthetised animals. The NO release-inducing substances S-nitrosoacetylpenicillamine (SNAP), S-nitrosoglutathione (SNOG), and sodium nitroprusside (SNP) increased extracellular concentrations of aspartate (Asp), glutamate (Glu), gamma-aminobutyric acid (GABA), taurine (Tau), acetylcholine (ACh), and serotonin (5-HT). Dopamine (DA) concentrations were decreased by SNAP but were increased by SNOG and SNP. An NO scavenger, haemoglobin, blocked or reduced the effects of SNAP on transmitter release. However, the control carrier compounds for SNAP, SNOG, and SNAP (penicillamine, glutathione, and potassium ferricyanide, respectively, which do not induce release of NO) also increased GABA, Tau, DA, and 5-HT concentrations. When NO gas was given directly by dissolving it in degassed Ringer's solution, DA concentrations decreased significantly, and those of Asp, Glu, GABA, Tau, ACh, and 5-HT increased. These effects of NO gas were all inhibited by coadministration of haemoglobin and for GABA, Tau, ACh, and DA showed some calcium dependency. The cyclic GMP agonists 8-bromo-cyclic GMP and dibutryl-cyclic GMP stimulated dose-dependent increases in Asp, Glu, GABA, Tau, ACh, DA, and 5-HT concentrations. Increased striatal transmitter release in response to NO may therefore be mediated by its stimulatory action on cyclic GMP formation. NO inhibition of DA release may be mediated indirectly through its stimulation of local cholinergic and GABAergic neurones.

Dawson TM, Snyder SHGases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 14:5147-5159

Article

Full-text available

Oct 1994

In a remarkably brief period of time, NO and CO have been recognized as putative neurotransmitters. These two novel messenger molecules have greatly expanded the criteria for candidacy of a chemical for the status of neurotransmitter and our notions about how synaptic transmission takes place. The involvement of NO and CO in several important aspects of neuronal function suggests that agents affecting the synthesis, transactions, and disposition of these gases are bound to have clinical relevance.

Presynaptic Modulation of Neurochemical Transmission

Chapter

Dec 1979

E. S. Vizi

Nitric Oxide Modulates Dopamine Release During Global Temporary Cerebral Ischemia

Article

Apr 1996
Surv Anesthesiol

Effect of nitric oxide donors on endogenous dopamine release from rat striatal slices - I: Requirement to antioxidants in the medium

Article

Jan 1997

Rıfat Levent Buyukuysal

Sodium nitroprusside (SNP) significantly decreased basal dopamine (DA) release when rat striatal slices were incubated in a physiological medium deficient in antioxidants. Depolarization-induced DA release (KCl 25 mM), which was accompanied with a 85% decline in tissue DA levels, was also inhibited by SNP and hydroxylamine (HA). Contrary to these findings, SNP did not protect the slices against depolarization-induced DA depletion. With HA, moreover, tissue DA levels were found to be depleted more than the control levels, indicating that DA, which is released from or stored in the slices, might be converted to an undetectable product under these conditions. Supporting this conclusion, incubation of the DA standards with SNP caused a dose-dependent loss in DA levels, an effect that was reversed partially by oxyhemoglobin and inhibited completely by antioxidants. Consistently, both SNP and HA, but not L-arginine, significantly increased basal DA release when striatal slices were incubated in antioxidants-containing medium. These results indicate that nitric oxide (NO), which is generated from SNP and HA by different mechanisms, stimulates DA release from rat striatal slices. Observation of this effect, however, requires the presence of antioxidants in the medium.

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide

Article

Dec 1987

The objective of this study was to determine whether nitric oxide (NO) is responsible for the vascular smooth muscle relaxation elicited by endothelium-derived relaxing factor (EDRF). EDRF is an unstable humoral substance released from artery and vein that mediates the action of endothelium-dependent vasodilators. NO is an unstable endothelium-independent vasodilator that is released from vasodilator drugs such as nitroprusside and glyceryl trinitrate. We have repeatedly observed that the actions of NO on vascular smooth muscle closely resemble those of EDRF. In the present study the vascular effects of EDRF released from perfused bovine intrapulmonary artery and vein were compared with the effects of NO delivered by superfusion over endothelium-denuded arterial and venous strips arranged in a cascade. EDRF was indistinguishable from NO in that both were labile (t1/2 = 3-5 sec), inactivated by pyrogallol or superoxide anion, stabilized by superoxide dismutase, and inhibited by oxyhemoglobin or potassium. Both EDRF and NO produced comparable increases in cyclic GMP accumulation in artery and vein, and this cyclic GMP accumulation was inhibited by pyrogallol, oxyhemoglobin, potassium, and methylene blue. EDRF was identified chemically as NO, or a labile nitroso species, by two procedures. First, like NO, EDRF released from freshly isolated aortic endothelial cells reacted with hemoglobin to yield nitrosylhemoglobin. Second, EDRF and NO each similarly promoted the diazotization of sulfanilic acid and yielded the same reaction product after coupling with N-(1-naphthyl)-ethylenediamine. Thus, EDRF released from artery and vein possesses identical biological and chemical properties as NO.

Role of nitric oxide synthases in psoriasis

Article

Apr 2011

Background: Psoriasis is a chronic inflammatory cutaneous disorder characterized by hyperproliferative keratinocytes, defective barrier formation and vascular changes. It has been observed that Nitric Oxide Syntases (NOS) may have important physiological functions in healthy skin. Several studies on skin tissue have suggested that NOS may play key roles in the repair process and in modulation of skin proliferation.Objective: Aim of this study was to investigate the involvement of NOS and their relationship with Vascular Endothelial Growth Factor (VEGF), Nuclear Factor B (NF-kB) and survivin in the pathogenetic mechanisms of psoriasis.Methods: We detected by immunohistochemistry nNOS, iNOS, eNOS, VEGF, Survivin and NF-kB expression in fifteen psoriatic patients compared to eight control subjects.Results: In psoriatic skin compared to normal skin, nNOS and iNOS were diffusely overexpressed, while eNOS was strongly stained in the endothelial cells. Moreover we observed a significant increase of VEGF and survivin expression both at the epithelial and endothelial levels; while a modest NF-kB increase was detected in the epidermis. In addition we found a significant positive correlation between VEGF and iNOS expression.Conclusion: NOS activity may play a key role in some of the important regulatory mechanisms of psoriasis, such as cell proliferation, inflammation and angiogenesis, suggesting a possible NOS-based therapeutical approach.

Differential Release of Dopamine by Nitric Oxide in Subregions of Rat Caudate Putamen Slices

Article

Nov 1998
J NEUROCHEM

Fast cyclic voltammetry was used to measure NO and dopamine (DA) simultaneously in rat caudate putamen (CPu) slices. Analysis of electrochemical signals obtained from mixtures of DA and NO showed that subtraction of either the DA or the NO component revealed the contribution of the other component. Application of such data manipulation to signals obtained in CPu slices indicated that DA and NO components contributed to electrochemical signals. Following electrical stimulation (>1 s), site-dependent NO-like signals were observed. Pressure ejection of NMDA yielded a biphasic electrochemical signal. The first phase (lasting 10–20 s) had electrochemical characteristics of DA and was observed only during the first application of NMDA. The second phase developed more slowly, was of longer duration (1–3 min), and had electrochemical characteristics of a mixture of DA and NO. Generation of the NO-like signal by NMDA was antagonised by l-N-monomethylarginine. Pressure ejection of NO into CPu slices caused dose- and site-dependent DA release. More DA was released in the dorsolateral than in the dorsomedial CPu. Pressure ejection of DA did not generate NO. It is concluded that electrically stimulated DA release is not mediated by prior release of NO.

Involvement of Nitric Oxide in Dopaminergic Transmission in Rat Striatum: An In Vivo Electrochemical Study

Article

Nov 1995
J NEUROCHEM

In vivo electrochemical detection with a Nafion-coated carbon fiber working electrode, which provides information on the spatial and temporal dynamics of dopamine overflow, was used to investigate the involvement of nitric oxide (NO) in the dopaminergic transmission in the striatum of urethane-anesthetized Sprague-Dawley rats. A mixture of N-methyl-d-aspartate (NMDA) and nomifensine, a dopamine uptake blocker, was locally pressure-ejected to elicit a transient dopamine overflow from the dopamine-containing nerve terminals in the striatum. Local application of Nω-nitro-l-arginine methyl ester (l-NAME), which blocks endogenous NO formation, increased the magnitude of dopamine release evoked by a subsequent NMDA and nomifensine application but resulted in no significant alteration in the time course. Furthermore, microejection of l-arginine, an NO precursor, or sodium nitroprusside (SNP), an NO generator, did not cause detectable changes in dopamine level in the striatal extracellular space. However, NMDA-induced dopamine release was profoundly inhibited with l-arginine or SNP pretreatment. In addition, NO affects dopamine uptake in rat striatum. Exogenous dopamine applied through a micropipette, reversibly and reproducibly, elicited an electrochemical signal. The time course of these signals was significantly prolonged by l-NAME treatment. These data suggest that NO is diversely involved in regulating dopaminergic transmission in rat striatum.

Release of false transmitter serotonin from the dopaminergic nerve terminals of the rat pituitary intermediate lobe

Article

Aug 1995
NEUROSCI RES

Rat pituitary intermediate lobe contains two types of serotonin-immunoreactive nerve terminals. Most of them are dopaminergic, in which serotonin acts as a false transmitter, while the rest are true serotonergic nerves. In the present study, release of the false transmitter serotonin from the dopaminergic nerve terminals was studied by loading the neurons in vivo with serotonin precursor l-tryptophan and MAO inhibitor pargyline, which results in accumulation of false transmitter serotonin. Subsequently pituitary neurointermediate lobe complexes were incubated in the presence of various agents. Potassium induced dramatic release of serotonin. This release was Ca2+-dependent, as demonstrated by an inhibition by Mg2+, and transporter-independent, since it was unaffected by GBR 12909 (a dopamine transport inhibitor). Tyramine and sodium nitroprusside, a nitric oxide donor, caused slight to remarkable release of serotonin. This release was inhibited by GBR 12909, suggesting that it was transporter-dependent. Presynaptic stimulation with apomorphine or haloperidol, dopamine receptor agonist or antagonist, respectively, or isoproterenol, agonist of the β-adrenergic receptor, did not significantly release serotonin. Thus, it seems that presynaptic receptors per se cannot induce release of significant amounts of serotonin from the IL dopaminergic fibers. Our results suggest that false transmitter serotonin in the IL dopaminergic nerve terminals is released primarily by the classical exocytotic release mechanism, but may also be partly released by the transporter-dependent, non-exocytotic release.

Effects of L- and D-enantiomers Nw-nitro-arginine on NMDA-evoked striatal dopamine overflow

Article

Feb 1994
BRAIN RES BULL

The microdialysis method was utilized to study the effects of (L-NNA) and (D-NNA), an inhibitor of nitric oxide (NO) synthesis from l-arginine and its d-enantiomer, on spontaneous and (NMDA)-evoked overflow of striatal extracellular do-pamine (DA) in unanesthetized, freely moving rats. Perfusion of 3–10 mM NMDA through the microdialysis probe resulted in a dose-dependent increase in striatal DA overflow. Perfusion of 500 μM L-NNA alone did not change the DA level significantly, but when added to 3 mM NMDA, it substantially suppressed the NMDA-evoked increase of DA. Perfusion of 500 μM D-NNA altered neither the basal nor the NMDA-evoked DA level. Data suggest that the stimulatory effect of NMDA in DA release involves activation of the l-arginine-NO pathway in the striatum.

Role of Nitric Oxide in Modulating the Release of Dopamine, Glutamate, and GABA in Striatum of the Freely Moving Rat

Article

Feb 1998
BRAIN RES BULL

This study investigated the role of nitric oxide (NO) in modulating the basal and N-methyl-D-aspartate (NMDA)-induced release of dopamine (DA), glutamate (GLU), and gamma-aminobutiric acid (GABA) in striatum of the freely moving rat using microdialysis. Intrastriatal infusion of NMDA (5 mM) for 15 min increased extracellular concentrations of DA, GLU, and GABA. NMDA also decreased extracellular concentrations of DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenylacetic acid (HVA), and of the GLU and GABA precursor, glutamine (GLN). Perfusion of N-nitroarginine (1-5 mM), an inhibitor of the synthesis of NO, potentiated NMDA-induced increases in extracellular concentrations of DA and attenuated increases of extracellular GLU. NMDA-induced decreases of extracellular concentrations of DOPAC were also attenuated by N-nitroarginine. N-nitroarginine had no effect on NMDA-induced changes of extracellular concentrations of GABA, HVA, and GLN. N-nitroarginine decreased basal concentrations of DOPAC and HVA, and increase basal concentrations of GLN, but had no effect on basal DA, GLU, and GABA. These results suggest a role for NO in modulating the NMDA-induced release of DA and GLU in striatum. They also suggest that NO could be regulating the basal metabolism of DA, GLU, and GABA.

Nitric Oxide Release Accounts for the Biological Activity of Endothelium-Derived Relaxing Factor

Article

Jun 1987

Endothelium-derived relaxing factor (EDRF) is a labile humoral agent which mediates the action of some vasodilators. Nitrovasodilators, which may act by releasing nitric oxide (NO), mimic the effect of EDRF and it has recently been suggested by Furchgott that EDRF may be NO. We have examined this suggestion by studying the release of EDRF and NO from endothelial cells in culture. No was determined as the chemiluminescent product of its reaction with ozone. The biological activity of EDRF and of NO was measured by bioassay. The relaxation of the bioassay tissues induced by EDRF was indistinguishable from that induced by NO. Both substances were equally unstable. Bradykinin caused concentration-dependent release of NO from the cells in amounts sufficient to account for the biological activity of EDRF. The relaxations induced by EDRF and NO were inhibited by haemoglobin and enhanced by superoxide dismutase to a similar degree. Thus NO released from endothelial cells is indistinguishable from EDRF in terms of biological activity, stability, and susceptibility to an inhibitor and to a potentiator. We suggest that EDRF and NO are identical.

Modulation of striatal dopamine release in cerebral ischemia by L-arginine

Article

May 1995

The effect of L-arginine, the precursor of nitric oxide, on ischemic dopamine release from the striatum was investigated in Mongolian gerbils subjected to bilateral carotid artery occlusion (15 min) alone or with reflow (2 h). Dopamine and its metabolites were measured in the striatal extracellular space dialysate after continuous perfusion (2 microliters/min) of artificial extracellular fluid in the presence or absence of 15 mmol/liter L- or D-arginine or 1 mmol/liter nitro-L-arginine. L-Arginine but not D-arginine increased the striatal content of dopamine in pre- and postischemia whereas it lowered the levels of dopamine and 3-methoxytyramine induced by ischemia. In contrast, nitro-L-arginine reduced the preischemic levels of dopamine and 3,4-dihydroxyphenyl-acetic acid, and had no effect on the ischemic release of dopamine. These findings indicate that L-arginine stereospecifically modified the ischemic release and metabolism of dopamine. The data also suggest that the basal level of nitric oxide is not involved in dopamine release during ischemia but may participate in regulating dopamine release under physiological conditions.

L-Arginine induces dopamine release from the striatum in vivo

Article

Dec 1994
NEUROREPORT

Recent reports indicate that induction of nitric oxide (NO) evokes dopamine (DA) release from the striatum in vitro. In this study, we used L-arginine (L-Arg) to demonstrate the in vivo stimulation of DA release from the striatum of Mongolian gerbils using microdialysis. The content of DA in the striatal extracellular fluid (ECF) increased 7-15-fold in the presence of L-Arg in the perfusate as compared with that of the controls (DA level in drug-free perfusate varied from 0.050 +/- 0.009 to 0.092 +/- 0.023 pmol 10 microliters-1). Simultaneous perfusion of L-Arg with nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, markedly reduced the L-Arg effect on DA release from the striatum. The NLA-perfused animals contained DA levels significantly lower than those observed in the control striatal dialysate. These findings indicate for the first time that DA release in vivo can be induced by L-Arg, the precursor of NO. The data strongly suggest that NO may modulate striatal DA release.

Nitric oxide induces neurotransmitter release from hippocampal slices

Article

Oct 1992
EUR J PHARMACOL

Hydroxylamine (1-300 microM), a nitric oxide generator, stimulated the release of [3H]norepinephrine ([3H]NE) and [14C]acetylcholine ([14C]ACh) from rat hippocampal slices in a concentration-dependent manner (EC50 approximately 30 microM). A maximally effective concentration of hydroxylamine (300 microM) produced a 24-fold increase in the basal [3H]NE and 3.6-fold increase in the in the basal [14C]ACh efflux. Sodium nitroprusside (SNP), also stimulated the release of [3H]NE, but only at high concentrations (10-30 mM). Calcium-free experimental buffer (1 mM EGTA) abolished the response. Hemoglobin (0.3 microM) inhibited the effect of 100 microM hydroxylamine in a manner which was specific for nitric oxide. In addition, 100 microM hydroxylamine increased the efflux of endogenous GABA and glutamate by 3- and 6-fold, respectively.

Effect of Nitroprusside (Nitric Oxide) on Endogenous Dopamine Release from Rat Striatal Slices

Article

Oct 1992

It is becoming apparent that the synthesis of nitric oxide (NO) from L-arginine not only explains endothelium-dependent vascular relaxation, but is a widespread mechanism for the regulation of cell function and communication. We examined the role of NO on the endogenous dopamine (DA) release from rat striatum. Nitroprusside, in the concentration range of 3-100 microM, induced a dose-dependent increase in the endogenous DA release from rat striatal slices. The maximal response was 330% over the baseline release. A higher concentration of nitroprusside (300 microM) produced an inhibitory effect on the spontaneous release of DA. L-Arginine (10 and 100 microM), a substrate in the NO-forming enzyme system, also produced an elevation of DA release. L-Arginine-induced DA release was attenuated by NG-monomethyl-L-arginine, an inhibitor of NO synthase. NADPH (1 microM), a cofactor of NO synthase, enhanced L-arginine-induced DA release. These results suggest a possible involvement of NO in the DA release process in rat striatum.

Role of nitric oxide in NMDA-evoked release of [3H]-dopamine from striatal slices

Article

Jun 1992
NEUROREPORT

Evidence that excitatory amino acids act via N-methyl-D-aspartate (NMDA) receptors to evoke the release of catecholamines from axonal terminals and synaptosomes has been used to argue for the presence of pre-synaptic NMDA receptors. NMDA receptor agonists also generate nitric oxide (NO) which rapidly diffuses through neural tissue. We find that exogenously applied NO evokes [3H]-dopamine release from cultured neurons. This release is not blocked by the NMDA antagonist MK-801 nor by tetrodotoxin. Both NG-nitroarginine which inhibits NO synthesis, and hemoglobin which binds extracellular NO, block NMDA-evoked [3H]-dopamine release from striatal slices. A major role of endogenously-synthesized NO may be to evoke neurotransmitter release in local volumes of neural tissue.

Non-synaptic Interactions at presynaptic level

Article

Feb 1991
PROG NEUROBIOL

Ignarro LJ, Buga GM, Wood KS, Bryns RE, Chaudhuri GEndothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265-9269

Article

Jan 1988

A New Perspective on the Inhibitory Role of Nitric Oxide in Sympathetic Neurotransmission

Article

Dec 1995

By using, as a model of sympathetic neurons, immortalized rat pheochromocytoma (PC12) cells differentiated by nerve growth factor (NGF), the effect of nitric oxide on sympathetic neurotransmission was examined. The NO donor sodium nitroprusside (SNP; 10(-4)-3 x 10(-4) M) caused an apparent inhibition of dopamine release from PC12 cells, as measured by HPLC. Studies, in the absence of cells, involving the incubation of dopamine (20 ng/ml) or norepinephrine (15 ng/ml) with SNP (10(-6)-3 x 10(-4) M) or authentic NO (6 x 10(-6)-3 x 10(-5) M) revealed a similar reduction in the detection of the catecholamines. In addition, absorption spectroscopy studies showed dopamine and norepinephrine to be oxidized by NO resulting in the formation of their respective quinone products. These observations, coupled with the finding that the ability of dopamine to raise cAMP levels within PC12 cells was reduced after incubation with SNP, reveal that NO inhibits the biological activity rather than the release of catecholamines.

Role of NO production in NMDA receptor-mediated transmitter release in cerebral cortex

Article

Mar 1994

L-Glutamate and norepinephrine are examples of a major excitatory neurotransmitter and a neuromodulator in the cerebral cortex, respectively. Little is known of how chemical signaling between the anatomically distinct chemical pathways occurs. Specific activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptor in synaptosomal preparations from guinea pig cerebral cortex caused release of both of these chemicals, and this release was blocked by agents that inhibit nitric oxide (NO) production or remove NO from the extracellular space. Furthermore, neurotransmitter release correlated with cortical NO production after NMDA receptor stimulation. These results suggest that NO production and its extracellular movement may be links in the pathway from NMDA receptor activation to changes in chemical signaling in surrounding synaptic terminals in the cerebral cortex.

Nitric oxide modulates endogenous dopamine release in bovine retina

Article

Feb 1994
NEUROREPORT

A study of the possible modulation by nitric oxide (NO) of endogenous dopamine (DA) release was performed in bovine retina in vitro. NO synthase activity was measured in retinal homogenates and totally blocked by L-nitroarginine methyl ester (L-NA). Intact retinas were also exposed to hydroxylamine, an NO-generator which significantly decreased both basal and potassium-induced liberation of DA. In contrast, dibutyryl cGMP was ineffective. Furthermore, L-NA was able to increase basal DA release, its effects being potentiated in calcium free medium. Taken together, these results suggest that endogenous NO regulates DA release via cGMP independent mechanisms.

Nitric Oxide: A Physiologic Messenger Molecule

Article

Feb 1994

Differential effects of nitric oxide gas and nitric oxide donors on depolarization-induced release of [3H]norepinephrine from hippocampal slices

Article

Dec 1994
NEUROPHARMACOLOGY

The NO-generating compounds sodium nitroprusside (NP), nitroglycerin (NTG), and isosorbide dinitrate (ISDN) all significantly inhibited N-methyl-D-aspartate (NMDA)-stimulated release of tritiated norepinephrine ([3H]NA) from preloaded hippocampal slices of adult male Sprague-Dawley rats with IC50's of 114 microM, 1.2 mM, and 1.7 mM respectively. NTG and ISDN also inhibited KCl-stimulated release, while NP had no significant effect on KCl-stimulated release. Although these results suggest that the inhibitory effects of these compounds were mediated by release of NO, NTG and ISDN did not generate detectable levels of NO, and iron-cyanide complexes similar in structure to NP but lacking NO also inhibited release. In contrast, both S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and authentic NO gas significantly enhanced NMDA-stimulated release of [3H]NA (EC50's: 331 and 3.4 microM respectively). This enhancement was not selective for NMDA-stimulated release, since both SNAP and NO potentiated KCl-stimulated release as well. In addition, NO gas significantly enhanced NMDA-stimulated release of tritiated dopamine ([3H]DA) from striatal slices and [3H]NA from cortical and cerebellar slices. Analogs of cyclic guanosine monophosphate (cGMP) had no significant effect on NMDA-stimulated transmitter release, suggesting that the observed increase in release is via a cGMP-independent mechanism. While exogenous NO enhanced both NMDA- and KCl-stimulated neurotransmitter release, it appears that endogenous NO does not play a role in this depolarization-induced release since NO synthase inhibitors did not significantly reduce NMDA-stimulated [3H]NA release. The possibility remains that endogenous NO could modulate neurotransmitter release in other circumstances.

Diverse roles for nitric oxide in synaptic signalling after activation of NMDA release-regulating receptors

Article

Dec 1994
NEUROPHARMACOLOGY

NMDA receptors regulating transmitter release were studied in three model systems to investigate whether their activation involves the NO transduction system. In superfused slices of rat brain, the release of [3H]D-aspartate, [3H]noradrenaline and [3H]GABA evoked by NMDA could be modulated by nitrergic drugs. Tetrodotoxin (0.1 microM) exerted differential effects in the three systems indicative of the NMDA receptors (and hence sites of NO generation) being pre- or extra-synaptic, or a combination of both types of localization. L-Arginine (100 microM) enhanced NMDA-evoked release of [3H]GABA (110%), [3H]NA (120%) and [3H]D-ASP (700%). Exogenous NO donors could increase NMDA-induced release of [3H]NA and [3H]D-ASP from hippocampal slices, although differential effects were noted, whilst inhibitors of NO synthase (NG-nitro- and NG-amino-L-arginine, both 100 microM) attenuated (60-85%) the release. NMDA-evoked release of [3H]GABA from striatal slices were insensitive to exogenous NO donors, but NG-nitro- and NG-amino-L-arginine produced 100% increases. In all cases, the NMDA receptors regulating release are linked to a NO system, although the link to the receptors modulating release of [3H]GABA appeared different. The actions of the nitrergic drugs may depend upon the redox state and/or cellular milieu of the individual NMDA receptors involved.

Increased striatal dopamine efflux

Article

Feb 1995

The role of nitric oxide (NO) in striatal dopamine release has been controversial. Most NO synthase inhibitors affect more than one isoform of the enzyme and exert vasoconstrictor effects which may also affect striatal dopamine function. We now report on the effect of a soluble monosodium salt of the selective brain NO synthase inhibitor 7-nitro indazole (7-NINA). Using 7-NINA the first study of selective inhibition of the brain isoform of NO synthase on dopamine efflux in rat striatum was undertaken by use of in vivo microdialysis. Perfusion with 7-NINA (1 mM) increased striatal dopamine efflux. The effect of 7-NINA was partially antagonized (67%) by co-perfusion with L-arginine (1 mM), the precursor of NO formation in vivo. This suggests that 7-NINA induces a competitive inhibition of NO synthase activity. These data show that endogenous NO has an inhibitory effect on striatal dopamine efflux in vivo.

Roles for Nitric Oxide as an Intra- and Interneuronal Messenger at NMDA Release-Regulating Receptors: Evidence from Studies of the NMDA-Evoked Release of [3H]Noradrenaline and D-[3H]Aspartate from Rat Hippocampal Slices

Article

Jun 1995

N-Methyl-D-aspartate (NMDA) receptors regulating the release of [3H]noradrenaline ([3H]NA) and D-[3H]aspartate (D-[3H]Asp) were investigated in superfused slices of rat hippocampus in the presence and absence of nitrergic drugs to examine a possible role for nitric oxide (NO) in the release process. In Mg(2+)-free Krebs-Henseleit buffer, the NMDA-evoked release of [3H]NA and D-[3H]Asp was Ca2+ dependent and inhibited by the NMDA antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid. NMDA-stimulated release of [3H]NA was tetrodotoxin (TTX; 0.1-2 microM) sensitive, whereas that for D-[3H]Asp was TTX insensitive, indicating that the NMDA receptors involved are differentially localized; those for D-[3H]Asp appear to be presynaptic, whereas those for [3H]NA are extrasynaptic in location. L-Arginine (100 microM), the natural precursor of NO synthesis, enhanced NMDA-evoked release of [3H]NA (100%) and D-[3H]Asp (700%). Exogenous NO donors--sodium nitroprusside, 3-morpholinosyndnomine, and S-nitroso-N-acetylpenicillamine (all 100 microM)--stimulated the NMDA-evoked release. An exception was the inhibition by nitroprusside of NMDA-evoked release of [3H]NA, where the presence of antioxidants may influence channel activity. Inhibitors of NO synthase (NG-nitro-, NG-methyl-, and NG-amino-L-arginine, all 100 microM) attenuated (50-80%) the NMDA-stimulated release of [3H]NA and D-[3H]Asp, as did KN-62 (10 microM), a specific inhibitor of calmodulin kinase II. Our data support roles for the NO transducing system subsequent to the activation of NMDA release-regulating receptors as both an intraneuronal (presynaptically) and an extraneuronal messenger.

Nitric Oxide in the Regulation of Blood Flow and Arterial Pressure

Article

Feb 1995

Nitric Oxide: Pathophysiological Mechanisms

Article

Feb 1995

Inhibition of potassium-stimulated dopamine release by the nitric oxide generator isosorbide dinitrate

Article

Mar 1995
NEUROPHARMACOLOGY

In PC12 cells, isosorbide dinitrate (ISDN) and S-nitrosol-acetyl-penicillamine (SNAP), both nitric oxide (NO) generators, attenuated K+ (56 mM)-stimulated release of dopamine. The attenuation was not observed with isosorbide, an ISDN analog lacking NO generating capacity. In this model, A23187 (Ca2+ ionophore), Bay K8644 (Ca2+ slow channel agonist) and veratridine (Na+ channel agonist) stimulated dopamine release. Treatment with ISDN enhanced Bay K8644 and veratridine-evoked dopamine release, while ISDN had no significant effect on the A23187 response. Incubation with 8-bromo-cGMP (membrane permeable cGMP analog) had no effect on basal or stimulated dopamine release in these cells, suggesting NO's response was not mediated by cGMP. In additional studies, K+ (56 mM), Bay K8644 and veratridine elevated cytosolic free calcium levels ([Ca2+]i). ISDN reduced K(+)-stimulated increase in [Ca2+]i, but enhanced the increases of [Ca2+]i induced by Bay K8644 or veratridine. These results suggest NO interacts with K(+)-induced membrane depolarization (possibly by inhibiting membrane conductance to K+) to attenuate Ca2+ influx and Ca(2+)-mediated dopamine secretion stimulated by K+.

Characterization of nitric oxide generator-induced hippocampal [3H]norepinephrine release. I. The role of glutamate

Article

Oct 1995

In this study we compared the effects of two nitrogen monoxide (NO) generators, hydroxylamine and S-nitroso-L-cysteine (NO-CYS), on hippocampal [3H]norepinephrine ([3H]NE) release. A 10-min incubation with hydroxylamine (3-3,000 microM) or NO-CYS (30-10,000 microM) induced a concentration-dependent increase in the basal [3H]NE efflux with EC50 values of approximately 100 microM and 1 mM, respectively. Reduced hemoglobin, a NO scavenger, blocked both hydroxylamine- and NO-CYS-evoked [3H]NE release. Long-term exposure (> or = 25 min) to 100 microM hydroxylamine, or to millimolar concentrations of NO-CYS, evoked a tetrodotoxin-insensitive [3H]NE release. However, a 10-min stimulation with either 100 microM hydroxylamine or 300 microM NO-CYS was sensitive to 0.5 microM tetrodotoxin, a voltage-sensitive sodium channel blocker. This suggested that under these conditions hydroxylamine and NO-CYS induce [3H]NE release indirectly in part, perhaps via releasing an excitatory neurotransmitter. Indeed, kynurenate, a nonselective ionotropic glutamate receptor antagonist, produced an 80% inhibition of the NO generator-evoked [3H]NE release. CGS 19755, a N-methyl-D-aspartate receptor antagonist, had no significant effect, whereas the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor antagonists, CNQX and GYKI 52446, inhibited the hydroxylamine response by 50%. In synaptosomes, a preparation in which synaptic interactions are nonsignificant, NO-CYS induced a dose-dependent release of both [3H]NE and [3H]glutamate. These data suggest that, in hippocampal slices, NO generators evoke [3H]NE release both directly from noradrenergic terminals and indirectly via releasing glutamate.

Characterization of nitric oxide generator-induced hippocampal [3H]norepinephrine release. II. The role of calcium, reverse norepinephrine transport and cyclic 3',5'-guanosine monophosphate

Article

Nov 1995

The mechanisms by which two nitrogen monoxide (NO) generators, hydroxylamine and S-nitroso-L-cysteine (NO-CYS), induce hippocampal [3H]norepinephrine ([3H]NE) release was investigated. Neither hydroxylamine- nor NO-CYS-induced release was affected by the guanylate cyclase inhibitors, methylene blue or LY 83,583. The effect of hydroxylamine was completely dependent on extracellular Ca++ and reduced by 40% in the presence of omega-conotoxin GVIA, an N-type Ca(++)-channel antagonist; however it was unaffected by Ni++, nifedipine, caffeine or thapsigargin. The stimulatory effect of hydroxylamine on hippocampal cyclic GMP formation was not significantly affected by removal of extracellular Ca++, indicating that Ca(++)-dependent release is not due to inhibition of NO formation from hydroxylamine. However, the response to NO-CYS was reduced by 35 to 50% in either nominally Ca(++)-free or 10 mM MgSO4-containing buffer. Interestingly, buffer containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid dramatically enhanced the formation of NO from NO-CYS and potentiated the NO-CYS response. Both NO-CYS- and hydroxylamine-induced [3H]NE release was inhibited by NE transport blockers, indicating a prominent role for reverse transport. NO-CYS completely inhibited synaptosomal uptake of [3H]NE (IC50 approximately, 300 microM). NO generator-induced [3H]NE release has a glutamate-dependent component (see accompanying article). Inhibition of glutamate-evoked [3H]NE release by mazindol, an inhibitor of NE transport, suggests that the glutamate-dependent component also involves reversal of the NE transporter. These data suggest that NO produced from hydroxylamine or NO-CYS evoke both vesicular and nonvesicular release of hippocampal [3H]NE. Putative NO target molecules and the role of extracellular Ca++ are discussed.

Nitric oxide induces intracellular Ca2+ mobilization and increases secretion of incorporated 5-hydroxytryptamine in rat pancreatic β-cells

Article

Oct 1995

This study is the first to demonstrate that low concentrations of aqueous NO induce intracellular Ca2+ mobilization and an increase in secretory activity of rat pancreatic beta-cells. Application of NO solution (2 microM) resulted in a transient increase in the free intracellular Ca2+ concentration ([Ca2+]i) of isolated cells, as assessed by video ratio imaging and single wavelength microfluorimetry. Amperometry revealed a simultaneous increase in the release of preloaded 5-hydroxytryptamine from the isolated cells. The NO-induced Ca2+ response primarily involves mobilization of endoplasmic reticulum Ca2+ stores, since the response was retained when cells were transferred to low Ca2+ medium, and completely inhibited when cells were pretreated with 10 microM thapsigargin. The Ca2+ response was also inhibited when cells were incubated with a high concentration of ryanodine (200 microM), suggesting that Ca2+ mobilization is via a ryanodine-sensitive store.

Involvement of nitric oxide synthase in 3,4-diaminopyridine-evoked noradrenaline release in rat hippocampus

Article

Jun 1993
EUR J PHARMACOL

The release of tritiated noradrenaline, evoked by stimulation of rat hippocampus slices with 3,4-diaminopyridine (200 microM, 2 min), was enhanced by the nitric oxide (NO) synthase substrate, L-arginine (but not by D-arginine), by NO donors (sodium nitroprusside, 3-morpholino-sydnonimine), and by 8-Br-cGMP. The effect of L-arginine was stereospecifically antagonized by NG-nitro-L-arginine, which given alone was inhibitory. From these findings we conclude that endogenously formed NO facilitates 3,4-diaminopyridine-evoked noradrenaline release in rat hippocampus.

Role of nitric oxide in modulating neurotransmitter release from rat striatum

Article

Feb 1995
BRAIN RES BULL

The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on the basal and stimulation-evoked release of dopamine (DA) and acetylcholine (ACh) was investigated in rat striatum. The experiments were carried out in isolated superfused striatal slices, loaded with either [3H]-dopamine or [3H]-choline. We have found that L-NAME reduced the electrical field stimulation-evoked release of DA, while its enantiomer N-nitro-D-arginine methyl ester (D-NAME) was ineffective. In the presence of the nitric oxide (NO) precursor L-arginine, L-NAME failed to influence DA release. Furthermore, treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely reversed the effect of L-NAME on striatal DA release. In contrast, L-NAME had no effect on either the basal or the stimulation-evoked ACh release in any experimental conditions studied. Our data indicate that endogenously produced NO is involved in the modulation of striatal DA, but not in ACh release. Furthermore, it seems likely that the modulatory effect of NO is linked to activation of presynaptic NMDA receptors located on the striatal dopaminergic nerve terminals.

Nitric Oxide Modulates Dopamine Release During Global Temporary Cerebral Ischemia

Article

Jun 1995
ANESTH ANALG

Dopamine (DA) is released in large quantities from the striatum during cerebral ischemia. Along with excitatory neurotransmitters, DA plays a role in cellular neuronal ischemic injury. In this study we examined the role of nitric oxide (NO) in the ischemia-induced release of DA. A microdialysis probe was stereotactically placed into the corpus striatum of 16 Sprague-Dawley rats for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) level determinations. After probe stabilization, the animals received either NG-nitro-L-arginine-methyl ester (L-NAME), a NO synthase inhibitor, or vehicle through the microdialysis probe. Temporary global forebrain ischemia was induced using bilateral carotid artery ligature tightening and controlled hemorrhagic hypotension for 15 min. L-NAME administration caused a reduction in ischemic estimated extraneuronal DA concentration by 60% (P < 0.005) compared with control. There was an increase in both DOPAC and HVA concentrations during the recovery period compared to baseline values in the control group (P < 0.05). L-NAME also caused a reduction in HVA concentration compared to vehicle administration during the latter part of recovery (P < 0.05). These data support the concept that ischemic dopamine release may be mediated by NO. This NO-modulated DA release may contribute to the previously reported deleterious neurotoxic effects of NO during ischemia.

The effects of a photosensitive nitric oxide donor on basal and electrically-stimulated dopamine efflux from the rat striatum in vitro

Article

Dec 1994
NEUROPHARMACOLOGY

The reported effects of nitric oxide (NO) on dopamine release from the striatum are variable and its precise effect on striatal nerve terminals is unclear. In the present study a novel method of applying NO to brain tissue in situ was employed. Photo-activation of Roussin's Black Salt (RBS), retained in isolated perfused brain tissue, was used to release NO at will upon illumination. Basal and electrically-stimulated dopamine efflux from the rat striatum in vitro was measured in real time using fast cyclic voltammetry. Illumination of an RBS pre-treated brain slice elicited a light intensity-related increase in basal dopamine efflux. Concomitantly there was a decrease in the level of electrically-stimulated dopamine efflux. Illumination in the absence of RBS pre-treatment had no effect on basal or stimulated dopamine efflux. The increase in basal dopamine efflux upon photo-activation of RBS was reduced by the presence of 10 microM oxyhaemoglobin, but was insensitive to the removal of extracellular calcium or the addition of 1 microM sulpiride. The decrease in electrically-stimulated dopamine efflux following illumination was not affected by the presence of either oxyhaemoglobin or sulpiride. It is concluded that NO, produced by photo-activation of RBS, releases dopamine from the rat striatum in vitro by a mechanism independent of extracellular calcium entry.

Nitric oxide inhibits [3H]dopamine uptake

Article

Apr 1994
BRAIN RES

Sodium nitroprusside (SNP), a generator of nitric oxide (NO), decreased [3H]dopamine uptake into rat striatal synaptosomal preparations in a dose-, time- and temperature-dependent fashion. Reduced hemoglobin, a substance that binds NO, prevented the SNP-induced decrease in uptake. Potassium ferri- and ferrocyanide, compounds similar to SNP that do not produce NO, were without effect on uptake. SNP inhibited [3H]dopamine uptake in synaptosomes from nucleus accumbens and olfactory tubercle as well but with a lower potency. SNP inhibited [3H]serotonin and [3H]glutamate uptake but had no effect on [3H]norepinephrine uptake. S-Nitroso-N-acetylpenicillamine (SNAP), another generator of NO, had effects similar to those of SNP. The SNP-induced decrease in [3H]dopamine uptake was due to a Vmax decrease at 100 microM SNP and to both a Vmax and Km change at 300 microM SNP. Depletion of calcium by omission of calcium from buffers and addition of EGTA increased the potency of SNP in inhibiting uptake. There was no change in [3H]WIN 35428 binding to the dopamine transporter with doses of SNP that inhibited uptake. These data indicate that NO can decrease [3H]dopamine transporter function.

Inhibitory Effects of Nitric Oxide on the Uptake of [3H]Dopamine and [3H]Glutamate by Striatal Synaptosomes

Article

Dec 1994

Ten-minute incubation with 1 mM S-nitroso-L-cysteine (NO-CYS), a nitric oxide (NO) generator, induced a 3.5-fold increase in the basal dopamine (DA) efflux from rat striatal slices. Reduced hemoglobin (100 microM), a NO scavenger, blocked this response. Nomifensine (10 microM), an inhibitor of high-affinity DA transport, reduced the NO-CYS effect by 39%. In a synaptosomal preparation, NO-CYS induced a concentration-dependent efflux of [3H]DA that was also significantly inhibited by 10 microM nomifensine. Because these findings indicated that NO could alter the activity of the striatal DA transporter, we tested the effect of NO and NO-CYS on the uptake of [3H]DA into crude striatal synaptosomes. Although both compounds inhibited [3H]DA uptake with similar dose-response characteristics (IC50 approximately 300 microM and approximately 400 microM, respectively), the effect of NO was quicker in onset. The presence of superoxide dismutase (30 U/ml) and catalase (50 U/ml) had a small impact on the NO-CYS inhibition of [3H]DA uptake (1.8-fold increase in IC50). NO (1 mM) inhibited striatal [3H]glutamate uptake by 23%, but lower concentrations had no significant effect. The duration of the effect of NO gas on [3H]DA uptake varied from < 5 min to > 10 min, depending on the concentration used. All concentrations of NO-CYS tested produced an inhibition of [3H]DA uptake that lasted at least 10 min. However, only concentrations < or = 1 mM NO-CYS (or NO) were washable. The effect of 3 mM NO-CYS lasted > 20 min and could not be reversed by washing. Reduced hemoglobin (300 microM) prevented the action of 3 mM NO-CYS, whereas methemoglobin had no effect. The action of 3 mM NO-CYS was temperature dependent and took about 2 min to fully develop. Scatchard analysis revealed that NO-CYS diminished the capacity of the DA transporter without having a significant effect on the affinity. NO-CYS had no effect on striatal [3H]-mazindol binding, suggesting that NO-CYS did not interact with the DA recognition site of the transporter. These data suggest that NO may play a role in the regulation of DA and, to a lesser extent, glutamate transport in the striatum.

NMDA receptors are not involved in the MK-801-induced increase of striatal dopamine release in rat: A microdialysis study

Article

Apr 1994
BRAIN RES

Brain microdialysis and high-performance liquid chromatography with electrochemical detection were utilized to study the effect of the selective non-competitive NMDA antagonist MK-801 (dizocilpine) on striatal dopamine (DA) release in the anesthetized rat. Perfusion of 100 microM and 300 microM (+/-)-MK-801 through the probe did not significantly change the basal release of DA. These results suggest that excitatory amino acids do not exert a tonic excitatory influence on striatal DA release through NMDA receptors. 1 mM and 3 mM (+/-)-MK-801 caused a significant increase (398% and 580%, respectively), while there was no change in the level of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). To clarify the mechanism of the (+/-)-MK-801-induced increase, the differential effect of its enantiomers (the active (+)-MK-801 and the less active (-)-MK-801) was determined. There was no difference in the action of these compounds: both drugs increased the striatal DA release with the same efficacy. Our data suggest that the MK-801-induced increase of striatal DA release is not an NMDA receptor-mediated effect.

Lonart G, Cassels KL, Johnson KM. Nitric oxide induces calcium-dependent [3H]dopamine release from striatal slices. J Neurosci Res 35: 192-198

Article

Jun 1993

Hydroxylamine (0.01-30 mM), a nitric oxide (NO) generator, produced a concentration-dependent release of [3H]dopamine ([3H]DA) from rat striatal slices. Hemoglobin (10 microM), a NO scavenger, reduced basal [3H]DA release and blocked hydroxylamine (100 microM)-stimulated [3H]DA efflux. Tetrodotoxin (0.5 microM) had no significant effect. Sodium cyanide was used as a model compound to test the possibility that NO acted through blockade of mitochondrial electron transport. Calcium-free experimental buffer (1 mM EGTA) reduced basal release and the hydroxylamine response, while sodium cyanide-induced release did not change under these experimental conditions. Cadmium (200 microM), a non-selective inhibitor of voltage-dependent calcium channels, reduced the hydroxylamine response by 69%. Methylene blue (10 microM), an inhibitor of guanylate cyclase, produced a 3-fold increase in the basal release but had no significant effect on the hydroxylamine response. These data suggest that NO induces calcium-dependent [3H]DA release from the striatum via a mechanism which is independent of blockade of electron transport or activation of guanylate cyclase.

Nitric oxide increases dopamine and serotonin release in medial preoptic area

Article

Nov 1993
NEUROREPORT

Nitric oxide (NO) is becoming recognized as an important intercellular messenger in the brain. The present experiment used microdialysis to examine the potential role of NO in the regulation of dopamine (DA) and serotonin (5-HT) release in the medial preoptic area (MPOA) of freely moving male rats. The NO precursor L-arginine (L-Arg, 100 microM), administered into the MPOA via the dialysis probe, increased extracellular levels of DA, 5-HT, and the major metabolites of DA. These increases were blocked by the coadministration of the NO synthase inhibitor N-monomethyl L-arginine (NMMA, 400 microM). The inactive isomer D-arginine (100 microM) was ineffective, and NMMA by itself decreased DA below baseline levels. Thus, NO may modulate the release of DA and 5-HT in the MPOA.

Evidence that Nitric Oxide Causes Calcium-Independent Release of [3H]Dopamine from Rat Striatum In Vitro

Article

Feb 1996

Nitric oxide (NO), liberated from the photoactive donor Roussin's black salt (RBS), was investigated for its ability to release tritium from [3H]dopamine-loaded rat striatal slices. Our results show that illumination of RBS-pretreated striatal slices caused an increase in basal dopamine release, which was reduced by approximately 73% in the presence of oxyhaemoglobin (10 microM), indicating that it was mediated by liberation of NO. The release was insensitive to removal of extracellular calcium yet was not due to gross cellular damage of the tissue, as there was no detectable increase in lactate dehydrogenase release. Chelation of intracellular calcium with 1,2-bis(o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM; 10 microM) had no effect on the dopamine release stimulated by illumination of RBS-pretreated slices. The concentration of BAPTA-AM was adequate to chelate intracellular calcium because it inhibited release evoked by the calcium ionophore ionomycin (10 microM). Superfusion with zaprinast (10 microM) had no effect on RBS-induced dopamine release, suggesting that a mechanism independent of cyclic GMP is involved. This study indicates that NO has a stimulatory effect on striatal dopamine release in vitro that is independent of calcium.

Mechanism for nitric oxide's enhancement of NMDA-stimulated [3H]norepinephrine release from rat hippocampal slices

Article

Aug 1995
NEUROPHARMACOLOGY

Previous studies in our laboratory have shown that nitric oxide (NO) gas enhances NMDA-stimulated release of preloaded tritiated norepinephrine ([3H]NA) from rat brain slices in a dose-dependent, oxygen-sensitive, and cyclic GMP-independent manner. In this study we have attempted to determine the mechanism for the enhancement of neurotransmitter release seen with NO. No-enhanced transmitter release was not due to buffer acidification or generation of NO degradation products, since reducing buffer pH below 7.3 inhibited NMDA-stimulated [3H]NA release and nitrite or nitrate ions (3-100 microM) had no significant effect on release. Carbon monoxide (CO, 10-300 microM), another diatomic gas with properties similar to NO including heme binding and guanylate cyclase activation, had no significant effect on depolarization-induced [3H]NA release. The NO effect was probably not due to mono-ADP-ribosylation of cellular proteins, since the ADP-ribosyltransferase (ADPRT) inhibitors nicotinamide (10 microM-10 microM) and luminol (1 microM-1mM) did not diminish the enhancement of transmitter release seen with NO. The NA reuptake inhibitor desmethylimipramine (DMI, 10 nM-10 microM) neither mimicked nor blocked the effect of NO, suggesting that NO was not acting via inhibition or reversal of the NA transporter. Similar to NO, the metabolic inhibitors sodium azide (NaN3, 0.1-3 mM), potassium cyanide (KCN, 0.1-3 mM), and 2,4-dinitrophenol (2,4-DNP, 10-300 microM) also dose-dependently enhanced NMDA-stimulated [3H]NA release. These results suggest that NO may enhance neurotransmitter release by inhibiting cellular respiration and perhaps ultimately via altering calcium homeostasis.

Role of nitric oxide in the regulation of monoaminergic neurotransmission

Abstract

No full-text available

Recommended publications

The pathway for oxygen in brain

Oxidative Stress in Heart Failure: Current Understanding and Prospective

[The role of nitric oxide in normal and pathologic immunologic reactions]

Inside the Diabetic Brain