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Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats
Abstract
There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in central physiological mechanisms. NO is synthesized from L-arginine by nitric oxide synthase (NOS), as a response to activation of N-methyl-D-aspartate (NMDA) receptors by excitatory amino acids. NMDA receptor antagonists also produce antidepressant-like actions in preclinical models.
In the present study, the involvement of NO in the mechanism of depression was investigated. 7-Nitroindazole (7-NI) (15, 30, 60, 90 mg/kg IP), a selective inhibitor of neuronal NOS was examined.
The Porsolt forced swimming test (FST) has been used as a test for screening new antidepressant agents.
7-NI dose-dependently decreased the immobility time in FST, but produced no significant change in locomotor activity in naive rats. Neither L-arginine, nor D-arginine (100 mg/kg) affected the immobility time in the FST or revealed any effect on locomotion. L-Arginine but not D-arginine, given 10 min before 7-NI, reversed the 7-NI-induced effect on immobility time.
Our findings suggest that NO might be an important modulator of depression in rats.
... The observation that treatment with NMDA antagonists induces antidepressant-like effects in experimental protocols (16,17) raised the possibility that NO could also be involved in the neurobiology of depression. Since the first report by Jefferys and Funder (18), showing that systemic administration of NOS inhibitor reduces immobility time in the rat forced swimming test, several additional studies have confirmed an antidepressant-like effect in response to treatment with different NOS inhibitors in animals submitted to different models predictive of antidepressant activity (19)(20)(21)(22)(23)(24). Besides, antidepressants drugs are able to reduce NOS activity in hippocampus (25) while the discontinuation with imipramine treatment induces opposite effects in rats (26). ...
... Imipramine Hydrochloride (Sigma-Aldrich, Saint Louis, MO, USA) was administered i.p. at the dose of 15 mg/kg (according to (44)) and 7-nitroindazole (7-NI minimum 98%; Sigma-Aldrich, St Louis, MO, USA), a preferential nNOS inhibitor (45), was administered i.p. at the dose of 30 mg/kg (according to (21,46)). The drugs were dissolved in 40% dimethyl sulfoxide (DMSO; Gold Lab, Diadema, SP, Brazil), immediately before use, and administered at the volume of 2 ml/kg. ...
... (2) BDNF levels were increased in the hippocampus of animals repeatedly treated with 7-NI. This data agrees with several studies that pointed to the involvement of NO in the development of stressrelated disorders (18,21,22,46,(49)(50)(51). However, none of the previously published studies investigated if acute inhibition of nNOS either during the test assessment or immediately after stress presentation would be sufficient to induce antidepressant-like effect. ...
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.
... Similarly, in another study it is reported that NMDA receptor modulate the activity of NOS through PSD-95 protein and hence accelerates the formation of NO [68,69] . Nevertheless, this strong interplay between NMDA and NO in the antidepressant like effects of certain drugs, led the foundation to study the effect of NOS inhibitors in depression [70][71][72]. Undeniably, the effect of cGMP in depression is also well understood, as certain studies have shown that NO and cGMP is involved in the initiation of depression. Drugs which inhibit the L-arginine and NO-cGMP signaling are reported to have antidepressant effects during FST [61,[73][74][75]. ...
... There is a good match between our results and other studies, where they also reported that the antidepressant like activity of drugs like lithium, imipramine and venlafaxine can be halted by prior administration of L-arginine [76,77]. Other researchers confirmed that NOS inhibitors elicit antidepressant effect in a dose dependent manner [70][71][72]78]. Furthermore, a decrease in hippocampal nitric oxide level was found to attenuate the depressive symptoms, thus confirming the modulation of depression by endogenous high level of hippocampus nitric oxide [34]. ...
... Our results are consistent with other studies, where decrease in the immobility period during FST was documented with 7-nitroindazole [72,78] and methylene blue treatment [80]. In last decade, a study reported a synergistic effect of 7-nitroindazole and methylene blue with antidepressant drugs like venlafaxine in animals [76]. ...
... Trullas and Skolnick, in 1990, published the first work demonstrating that systemic administration of NMDA receptor antagonists to rats induced antidepressant-like effects in the FST [10]. Ten years later, Yildiz and coworkers reported that animals acutely treated with 7-NI -a NOS inhibitor -also exerted antidepressant-like behavior in the FST [11]. Similarly, systemic treatment with the sGC inhibitor ODQ induced antidepressant-like effects in rats submitted to the same test [12]. ...
... In addition, a comparison of DH and VH roles in the modulation of behavioral responses to stress by means of acute inactivation of each sub-region has not been reported yet. 10,11,9). (B) Bilateral intra-VH infusion of AP-7, N-PLA, ODQ or vehicle (n = 9, 10,7,9). Data are expressed as mean ± SEM of immobility time (s); *p < 0.05, **p < 0.01, ***p < 0.001 from control group. ...
... A total of 551 male Wistar rats weighing 200-270 g were used. The animals were housed in pairs in a temperature controlled room (24 ± 1 • C) under standard laboratory conditions with free access to food and water and a 12 h light/12 h dark cycle (light 11,9,14). Data are expressed as mean ± SEM of immobility time (s); *p < 0.05, **p < 0.01, ***p < 0.001 from control group. ...
Hodological and genetic differences between dorsal (DH) and ventral (VH) hippocampus may convey distinct behavioral roles. DH is responsible for mediating cognitive process, such as learning and memory, while VH modulates neuroendocrine and emotional-motivational responses to stress. Manipulating glutamatergic NMDA receptors and nitric oxide (NO) systems of the hippocampus induces important changes in behavioral responses to stress. Nevertheless, there is no study concerning functional differences between DH and VH in the modulation of behavioral responses induced by stress models predictive of antidepressant effects. Thus, this study showed that reversible blockade of the DH or VH of animals submitted to the forced swimming test (FST), by using cobalt chloride (calcium-dependent synaptic neurotransmission blocker), was not able to change immobility time. Afterwards, the NMDA-NO system was evaluated in the FST by means of intra-DH or intra-VH administration of NMDA receptor antagonist (AP7), NOS1 and sGC inhibitors (N-PLA and ODQ, respectively). Bilateral intra-DH injections after pretest or before test were able to induce antidepressant-like effects in the FST. On the other hand, bilateral VH administration of AP-7, N-PLA and ODQ induced antidepressant-like effects only when injected before the test. Administration of NO scavenger (C-PTIO) intra-DH, after pretest and before test, or intra-VH before test induced similar results. Increased NOS1 levels was associated to stress exposure in the DH. These results suggest that the glutamatergic-NO system of the DH and VH are both able to modulate behavioral responses in the FST, albeit with differential participation along time after stress exposure.
... NO is produced both presynaptically and postsynaptically in the brain as a result of the increase in cytosolic Ca 2+ concentration; it subsequently diffuses outside and affects the neighboring neuronal structures and glial cells. 1 NO has several effects on behavior, cognition, and emotion, and has been shown to play role in depression, anxiety, locomotion, aggression, tolerance, addiction, and learning. [2][3][4] NO has effects on the modulation of cognition; 5 however, role of NO in learning is not completely understood. ...
... Injections of 7-NI disturbed spatial memory and object recognition in rats and also had impairing effects in passive avoidance test in animal models. [26][27][28] The goal of this study was to further evaluate the effects of 7-NI (a nonselective inhibitor of NOS), l-arginine (an NO precursor combined with 7-NI), and 1H- [1,2,4]oxadiazole [4,3a]-quinoxaline-1-one (ODQ , a highly selective, irreversible inhibitor of sGC) on spatial memory in the modified elevated plus maze (mEPM), MWM, and radial arm maze (RAM) tests. Furthermore, these studies were aimed at further understanding the effects of NO on cognition because of the controversy in the literature. ...
... NMDA activation by glutamate can trigger nitric oxide (NO) synthesis in the brain, which is an important neurotransmitter involved in the modulation of behavioural responses to stress (15)(16)(17)(18). Similar to NMDA blockade, systemic inhibition of the neuronal NO synthase (nNOS) reduces NO levels in the brain and promotes antidepressant-like effects in rodents exposed to different preclinical models (19)(20)(21). Evidence from our research group suggests that blocking NMDA receptors and NO synthesis within brain regions that are dysfunctional in depression, such as the prelimbic part of the ventromedial prefrontal cortex (vmPFC-PL) (22) and the hippocampus (23,24), also induces antidepressant-like effects. ...
... In order to confirm the effectiveness of the TrkB and mTOR blockers used (k252a and rapamycin, respectively), we also showed that intra vmPFC-PL injection of these drugs blocked the antidepressant-like effects of BDNF. It is important to note that previous reports showed that the same dose range of the drugs used in the present work does not induce any changes on the locomotor behaviour of the animals (8,20,22,39), thus reinforcing the obtained OFT results. Such absence of locomotor changes rules out the influence of psychostimulant effects on FST results. ...
Objectives
NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.
Methods
Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.
Results
We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.
Conclusion
Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.
... Clinical studies have shown that plasma nitrate concentrations are significantly higher in depressed patients than in controls, suggesting NO production is upregulated in states of depression [42]. In addition, in preclinical studies using animal models, NOS inhibitors and guanylyl cyclase (GC) inhibitors (the levels of which are raised in the presence of NO) have displayed antidepressant properties [9,[43][44][45][46]. ...
... Persons with depression have been shown to have increased NO levels and, consequently, increased GMPc levels [42]. This explains the antidepressant-like effect of substances inhibiting NOS and soluble GC [43,45,47,48]. ...
In this study we evaluated the effect of frutalin (FTL) on mouse behavior. Mice (n = 6/group) were treated (i.p.) with FTL (0.25; 0.5 or 1 mg/kg) or vehicle and submitted to several tests (hole-board/HBT, elevated plus maze/PMT, open field/OFT, tail suspension/TST, or forced swimming/FST). Yohimbine, ketamine, l-NAME, aminoguanidine, 7-NI, methylene blue, l-arginine or dl-serine was administered 30 min before FTL (0.5 mg/kg). To evaluate the subchronic effect, animals were injected with FTL or vehicle for 7 days and submitted to the FST. Molecular docking was simulated using FTL against NOS and the NMDA receptor. No changes were observed in the HBT or the OFT. FTL (0.25 mg/kg) increased the number of entries into enclosed arms in the PMT. FTL reduced immobility in the TST (0.25 and 0.5 mg/kg) and the FST (0.25 mg/kg; 0.5 mg/kg). The effect of FTL was dependent on carbohydrate interaction and protein structure integrity and was reduced by ketamine, l-NAME, aminoguanidine, 7-NI and methylene blue, but not by l-arginine, yohimbine or dl-serine. The antidepressant-like effect remained after subchronic treatment. The molecular docking study revealed a strong interaction between FTL and NOS and NMDA. FTL was found to have an antidepressant-like effect mediated by the NMDA receptor/NO/cGMP pathway.
... In the brain, the NO/soluble guanilate cyclase (sGC)/cyclic guanilate monophosphate (cGMP) pathway has been implicated in the regulation of various behavioral and emotional functions, including anxiety and depression [3]. Systemic inhibition of sGC [4,5] as well as inhibition of NOS activity may produce antidepressant-like behaviors in rodents [6][7][8][9][10]. Moreover, injections of nNOS inhibitors in brain areas implicated in the modulation and expression of depressive-like behaviors, such as prefrontal cortex [11], hippocampus [12] and dorsal raphe nucleus [3], induce antidepressant-like effects in rodents. ...
... The reasons for these different results after single administration of 7NI and 1400W are unclear. Although non-specific NOS inhibitors [3,30] and iNOS inhibitors [10] produce antidepressant-like effects in rodents, the antidepressant-like effects in the FST have been largely attributed to the selective inhibition of nNOS by nNOS selective inhibitors such as 7-nitroindazole [3,8,31], TRIM [31], and N-propyl-l-arginine [10]. Moreover, increased expression of nNOS in limbic regions in stressed animals [32] and depressed patients [33], have linked nNOS with a depressive phenotype. ...
Clinical and experimental evidence indicates that nitric oxide (NO) is involved in the genesis of depression as well as in antidepressant drug effects. Inhibitors of nitric oxide synthases (NOS) exert antidepressant-like effect in several animal models, but also interfere with the locomotor activity. The involvement of different isoforms of NOS in the antidepressant-like effects is not clearly established. The objective of this study was to investigate the effects of acute or repeated administration of selective inhibitors of neuronal NOS (nNOS) and induced NOS (iNOS), 7 nitroindazole (7NI) and 1400 W, respectively, in mice subjected to open field (OF) and forced swim test (FST). We also investigated if the antidepressant-like effect of nNOS inhibitor, 7NI, was dependent on hippocampal serotonin. The results demonstrated that single or repeated (3 and 7 days) administration of 7NI resulted in antidepressant-like effects in mice, evidenced by a significant decrease in immobility time in the FST. However, antidepressant-like effects of the iNOS inhibitor, 1400W, were only identified after repeated administration for 3 or 7 days. The effects of both inhibitors were comparable to those obtained with the classical antidepressant fluoxetine. It was also demonstrated that the effect of 7NI was dependent of hippocampal serotonin. We concluded that inhibition of nNOS and iNOS result in antidepressant-like effects, and that these effects hold up after repeated administration.
... These findings imply that the inhibition of P/Q-type and L-type calcium channels might contribute to the central effects of Gab, such as its antiepileptic and neuroprotective properties 14 . In the past two decades, several preclinical studies have indicated that inhibition of NOS can produce antidepressant behavioral effects in various animal models 5,[27][28][29] . ...
... Elevated levels of arginine and ribo avin were also found in peripheral blood of FP chickens, suggesting a potential role of these two differential metabolites. Previous studies have found a signi cant trend of increasing serum arginine concentrations in people with depression [44]; arginine supplementation can activate central NMDA receptors through the arginine-nitric oxide pathway, causing depressive-like behavior in mice [45]. ...
Background
Feather pecking (FP), characterized by pecking at and pulling out of feathers of conspecifics, is a serious welfare and economic problem in laying hen husbandry. There is increasing evidence pointing pout to a critical role of gut microbiota in regulating host behaviors. However, the biological mechanism underlying the role of gut microbiota in FP is still unclear, evidenced by the lack of an appropriate treatment.
Results
In this work, we applied a multi-omics approach combined with a series of physiology assays to investigate the gut-brain axis of FP behavior. We show that chronic treatment with environmental stress induced severe FP accompanied by reduced production performance and increased anxiety- and depression-related behaviors, in comprison with control-treated laying hens. In addition, the immune system was severely suppressed in FP chickens. It is worth noting that the diversity and composition of gut microbiota were significantly altered, and thus leading to the reduced stability in microbial community. Importantly, a variety of differential metabolites were identified from non-targeted metabolomic analysis, which were mainly associated with arginine and histidine biosynthesis. A significant increase of glutamate levels was also observed in the hippocampus of FP chickens. Moreover, the eukaryotic transcriptome sequencing analysis revealed that the expressions of two glutamate-related receptors, GRIN2A and SLC17A6, were significantly upregulated in the hippocampus. Spearman correlation analysis showed that both genes GRIN2A and SLC17A6 in the hippocampus were significantly positively correlated with arginine levels in the duodenum, and Romboutsia in the duodenum were significantly negatively correlated with arginine.
Conclusions Romboutsia
and other bacteria genera in the intestine may increase the plasma levels of arginine and histidine by increasing the synthesis of arginine and histidine and decreasing the metabolism of arginine, which in turn increases glutamate levels and GRIN2A and SLC17A6 gene expression in the hippocampus, and regulates the glutamatergic system to influence the FP behavior of laying hens.
... The time used by a rat floating on the water without attempting to swim was taken as the immobility duration. Twenty-four hours before the FST experiment, all the animals were tested for fitness by subjecting them to a 15-minute swimming session as prescribed by the standard method (Yildiz et al. 2000). ...
The methanol leaf extract of Jatropha tanjorensis was analyzed for its bioactive components, in-vitro antioxidant, antidepressant, anxiolytic and anti-inflammatory activities using established methods. The phytochemicals detected were saponins, tannins, terpenoids, phenolic compounds, alkaloids, flavonoids and eugenols. The total phenolic content (TPC) was 36.48 mgGAE/g, while the total flavonoid content (TFC) was 145.92 mgQE/g of the extract. 1, 1-diphenyl-2-picrylhydrazyl radical scavenging activity gave an IC 50 of 185.02 and 5.15 µg/mL for the extract and ascorbic acid (standard), respectively. The 50% lethal dose (LD 50) was greater than 5000 mg/kg, while graded doses of 50, 100 and 200 mg/kg of the plant extract relieved depression in mice to 93.3, 100 and 80.8%, respectively when compared with 10 mg/kg amitriptyline (positive control). A significant anxiety reduction, exemplified by a decrease in the frequency of head dip, was observed for animals administered with the plant extract compared with untreated control (p < 0.05). The reduction of formalin-induced paw edema was significant (p < 0.01) at 50 mg/kg of the plant extract, when compared with the control. The methanol extract of J. tanjorensis leaf is therefore a potential source of plant medicine with remarkable pharmacological activities.
... In a study conducted on the rat hypothalamus, it was noticed that NO donors at low concentration decreased serotonin release in a cyclic guanosine monophosphate (cGMP)dependent manner, while at high concentration increased serotonin release [6]. Anxiolytic and antidepressant effects were observed in other studies using NOS inhibitors, and it was suggested that these effects are mediated by serotonin [7,8]. ...
L-arginine, a NO donor; Sodium hydrosulphide (NaHS), a hydrogen (H2 S) donor; Tricarbonyldichlororuthenium (II) dimer (CORM-2), CO donor are characterized as bioactive gas mediators that have been researched for their roles in human physiology. This study aimed to compare the effects of these mediators on pain, anxiety and depression. Ninety-one adult male Sprague-Dawley rats were used for the experiments. Locomotor activity, elevated plus maze, forced swimming, tail clip, hot plate, and writhing tests were used for the assessments after the administration of L-arginine (30-100 mg/kg), a NO donor; Sodium hydrosulphide (NaHS) (5-10 mg/kg), a hydrogen (H2 S) donor; Tricarbonyldichlororuthenium (II) dimer (CORM-2) (5-10 mg/kg), CO donor. i.p. H2 S, NO, MDA, GSH, and TNF-alpha levels were determined by ELISA. No statistical significance was found in the locomotor activity. NO and CO significantly extended latency at high doses in tail clip test. No significant activity was observed at any dose of all three substances on a hot plate. Both doses of CO and high doses of NO and H2 S showed an antinociceptive effect in the writhing test. While the opioidergic system plays a role in the spinal antinociceptive effect of L-arginine, both serotonergic and opioidergic systems play a role in its peripheral antinociceptive effect. The serotonergic system plays a role in the peripheral antinociceptive effect of CORM-2. The time spent in open-arm increased significantly in all groups an elevated plus maze. High doses of all three substances significantly increased the duration of immobility in the forced swimming test. No statistical significance was observed in MDA, GSH and TNF-α levels. High doses of NO and CO showed a spinal antinociceptive effect. Both doses of CO and high doses of NO and H2 S showed a peripheral antinociceptive effect. All three agents showed anxiolytic and depression-like effects.
... Nitric oxide (NO) is an important modulator of depression [19,20] because NO production is increased in depression. Moreover, In brain, No is an essential neurotransmitter that normalize depression, behavioral, cognitive and emotional processes [21]. ...
... Values are expressed as mean ± S.E.M. *p < 0.05 and **p < 0.01 compared to the saline/vehicle-treated control animals (n ¼ 6/group). inhibitors exert antidepressant-like effects in experimental studies (Ero glu & Ca glayan, 1997;Yildiz, Erden, Ulak, & Gacar, 2000). ...
... Stresle yapmış olduğu bu artış nNOS ekspresyonu, çesitli nörotransmiterlerin salınımını ile modüle etmektedir ve stres ile birlikte nNos çeşitli nörotansmiterlere salımında, oldukça etkili bir modületördür [46 ve 47]. [48,49,50]. Merkezi sinir sisteminde NO nöromodelatör olarak işlevi göstermektedir [51]. ...
... The low number of patients participating in the study may be the reason for no significant correlation between saliva NO and anxiety. It was reported that NO is one of the agents involved in neurotransmitter dysfunction during anxiety and depression, and if anxiety and depression are an adaptation, NO may be involved during this adaptation (13). Also, it was shown that salivary NO levels of patients with periodontitis were higher than healthy individuals (14). ...
Z ORIGINAL ARTICLE ORİJİNAL ARAŞTIRMA Objective: Anxiety due to the dentist and dental treatment is a problem encountered in many children. The aim of the present study is to determine salivary nitric oxide, lactoferrin, α-amylase and cortisol levels of children in primary and mixed dentition, and to evaluate their relation with stress due to dental treatment. Material and Method: The study consisted of 50 children in primary and mixed dentition. The children were evaluated clinically and according to Frankl Behavior Rating Scale. Salivary flow rate was calculated, and nitric oxide, lactoferrin, α-amylase and cortisol levels were measured in saliva. Results: 68% percent of the children were found to be negative according to the Frankl Behavior Rating Scale (category 2), and significantly decreased salivary flow rate was evident in these children when compared with children that were categorized as completely negative (category 1). The DMFT+dft index was 7.56±4.29, and positive correlations were found between DMFT+dft indices and salivary nitric oxide, lactoferrin, cortisol and α-amylase levels (p<0.05). These parameters were not different between genders. Positive correlations were found between salivary nitric oxide and α amilase, cortisol and α amilase, cortisol and lactoferrin; and also between α-amilase and lactoferrin levels (p<0.05). Conclusion: Salivary lactoferrin, α-amylase and cortisol may be suggested as important parameters of oral health. Amaç: Diş hekimi ve diş tedavisine bağlı anksiyete birçok çocukta karşılaşılan bir sorundur. Bu çalışmanın amacı, süt ve karışık diş-lenme dönemindeki çocuklarda tükürük nitrik oksit, laktoferrin, α-amilaz ve kortizol seviyelerini tespit etmek ve diş tedavisinden kaynaklanan stresle ilişkilerini değerlendirmektir. Gereç ve Yöntem: Çalışma süt ve karışık dişlenme dönemindeki 50 çocuktan oluşmaktadır. Çocuklar klinik olarak ve Frankl Davranış Değerlendirme Ölçeğine göre değerlendirildi. Tükürük akış hızı he-saplandı ve tükürükte nitrik oksit, laktoferrin, α-amilaz ve kortizol seviyeleri ölçüldü. Bulgular: Çocukların %68'i Frankl Davranış Değerlendirme Öl-çeğine göre negatif (Kategori 2) olarak bulundu ve bu çocuk-larda, tamamen negatif olarak sınıflandırılan çocuklarla karşı-laştırıldığında (Kategori 1) anlamlı derecede azalmış tükürük akış hızı belirlendi. DMFT + dft indeksi 7,56±4,29 idi ve DMFT + dft indeksleri ile tükrük nitrik oksit, laktoferrin, kortizol ve α-a-milaz seviyeleri arasında pozitif korelasyon bulundu. Bu para-metreler cinsiyetler arasında farklı değildi. Tükürük nitrik oksit ile amilaz, kortizol ve amilaz, kortizol ve laktoferrin ve ayrıca a-amilaz ve laktoferrin seviyeleri arasında pozitif korelasyon bulundu. Sonuç: Tükürük laktoferrin, α-amilaz ve kortizol, ağız sağlığı ve anksiyete için önemli parametreler olarak önerilebilir.
... Forced swimming test has been successfully used to evaluate the antidepressant activity of imipramine 30 , fluoxetine, reboxetine, moclobemide 31 and nitroindazole. 32 It is proven that serotonin-selective reuptake inhibitors (fluoxetine, certraline, sertraline) increase swimming behaviour. Drugs that increase norepinephrine and dopamine improves climbing behaviour. ...
Non-motor symptoms such as depression, dementia, autonomic nervous system problems may be more evident in the later part of Parkinsonism. L-dopa is largely ineffective for non-motor symptoms. The objective of the present study was to evaluate the anti-depressant and neuroprotective role of captopril and perindopril in paraquat mice model of Parkinsonism. Adult Swiss albino mice were divided into five groups of six each. Parkinsonism was induced with paraquat (7mg/kg bodyweight at an interval of 2 days) in four groups. Experimental group was treated with captopril (20mg/kg intraperitoneal) and perindopril (5mg/kg intraperitoneal). Depression influences on behaviour was studied with forced swim test and tail suspension test. Oxidative stress markers – glutathione, lipid peroxidation assay, myeloperoxidase activity, catalase, superoxide dismutase, monoamine oxidase A and B are carried out in one hemisection of the mice brain to evaluate the neuroprotective role of the test drugs. The test group mice exposed to captopril and perindopril had significantly less immobility time in both forced swim test and tail suspension test in comparison to the paraquat group, indicating anti-depressant effects of these drugs. Lipid peroxidation, myeloperoxidase activity, catalase, superoxide dismutase, monoamine oxidase B levels were significantly increased in both captopril and perindopril groups in comparison to the control group. Captopril and perindopril have shown beneficial effects for depression (as evidenced through forced swimming test and tail suspension test) in paraquat model of Parkinsonism. These drugs reduce the oxidative stress in paraquat mice model of Parkinsonism
... Melatonin has been shown to exert an antidepressant effect through an interaction with NMDA receptors and L-arginine-NO pathway [15]. A flavanone glycoside hesperidin exhibited antidepressant activity involving NO -GMP pathway [30]. These authors provided evidence that NO donor L-arginine could attenuate the antidepressant effect of hesperidin. ...
Objectives: This research was designed to investigate the antidepressant activity of a few structurally related flavones (flavone, 3‑hydroxyflavone, and 7‑hydroxyflavone) and the possible mechanisms involved. Methods: Antidepressant activity was evaluated in mice by subjecting them to forced swim test and tail suspension test. The involvement of adrenergic, serotonergic, nitric oxide (NO), and opioid mechanisms was investigated using suitable interacting chemicals. Results: Flavone, 3‑hydroxyflavone, and 7‑hydroxyflavone exhibited a significant and dose‑dependent reduction in total time of immobility in the forced swim test and tail suspension test. Pre‑treatment with alpha‑methyl‑para‑tyrosine and parachlorophenyl alanine attenuated the reduction in immobility period produced by flavone and its derivatives in forced swim test. Naloxone pre‑treatment partially reversed the effect of flavone while L‑arginine pre‑treatment did not alter their effect. Conclusion: The investigated flavones exhibited promising antidepressant activity in both the animal models of depression. However, the flavone compounds did not alter the motor coordination and ambulatory behavior in the Rotarod and locomotor activity test. The participation of serotonergic, adrenergic, and opioid mechanism in the antidepressant activity of these compounds was elucidated from the results, and the role of NO pathway was excluded.
... Therefore, the administered dose of AG used in the present study (50 mg/kg) was chosen based on the previous studies reporting acute antidepressant-like effects of systemically administered AG in a dosage range of 50-100 mg/kg (Harvey et al.,2005;Montezuma et al.,2012). As with iNOS inhibitors, selective nNOS inhibitors including 7-nitroindazole have been reported to have antidepressantlike effects (Mutlu et al.,2009;Yildiz et al.,2000;Zhou et al.,2007). Unlike 7-nitroindazole, our knowledge regarding the more selective derivative 3-Br-7-NI is limited. ...
Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1β) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1β. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1β. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.
... Clinical widely used medicines such as fluoxetine, imipramine (44) and venlafaxine (35) were also reported to enhance the antidepressant-like effect with 7-NI. Our results demonstrated that ineffective YJ could decrease the immobility time in mice with 7-nitroindazole and methylene blue treatment, which was consistent with other researches (52)(53)(54). ...
The present study aims to evaluate the involvement of N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in antidepressant-like effects of Yueju pill, a Chinese herbal medicine. The immobility time in tail suspension test (TST) and forced swim test (FST) were used to assess the antidepressant effects. Prior administration of L-arginine (750 mg/kg, i.p.), a nitric oxide synthase substrate that enhances NO signaling or sildenafil (5 mg/kg, i.p.), a phosphodiesterase 5 inhibitor that enhances cGMP，blunted the antidepressant-like activity of Yueju pill (2.7g/kg, i.g.). Co-treatment of ineffective dose of Yueju pill (1.35g/kg, i.g.) with one of the reagents that suppress the NO/cGMP signaling, including methylene blue (10mg/kg, i.p.), an inhibitor of NOS; 7-NI (7-nitroinidazole, 30mg/kg, i.p.), an nNOS specific inhibitor; L-NAME (10 mg/kg, i.p.), a non-specific inhibitor of nitric oxide synthase; and MK-801 (0.05 mg/kg, i.p.), an NMDA receptor antagonist, reduced the immobility time in TST and FST, compared to those in vehicle or single drug treatment groups. Neither above drugs alone or co-administrated with Yueju pill affected locomotor activity or anxiety behavior in open field test. Thus, our results suggest that the antidepressant-like action of Yueju pill may depend on the inhibition of NMDA/NO/cGMP pathway.
... A comprehensive review of these compounds lies beyond the scope of this text and can be found elsewhere . Briefly, acute systemic administration of both iNOS and nNOS inhibitors, such as 7-NI, 1-(2-trifluoromethylphenyl)-imidazole (TRIM) or 1400W, has antidepressant-like effects but does not affect locomotion (Harkin et al. 2003;Heiberg et al. 2002;Montezuma et al. 2012;Spiacci Jr et al. 2008;Volke et al. 2003;Yildiz et al. 2000). Both 7-NI and TRIM have proven to be effective in other animal models with better face validity, such as the chronic mild stress model of depression (Mutlu et al. 2009;Yazir et al. 2012) and the learned helplessness paradigm (Stanquini et al. 2018). ...
Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO
system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.
... In this sense, the involvement of NO in the anxiety-related behavior was investigated in both rats and mice by the use of NOS inhibitors and NO donors [96]. The administration of NOS inhibitors showed an anxiolytic-like profile, whereas NO donors induced an anxiogenic-like effect in the EPM [97][98][99][100][101]. Also, It has been suggested that NO is involved in the pathophysiology of major depression [102,103]. ...
Nickel (Ni) toxicity has been reported to produce biochemical and behavioral dysfunction. The present study was undertaken to examine whether Ni chronic administration can induce alterations of affective and cognitive behavior and oxidative stress in male and female rats. Twenty-four rats, for each gender, divided into control and three test groups (n = 6), were injected intraperitoneally with saline (0.9% NaCl) or NiCl2 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) for 8 weeks. After treatment period, animals were tested in the open-field, elevated plus maze tests for anxiety-like behavior, and forced swimming test for depression-like behavior. The Morris Water Maze was used to evaluate the spatial learning and memory. The hippocampus of each animal was taken for biochemical examination. The results showed that Ni administration dose dependently increased anxiety-like behavior in both tests. A significant increase in depression-like symptoms was also exhibited by Ni treated rats. In the Morris Water Maze test, the spatial learning and memory were significantly impaired just in males treated with 1 mg/kg of Ni. With regard to biochemical analysis, activity of catalase (CAT) and superoxide dismutase (SOD) were significantly decreased, while the levels of nitric oxide (NO) and lipid peroxidation (LPO) in the hippocampus were significantly increased in the Ni-treated groups. Consequently, chronic Ni administration induced behavioral and biochemical dysfunctions.
... A role for endogenous NO system has also been suggested in the pathogenesis of depression. [34,35] It has been proposed that the antidepressant effect of imipramine and venlafaxine involves the suppression of NO synthesis. [36] Flavonoids like hesperidin exerted antidepressant effect involving NO-cyclic guanosine 3'5'-monophosphate pathway [37] and L-arginine pre-treatment could reverse the protective effect of rutin against the immobilization stress-induced anxiety-like behavior. ...
Background: In the treatment of depression, drugs with a quick onset of action and high margin of safety are intensely being searched. Previous studies indicate flavonoids as a potential source for such drugs. Hence, in the present study, four dihydroxy flavones have been selected for investigation.
Aims and Objectives: The aim of this study is to investigate the potential antidepressant effect and the mechanism of action of dihydroxy flavone derivatives in mice.
Materials and Methods: Mice were subjected to forced swim test and tail suspension test for 6 min. The period of immobility in these animals was recorded after treatment with different doses of 3,7-dihydroxy flavone, 3,3’-dihydroxy flavone, 6,3’-dihydroxy flavone, and 5,6–dihydroxy flavone. Interacting drugs such as para chlorophenylalanine, alpha-methyl-para-tyrosine, L-arginine, and naloxone were employed to delineate the role of various mechanisms involved in the action of these dihydroxy flavones in forced swim test.
Results: A dose-dependent reduction in the immobility period of mice was recorded in both forced swim test and tail suspension test for dihydroxy flavones indicating the antidepressant-like effect of these compounds. However, 6,3’-dihydroxy flavone was found to be less effective than the other three compounds. Various interacting drugs differentially modulated the reduction of immobility period produced by dihydroxy flavones in forced swim test. Monoaminergic, opioid, and nitric oxide pathways were evident in the action of dihydroxy flavones.
Conclusion: The present study identified the potential antidepressant effect of a few dihydroxy flavone derivatives involving novel mechanisms.
KEY WORDS: Dihydroxy Flavones; Forced Swim Test; Tail Suspension Test; Antidepressant
... Various reports show that NO can modulate different processes in the brain as it is capable of modulating the release of neurotransmitters and affect neuronal plasticity (90,92). Many preclinical studies regarding depression have demonstrated that NO inhibitors induce antidepressant-like effects in animal models such as the forced swim test (93)(94)(95) and chronic mild stress (96,97). Nonetheless, none of these drugs is available for clinical use so far. ...
Although monoaminergic-targeted drugs have prompted great advances in the development of treatments for depression, the need for new options persists, since these drugs still have a delayed clinical effect and most patients do not respond properly to them. Recently, the observation of the antidepressant effects of ketamine brought on a new wave of studies regarding the comprehension of the neurobiology of depression and the development of new and more effective antidepressant drugs.
Thus, in this paper, we present a historical review of the development of monoaminergic antidepressant drugs and the role of ketamine as the introductory agent of a new era in the research of the neurobiology of depression.
Firstly, we review how the pharmacological treatment for major depression started, and we point out the main drugs discovered, the researchers involved, and how the studies developed have contributed to the understanding of the neurobiology of depression. Secondly, the major problems regarding the clinical efficacy and acceptance of these drugs are discussed, and the introduction of the glutamatergic system as a target for antidepressant drugs is presented. Finally, we review how ketamine revealed itself as an exciting option towards obtaining pharmacological agents to treat depression, through the understanding of biological markers.
Ketamine contributed to confirm that different targets of the glutamatergic system and neurotrophic pathways are strictly related to the neurobiology of depression. There are several antidepressant drugs based on ketamine’s mechanism of action already in the pipeline, and glutamatergic-targeted antidepressants may be on the market in the near future.
... MDD patients who are suicidal were reported to have higher plasma NO levels (Lee et al. 2006). The non-selective NOS inhibitor L-NG-nitroarginine methyl ester (L-NAME) and the selective nNOS inhibitor 7-nitroindazole induced dose-dependent antidepressant-like effects in the forced swimming test (FST) (Yildiz et al. 2000;Spiacci et al. 2008;Ferreira et al. 2012). Furthermore, hippocampal nNOS expression was significantly increased in depressed patients ). ...
Background:
Nitric oxide (NO) is a neurotransmitter that may be related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces a dose-dependent antidepressant-like effect. NO modulates major neurotransmitters involved in the neurobiology of MDD, such as norepinephrine, serotonin, dopamine, and glutamate. In this study, we investigated the effects of antidepressants as NO modulators in acute and sub-chronic treatments.
Methods:
Rats were injected with the SSRI paroxetine (PAR, 10 mg/kg), the SNRI milnacipran (MIL, 30 mg/kg), or the NaSSA mirtazapine (MIR, 10 mg/kg) for acute (1 h) or sub-chronic (3 weeks) treatment prior to analysis of nine brain regions (frontal cortex, temporal cortex, striatum, thalamus, hippocampus, midbrain, pons, cerebellum, and olfactory bulb). The mRNA expression levels of three NOS subtypes (neuronal: nNOS, inducible: iNOS, and endothelial: eNOS) were analyzed using real-time PCR with Taqman probes.
Results:
Acute MIR treatment significantly increased nNOS mRNA expression in the hippocampus, midbrain, cerebellum and olfactory bulb, and iNOS mRNA expression in the frontal cortex and midbrain. Acute PAR and MIR treatments significantly increased eNOS mRNA expression in most brain regions. Conversely, sub-chronic treatment with all types of antidepressants resulted in significant decreases of eNOS mRNA expression in most brain regions.
Conclusions:
Sub-chronic treatment with the three types of antidepressants consistently decreased eNOS mRNA expression levels in the rat brain. These effects may be associated with the involvement of the NO system in the mechanism of action of antidepressants.
... The role of NO in major depressive disorder (MDD) is controversial. Several studies reported increased levels of NO in patients with major depression (Akpinar et al., 2013;Lee et al., 2006;Lu et al., 2014;Moreno et al., 2013;Suzuki et al., 2001) and an antidepressive effect of various NOS inhibitors in animal models of MDD (Joca and Guimarães, 2006;Yildiz et al., 2000). Others, however, demonstrated decreased levels of NO and eNOS expression in platelets and endothelial cells of patients with MDD or panic disorder compared to healthy controls (Chrapko et al., 2004;García et al., 2011;Huang et al., 2014;Selley, 2004;Yapislar et al., 2012). ...
... Several studies have suggested that the NMDA-NO pathway could be involved in the neurobiology of depression. Indeed, systemic administration of NMDA antagonists or nonselective NOS inhibitors induces antidepressant-like effects in animal models (Jefferys and Funder, 1996;Zhang et al., 1997;Petrie et al., 2000;Yildiz et al., 2000;Heiberg et al., 2002;Khovryakov et al., 2010). Additionally, it is known that excessive cGMP levels may produce a depression-like behavior, whereas inhibiting sGC may produce antidepressant-like effects (Heiberg et al., 2002;Yazir et al., 2012). ...
Systemic or hippocampal administration of nitric oxide (NO) synthase inhibitors induces antidepressant-like effects in animals, implicating increased hippocampal levels of NO in the neurobiology of depression. However, the role played by different NO synthase in this process has not been clearly defined. As stress is able to induce neuroinflammatory mechanisms and trigger the expression of inducible nitric oxide synthase (iNOS) in the brain, as well as upregulate neuronal nitric oxide synthase (nNOS) activity, the aim of the present study was to investigate the possible differential contribution of hippocampal iNOS and nNOS in the modulation of the consequences of stress elicited by the forced swimming test. Male Wistar rats received intrahippocampal injections, immediately after the pretest or 1 h before the forced swimming test, of selective inhibitors of nNOS (N-propyl-L-arginine), iNOS (1400W), or sGC (ODQ), the main pharmacological target for NO. Stress exposure increased nNOS and phospho-nNOS levels at all time points, whereas iNOS expression was increased only 24 h after the pretest. All drugs induced an antidepressant-like effect. However, whereas the nNOS inhibitor was equally effective when injected at different times, the iNOS inhibitor was more effective 24 h after the pretest. These results suggest that hippocampal nNOS and iNOS contribute to increase in NO levels in response to stress, although with a differential time course after stress exposure.
... ADMA levels increase and NO levels decrease in major depression (13). Moreover, some studies have indicated that various NOS-inhibiting agents generate antidepressant effects in laboratory animals (16,17). Ferreira et al. observed that 7-nitroindazole, a central selective NOS inhibitor, potentiates the anxiolytic effects of alcohol in experimental anxiety created in rats (18). ...
Background/aim:
We aimed to investigate and compare to healthy controls the variations in the levels of nitric oxide (NO), asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and L-arginine levels in patients with obsessive-compulsive disorder (OCD).
Materials and methods:
We enrolled 30 patients with OCD and 30 healthy controls in the study consecutively. Diagnostic interviews of all participants were conducted with the Structured Clinical Interview for Axis I Disorders (SCID-I), and sociodemographic data of the participants were recorded. Patients scoring 10 points or more on the Yale-Brown Obsessive-Compulsive Scale were enrolled in the study.
Results:
The NO levels of patients with OCD were increased compared to the control group, but the increase was not statistically significant (P > 0.05). However, patients with OCD had significantly lower levels of ADMA, SDMA, and L-arginine compared with the controls (P < 0.001).
Conclusion:
We found a significant decrease in ADMA, SDMA, and L-arginine as NO inhibitors between the groups, possibly because of an increase in NO. However, the insignificant increase in NO suggests that ADMA, SDMA, and L-arginine play direct and potentially important roles in OCD biology.
... Physiologically, nNOS accounts for the majority of the NOS activity in neurons, and anxiolytic-like effects have been attributed to the selective inhibition of this NOS isoform (Volke, Wegener, Bourin, & Vasar, 2003;Yildiz, Erden, Ulak, Utkan, & Gacar, 2000). Moreover, increased expression of nNOS in limbic regions in stressed animals has also helped to link nNOS with anxiety-like behavior (de Oliveira et al., 2001). ...
... e l s e v i e r . c o m / l o c a t e / p h a r m b i o c h e m b e h 1992; Yildiz et al., 2000). It is now well recognized that NMDA receptors blockade by certain drugs can exhibit antidepressant activity. ...
... Similar to our consequences, the antidepressant-like properties of many drugs were also prevented by pretreatment with L-arginine (Dhir and Kulkarni 2007;Harkin et al. 2004). Indeed, numerous reports have established that NOS inhibitors, depending on their concentration, display antidepressant-like properties (Volke et al. 2003;Yildiz et al. 2000). Furthermore, due to the fact that a decrease of NO level within the hippocampus produces antidepressant-like effects, endogenous hippocampal NO is known to be involved in the pathophysiology of depression (Joca and Guimarães 2006). ...
Based on clinical studies regarding the beneficial effect of gabapentin in depression, we aimed to evaluate the antidepressant-like properties of gabapentin in mice and also the participation of nitric oxide (NO)/cyclic guanosine monophosphate pathway in this effect. The following drugs were used in this study: gabapentin; N(G)-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor; 7-nitroindazole, a specific neuronal NOS inhibitor; aminoguanidine, a specific inducible NOS inhibitor; L-arginine, a NO precursor; and sildenafil, a phosphodiestrase inhibitor. Finally, we studied the behavioral effects through the forced swimming test (FST) and the changes of the hippocampus NO level through nitrite assay. The immobility time was significantly reduced after gabapentin administration. Co-administration of non-effective doses of gabapentin and L-NAME or 7-nitroindazole (7-NI) resulted in antidepressant-like effect in FST, while aminoguanidine did not affect the immobility time of gabapentin-treated mice. Furthermore, the antidepressant-like property of gabapentin was prevented by L-arginine or sildenafil. Also, the hippocampal nitrite level was significantly lower in gabapentin-treated mice relative to saline-injected mice, and co-administration of 7-NI with sub-effective gabapentin caused a significant decrease in hippocampal nitrite levels. Our results indicate that the antidepressant-like effect of gabapentin in the mice FST model is mediated at least in part through nitric oxide/cyclic guanosine monophosphate (cGMP) pathway.
Depression and schizophrenia are 2 serious mental disorders. Their effective treatment is an urgent medical and social problem at present. Drug treatment is the basic measure to improve mental disorders, especially serious mental disorders. However, the side effects of traditional antipsychotic drugs cannot be avoided. Surprisingly, in recent years, it has been found that nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S) and hydrogen (H2) can regulate corresponding signal pathways to treat mental diseases in animal models. More importantly, as gas signal molecules, they will not bring toxicity and side effects after metabolism. Therefore, in this review, we analyzed the effects of gas on depression and schizophrenia through endogenous gas generation and external gas delivery strategies in some animal models. Endogenous gas generation strategy: summarized the therapeutic mechanism of gas signaling molecules on depression and schizophrenia, and listed the main ways to inhibit or stimulate gas generation. External gas delivery strategy: The common external stimuli-responsive gasotransmitter prodrugs and some study of these prodrugs in the treatment of depression and schizophrenia are summarized. We also analyzed the prospects of nano-gas carrier in the treatment of depression and schizophrenia. Through this review, we hope to provide guidance for treating depression and schizophrenia by regulating relevant gas signal pathways, and provide reference for developing safe and effective drugs for treating mental disorders by summarizing exogenous gas drugs.
Doxycycline is an antibiotic that has shown neuroprotective, anti-inflammatory, and antidepressant-like effects. Low doses of doxycycline revert the behavioral and neuroinflammatory responses induced by lipopolysaccharide treatment in a mice model of depression. However, the molecular mechanisms involved in the antidepressant action of doxycycline are not yet understood. Doxycycline inhibits the synthesis of nitric oxide (NO), which increases after stress exposure. Inducible NO synthase (iNOS) inhibition also causes antidepressant-like effects in animal models sensitive to antidepressant-like effects such as the forced swimming test (FST). However, no direct study has yet investigated if the antidepressant-like effects of doxycycline could involve changes in NO-mediated neurotransmission. Therefore, this study aimed at investigating: i) the behavioral effects induced by doxycycline alone or in association with ineffective doses of a NO donor (sodium nitroprusside, SNP) or an iNOS inhibitor (1400 W) in mice subjected to the FST; and ii) doxycycline effects in NO metabolite levels in the prefrontal cortex and hippocampus these animals. Male mice (8 weeks) received i.p. injection of saline or doxycycline (10, 30, and 50 mg/kg), alone or combined with SNP (0.1, 0.5, and 1 mg/kg) or 1400 W (1, 3, and 10 µg/kg), and 30 min later were submitted to the FST. Animals were sacrificed immediately after, and NO metabolites nitrate/nitrite (NOx) were measured in the prefrontal cortex and hippocampus. Doxycycline (50 mg/kg) reduced both the immobility time in the FST and NOx levels in the prefrontal cortex of mice compared to the saline group. The antidepressant-like effect of doxycycline in the FST was prevented by SNP (1 mg/kg) pretreatment. Additionally, sub-effective doses of doxycycline (30 mg/kg) associated with 1400 W (1 µg/kg) induced an antidepressant-like effect in the FST. Altogether, our data suggest that the reducing NO levels in the prefrontal cortex through inhibition of iNOS could be related to acute doxycycline treatment resulting in rapid antidepressant-like effects in mice.
Introduction : A côté du modèle monoaminergique dans le trouble dépressif unipolaire, la voie du monoxyde d’azote (NO) et de ses enzymes, les « nitric oxide synthase » (NOS) font l’objet de nombreuses recherches afin d’identifier des biomarqueurs de ce trouble et de réponse aux antidépresseurs. Ces recherches sont également en lien avec l’hypothèse immuno-inflammatoire du trouble dépressif. L’objectif de cette thèse est : 1) d’évaluer l’activité de la NOS comme biomarqueur de l’épisode dépressif caractérisé (EDC) dans un contexte de trouble dépressif unipolaire et son caractère prédictif vis-à-vis de la réponse au traitement antidépresseur ; 2) explorer les métabolites de la voie du NO ; 3) rechercher un possible lien entre l’activité plasmatique de la NOS et l’état inflammatoire des patients notamment en comparaison avec des sujets contrôles. Méthode : Les données originales de ce travail sont issues de la cohorte METADAP comparée à une cohorte contrôle, VARIETE. METADAP est une cohorte prospective, multicentrique incluant 624 patients présentant un EDC dans le cadre d’un trouble dépressif unipolaire et nécessitant l’introduction d’un traitement antidépresseur. Le traitement antidépresseur est prescrit de façon naturaliste. Les patients sont évalués à 3 et 6 mois après l’introduction du traitement antidépresseur. Les biomarqueurs étudiés sont l’activité plasmatique de la NOS à travers la mesure du ratio L-Citrulline/L-Arginine, les taux plasmatiques des métabolites impliqués dans la voie du NO (L-Arginine, L-Citrulline, L-Ornithine et la Diméthylarginine asymétrique (ADMA), l’activité plasmatique de l’arginase, en compétition avec l’activité de la NOS ; et enfin les taux plasmatiques des protéines de l’inflammation (CRP, IL-6 et TNF-alpha). Résultats : 1) Concernant l’activité de la NOS, nous retrouvons une diminution significative de son activité chez les patients présentant un EDC comparés aux sujets contrôles. Cette baisse d’activité est prédictive du statut de répondeurs à trois mois de l’introduction d’un traitement antidépresseur. Enfin, il existe une restauration de l’activité de la NOS au cours du temps suite à l’introduction d’un traitement antidépresseur. 2) Parmi les métabolites de la voie du NO, les taux plasmatiques de L-Arginine, L-Ornithine et l’ADMA sont significativement plus élevés et ceux de la L-Citrulline significativement diminués chez les sujets dépressifs comparés aux sujets contrôles. On ne retrouve pas de différence significative concernant l’activité de l’arginase. Aucun de ces métabolites n’a montré un caractère prédictif sur la réponse au traitement antidépresseur. Enfin, seuls les taux plasmatiques de la L-Citrulline varient au cours du temps suite à l’introduction d’un traitement antidépresseur. 3) Concernant les protéines de l’inflammation, leurs taux plasmatiques sont significativement augmentés chez les patients dépressifs comparés aux sujets contrôles. Seul le TNF-alpha est significativement associé à la réponse au traitement antidépresseur à 3 mois de traitement. A l’inclusion, les taux plasmatiques des marqueurs de l’inflammation sont associés à l’activité de la NOS. Enfin, on ne retrouve pas d’évolution au cours du temps des marqueurs de l’inflammation quelle que soit la classe d’antidépresseurs évaluée. Conclusion : Ce travail retrouve une diminution de l’activité de la NOS associée à une inflammation de bas grade chez les sujets dépressifs comparés aux sujets contrôles pouvant servir de marqueur prédictif de la réponse au traitement antidépresseur. Cependant, des recherches ultérieures devront être menées pour comprendre s’il existe des liens entre ces différents biomarqueurs et s’ils peuvent être utilisés dans la pratique clinique. La réplication de ces résultats par l’étude à posteriori de biothèques issues d’essais randomisés versus placebo chez des patients présentant un EDC pourrait être une première étape avant la réalisation d’études prospectives randomisées.
Depression is a disorder, which has serious social and economic effects. It is evident that effective treatment helps restore quality of life, as about 50%–60% of patients with depression respond adequately to existing treatments based primarily on the monoaminergic system. However, the neurobiology of depression is not yet fully understood and several preclinical and clinical studies demonstrate the involvement of the glutamatergic system and the l-arginine/NO/cGMP pathway in the pathophysiology of depression. In fact, the N-methyl-d-aspartate receptor (NMDA) is a binding or modulating site for new and classic antidepressants, while various antidepressants also demonstrate altered nitric oxide levels in the body. Given this information, studies with NMDA receptor antagonist molecules and nitric oxide synthase enzyme inhibitors appear as effective possibilities for treating depression. Thus, this chapter will provide an overview of the involvement of NMDA receptors and the l-arginine/NO/cGMP pathway in depression, as well as the mechanisms, which contribute to the antidepressant response.
Carbamazepine, an anticonvulsant drug, has shown
antidepressant effects in clinical and experimental
models. Nitric oxide (NO) is a neurotransmitter in the
central nervous system and has been involved in a
variety of diseases including depression. In the present
study, the involvement of NO/cyclic GMP/KATP channels
pathway in the antidepressant action of carbamazepine
was investigated in mice. The antidepressant-like
activity was assessed in the forced swim test (FST)
behavioral paradigm. Carbamazepine reduced (40mg/
kg, intraperitoneal) immobility period. The antidepressant-
like effect of carbamazepine (40mg/kg, intraperitoneal)
was prevented by pretreatment with L-arginine [substrate
for NO synthase (NOS), 750mg/kg, intraperitoneal],
sildenafil (a PDE-5 inhibitor, 5mg/kg, intraperitoneal) and
diazoxide (K+
channels opener, 10mg/kg). Pretreatment
of mice with L-NAME (a non-selective NOS inhibitor,
10mg/kg, intraperitoneal), methylene blue (direct
inhibitor of both NOS and soluble guanylate cyclase,
10mg/kg, intraperitoneal) and glibenclamide (an ATP-
sensitive K+
channel blocker, 1mg/kg, intraperitoneal)
produced potentiation of the action of a sub-effective
dose of carbamazepine (30mg/kg, intraperitoneal).
Also, carbamazepine (30mg/kg) potentiated the
antidepressant-like effect of fluoxetine through NO
modulation. The various modulators used in the study
did not produce any changes in locomotor activity per se.
The results demonstrated that the antidepressant-like
effect of carbamazepine in the FST involved an interaction
with the NO/cGMP/KATP channels pathway.
Evidences shows a dramatic relationship between depression and alcohol consumption. Depressed patients may abuse ethanol because this agent reduces the symptoms of depression. In current study, we aimed to investigate NMDA/nitric oxide/cGMP pathway in the antidepressant-like effect of ethanol in animal model of behavioral despair. Animals were subjected to locomotor activity in open-field test separately, followed by force swimming test. During forced swimming test (FST), ethanol (2 and 2.5 g/kg) significantly decreased the immobility time without altering the locomotor activity of animals. The antidepressant-like effect of ethanol (2.5 g/kg) was reversed by co-administration of N-methyl-D-aspartate (NMDA, 75 mg/kg), L-arginine (750 mg/kg), or sildenafil (5 mg/kg). Whereas, co-administration of MK-801 (0.05 mg/kg), ketamine (1 mg/kg), ifenprodil (0.5 mg/kg) as antagonists of NMDAR, and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), 7-nitroindazole (7-NI, 30 mg/kg), methylene blue (10 mg/kg) as inhibitors of nitric oxide synthase (NOS), or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (20 mg/kg) a nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) inhibitor, with a subeffective dose of ethanol (1.5 g/kg) significantly decreased the immobility time in FST. Furthermore, injection of ethanol 2.5 g/kg alone or 1.5 g/kg with 7-NI subeffective dose, significantly decreased the nitrite levels in the hippocampus and prefrontal cortex. Hence, it is concluded that blockade of NMDA receptors and nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) pathway might be involved in the antidepressant-like effect of ethanol in mice.
Background
Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment.
Methods
A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response.
Results
Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) −0.084 to −0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58–536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002–0.0067; p = 0.03).
Conclusions
Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.
Objective
The effects of aminoguanidine (AG) were investigated in a rat model of lipopolysaccharide (LPS)-induced anxiety- and depression-like behaviors.
Materials and Methods
The animals were allocated to five groups (n = 10 in each) and treated by: (1) saline as a control group, (2) LPS 1 mg/kg injected two hours before behavioral tests, (3-5) AG 50, 100 or 150 mg/kg before LPS. The open-field test (OFT), elevated plus maze test (EPT), and forced swimming (FS) tests were performed. The brains and blood were then collected to examine oxidative stress and inflammation criteria.
Results
LPS increased the immobility while decreased the active time in the FS test. In EPT, LPS decreased the time spent in the open arms, whereas it increased the time spent in the closed arms. In OFT, LPS decreased the time spent in the central zone compared with the controls. A higher dose of selenium improved the performances of the rats in behavioral tests. LPS injection also increased malondialdehyde (MDA) while it decreased thiol, superoxide dismutase (SOD), and catalase. LPS also increased interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), but decreased IL-10 in the LPS group. AG protected the brain from inflammation and oxidative damage
Conclusion
It was demonstrated that AG improves the behaviors of depression and anxiety in a rat model of LPS-induced anxiety- and depression-like behaviors. Moreover, the effects of AG were accompanied by improved inflammation and oxidative damage biomarkers in brain tissues.
Simvastatin, one of the lipophilic statins, has been shown to be effective in reducing depression in rodents. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of NO-cGMP-K ATP channels pathway and PPARγ using forced swimming test (FST) in mice. In addition, the interaction between simvastatin and fluoxetine as a reference drug was examined. After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin at doses (20, 30, and 40 mg/kg, i.p.) was administrated 30 min before the OFT or FST. To evaluate the involvement of NO-cGMP-K ATP channels pathway, mice were pre-treated intraperitoneally with L-arginine (a nitric oxide precursor, 750 mg/kg), L-NAME (a NOS inhibitor, 10 mg/kg), methylene blue (guanylyl cyclase inhibitor, 20 mg/kg), sildenafil (a PDE-5 inhibitor, 5 mg/kg), glibenclamide (ATP-sensitive K ⁺ channel blocker, 1 mg/kg), and diazoxide (K ⁺ channels opener, 10 mg/kg). Moreover, to clarify the probable involvement of PPARγ receptors, pioglitazone, a PPARγ agonist (5 mg/kg, i.p.), and GW9662, a PPARγ antagonist (2 mg/kg, i.p.), were pre-treated with simvastatin. Immobility time was significantly decreased after simvastatin injection. Administration of L-NAME, methylene blue, glibenclamide and pioglitazone in combination with the sub-effective dose of simvastatin (20 mg/kg, i.p.) reduced the immobility time in the FST compared to drugs alone, while co-administration of effective doses of simvastatin (30 mg/kg, i.p.) with L-arginine, sildenafil, diazoxide, and GW9662 prevented the antidepressant-like effect of simvastatin. In addition, simvastatin (20 mg/kg) potentiated the antidepressant-like effect of fluoxetine through the NO pathway. None of the drugs produced any significant alterations in locomotor activity using OFT. These results demonstrated that NO-cGMP-K ATP channels pathway and PPARγ receptors may be involved in the antidepressant-like effect of simvastatin.
Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders.
Lithium is still the main agent in the management of mood disorders such as depression. Likewise, agmatine protects the central nervous system (CNS) against depression. The aim of the present study was to examine the possible additive antidepressant-like effect of agmatine and lithium in mice forced swim test (FST) as well as exploration of the probable involvement of nitric oxide (NO) pathway in this response. Results showed that pretreatment with a subeffective dose of agmatine (0.01 mg/kg) augmented the antidepressant-like effect of lithium subeffective dose (3 mg/kg) (P < 0.001). L-NG-nitroarginine methyl ester (L-NAME, nonspecific nitric oxide synthase [NOS] inhibitor) at doses of 10 and 30 mg/kg, and 7-nitroindazole (7-NI, neuronal NOS inhibitor) at doses of 15 and 30 mg/kg potentiated the antidepressant-like effect of the subeffective combination of lithium (3 mg/kg) and agmatine (0.001 mg/kg) (P < 0.001, P < 0.01, respectively). However, various doses of aminoguanidine (25 and 50 mg/kg, inducible NOS inhibitor) failed to alter the immobility time of the same combination (P > 0.05). Moreover, pretreatment with subeffective doses of L-arginine (substrate for NOS, 300 and 750 mg/kg) reversed the augmenting antidepressant-like effect of agmatine (0.01 mg/kg) on lithium (3 mg/kg) (P < 0.001). Our results revealed that agmatine enhances the antidepressant-like effects of lithium and the NO pathway might mediate this phenomenon. In addition, constitutive NOS plays a dramatic role in this response.
Hemerocallis citrina Baroni (Liliaceae), a Liliaceae plant, has been widely used in food and traditional medicine. This study investigated the safety of ethanol extracts from Hemerocallis citrina (HCE) after oral treatment (p.o.) and evaluating the anti-inflammatory mechanism of HCE in a lipopolysaccharide (LPS)-induced depressive-like model. First, in an 8-week experimental procedure, blood and tissue samples collected from mice were used for biochemical and histopathological analysis every two weeks. Neither the body weight nor relative organ weights were affected by HCE administration. Only the total cholesterol levels were decreased by HCE administration. Histopathological analysis showed no significant liver and kidney changes caused by HCE. In addition, in an LPS-induced mouse depressive-like model, HCE significantly reversed the reduction of sucrose preference with LPS. The results also indicated that LPS activated the nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the prefrontal cortex. In contrast, these activations were normalized by HCE pretreatment. In summary, our study provided essential evidence for the safety of Hemerocallis citrina in both food and medicine. The results also demonstrated that HCE exhibited antidepressant-like effects that might be related to inhibition of the NF-κB signaling pathway.
There is an increasing interest in natural antioxidants that are candidates for prevention of brain damage occurring in major depressive disorders. Cecropia pachystachya is a tropical tree species of Central and South America and is a rich source of polyphenols, especially flavonoids. The aim of this study was to characterize the flavonoid profile of an enriched flavonoid fraction of C. pachystachya (EFF-Cp) and evaluate the antidepressant-like effects of its acute administration in behavior, cytokine levels, oxidative stress and energy metabolism parameters. The EFF-Cp chemical characterization was performed by HPLC/DAD and LC/QTOF. The antidepressant-like effects were performed by forced swimming test (FST), splash test and open field test. EFF-Cp showed 15 flavonoids, including 7 new glycosyl flavonoids for C. pachystachya. Quantitatively EFF-Cp showed isoorientin (43.46?mg/g), orientin (23.42?mg/g) and isovitexin (17.45?mg/g) as major C-glycosylflavonoids. Also, EFF-Cp at the dose of 50?mg/kg and 100?mg/kg reduced the immobility time in FST, without changing the locomotor activity and grooming time. In addition, EFF- Cp was able to prevent the oxidative damage in some brain areas. In conclusion, the results of this study suggest that enriched C-glycosyl flavonoid fraction of Cecropia pachystachya (EFF- Cp) exerts antidepressant-like effects by its antioxidant properties.
The pathogenesis of mood disorders remains elusive, but it is evident that multiple factors, genetic and environmental, play a crucial role for adult psychopathology and neurobiology. With regard to therapy, a significant proportion of affective disorder patients are partial or nonresponders, and there has been no major breakthrough in finding novel effective drug targets since the introduction of the current marketed antidepressant drugs in the 1950s to the 1980s, which all are based on monoaminergic pharmacological effects. Consequently, there exists a pressing need to develop novel treatment strategies – and ultimately understand the etiology and pathophysiology of affective disorders.
Nitric oxide serves an important role in the nervous system, where it acts as a messenger molecule in a number of physiological processes, including processes being linked to the major psychiatric diseases. This chapter will review general aspects of the NO system in major depressive disorder (MDD), as well as focus on the inhibition of NO production as putative therapeutic agents toward depression.
The activation of NMDA receptors is capable of increasing nitric oxide (NO) synthesis in the brain. The administration of NMDA antagonists (e.g., ketamine) or nitric oxide synthesis inhibitors (e.g., 7-NI) produce antidepressant-like effects in animals and highlights the potential of glutamatergic and nitrergic systems as
therapeutic targets for the treatment of major depression. The involvement of intracellular mechanisms associated to neural plasticity, such as BDNF-TrkBmTOR pathway, has been implicated in the antidepressant-like effects induced by systemic administration of NMDA antagonists. For instance, the antidepressant effects of ketamine are associated with increased BDNF synthesis and mTOR in the medial prefrontal cortex (vMPFC). In addition, injection of an NMDA antagonist (LY235959) into the vMPFC-PL produces antidepressant-like effect in animals. However, it is not yet known if the aforementioned antidepressant-like effects involve the modulation of NO synthesis or the activation of the BDNF-TrkB-mTOR pathway in the vMPFC. Therefore, this work investigated the involvement of glutamatergic and nitrergic neurotransmission of the vMPFC, as well as the participation of local BDNF-TrkBmTOR pathway, in the modulation of behavioral responses of animals submitted to forced swimming test, an animal model predictive of antidepressant effects. The administration of nNOS inhibitor (NPA), sGC inhibitor (ODQ) or NO scavenger (c-PTIO) into the vMPFC-PL produced antidepressant-like effects, similarly to what has been previously described with the local injection of LY235959. The effects of LY235959 were blocked by pretreatment with an antagonist of AMPA receptors (NBQX), but not the NPA effects. Thus suggesting a possible dissociation between NMDA- and NO-induced mechanism in the PL. BDNF administration in the PL induced antidepressant-like effect, which was blocked by prior administration of the TrkB receptor antagonist (K252a) or the mTOR inhibitor (rapamycin). The antidepressant-like effects induced by intra-PL administration of LY235959 and NPA, into vMPFC-PL were not altered in the presence of K252a. However, the prior administration of rapamycin was able to block the effects of LY235959, but not NPA-induced effect. This result further supports the dissociation of the NMDA-NO system in the PL in the modulation of immobility in the FST. Systemic treatment with ketamine (NMDA antagonist) or 7-NI (nNOS inhibitor) produced antidepressant-like effects in the FST, although these treatments did not affect the activation or the expression of TrkB receptors or mTOR in the MPFC of stressed animals. These results further corroborate the involvement of the glutamatergic and nitrergic neurotransmission in the modulation of behavioral consequences of the forced swim stress and highlight that the interaction of these systems with mTOR and trkB in the PL is considerably complex. Altogether, our data supports the possible modulation of BDNF-TrkBmTOR pathway of the PL in the effects induced by NMDA antagonist injection. However, the effects induced by inhibitors of the NO pathway semms dissociated from an interaction with the aforementioned pathway. Thus, further studies are necessary to clarify the interaction of glutamatergic and nitrergic neurotransmission with BDNF-TrkB-mTOR pathway into vMPFC-PL regarding the neurobiology of stress and depression.
Depression has become a common illness among individuals of every age group. Among numerous factors held responsible for depression stress is most vital. Behind the specified disorder various hypothesis has been laid out where Nitric Oxide is emerging target to treat stress induced depression. Antidepressant potential of piperine in stressed and unstressed condition was evaluated using tail suspension test and forced swim test whereas locomotor activity was evaluated by actophotometer. Results of the present study indicate the potential of antidepressant effect of piperine in stress. Methylene blue potentiated the effect of sub- effective dose of PP and SB-203580 enhanced effect of Piperine in stressed mice with no array on locomotor activity with direct influence on Nitric oxide. Piperine produced significant changes in Nitric oxide level which is pathophysiologic mediator(s) of depression, which validate the action of piperine on depression symptoms.
We studied the effects of nitric oxide (NO)-producing agents on N-methyl-D-aspartate (NMDA) receptor activation in cultured neurons. 3-Morpholino-sydnonimine (SIN-1) blocked both NMDA-induced currents and the associated increase in intracellular Ca2+. The actions of SIN-1 were reversible and suppressed by hemoglobin. A degraded SIN-1 solution that did not release NO was unable to block NMDA receptors. This showed that the SIN-1 effects were due to NO and not to another breakdown product. Similar results were obtained with 1-nitrosopyrrolidine (an NO-containing drug) and with NO released from NaNO2. Pretreatment with hemoglobin potentiated NMDA-induced effects, demonstrating that endogenous NO modulates NMDA receptors. Since NMDA receptor activation induces NO synthesis, these results suggest a feedback inhibition of NMDA receptors by NO under physiological condition.
Inescapable, but not escapable, stress inhibits the induction of Long Term Potentiation (LTP) in the CA1 region of hippocampus, a process that is dependent upon activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Since inescapable stress also produces a syndrome of behavioral depression sensitive to clinically effective antidepressants, we examined the actions of functional antagonists at the NMDA receptor complex in animal models commonly used to evaluate potential antidepressants. A competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid [AP-7]), a non-competitive NMDA antagonist (Dizolcipine [MK-801]), and a partial agonist at strychnine-insensitive glycine receptors (1-aminocylopropanecarboxylic acid [ACPC]) mimicked the effects of clinically effective antidepressants in these models. These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.
The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg-1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19-27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood-brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.
MK-801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever-pressing by unaviodable shock and (2) a simple conflict test in water-deprived animals that were shocked for licking water. The effect of MK-801 in both procedures was qualitatively similar to the benzodiazepines. Lever-pressing in the CER test was increased by MK-801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK-801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK-801 was without anticonflict activity when administered 1 hour prior to study.
In squirrel monkeys trained in a response-contingent conflict paradigm, a specific anticonflict effect for MK-801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK-801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK-801.
The mode of action for the antipunishment effect of MK-801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK-801 and chlordiazepoxide. In vitro, MK-801 was inactive (IC50 > 2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB-4101, dihydroalprenolol, QNB, and 2-chloroadenosine). An increase in 3H-diazepam binding in vitro in rat brain tissue was detected following acute, but not chronic, treatment in vivo with MK-801.
Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
A MAJOR problem in the search for new antidepressant drugs is the lack
of animal models which both resemble depressive illness and are
selectively sensitive to clinically effective antidepressant treatments.
We have been working on a new behavioural model in the rat which
attempts to meet these two requirements. The method is based on the
observation that a rat, when forced to swim in a situation from which
there is no escape, will, after an initial period of vigorous activity,
eventually cease to move altogether making only those movements
necessary to keep its head above water. We think that this
characteristic and readily identifiable behavioural immobility indicates
a state of despair in which the rat has learned that escape is
impossible and resigns itself to the experimental conditions. This
hypothesis receives support from results presented below which indicate
that immobility is reduced by different treatments known to be
therapeutic in depression including three drugs, iprindole, mianserin
and viloxazine which although clinically active1-3 show
little or no `antidepressant' activity in the usual animal
tests4-6.
The present study examined the effects of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test in rats and mice. Administered in a single dose or three times both examined compounds reduced the immobility time in rats. Active doses used in that test either did not change the locomotor activity or decreased it. A similar effect in both tests was shown by active (R)-enantiomers CGP 40116 and CGP 43487. Reduction of the immobility time induced by CGP 37849 and CGP 39551 in the forced swimming test in rats was antagonized by haloperidol and (+/-)-sulpiride, but not by SCH 23390 or prazosin. CGP 37849, but not CGP 39551, also reduced the immobility time in the forced swimming test in mice. The results obtained indicate that CGP 37849 and CGP 39551 induce an antidepressant-like effect in the forced swimming test, probably via an indirect dopamine activation resulting from blockade of NMDA receptors.
Nitric oxide (NO) is an important messenger both systemically and in the CNS. In digital Ca2+ imaging and patch-clamp experiments, clinically available nitroso compounds that generate NO are shown to inhibit responses mediated by the NMDA subtype of the glutamate receptor on rat cortical neurons in vitro. A mechanism of action for this effect was investigated by using the specific NO-generating agent S-nitrosocysteine. We propose that free sulfhydryl groups on the NMDA receptor-channel complex react to form one or more S-nitrosothiols in the presence of NO. If vicinal thiol groups react in this manner, they can form a disulfide bond(s), which is thought to constitute the redox modulatory site of the receptor, resulting in a relatively persistent blockade of NMDA responses. These reactions with NO can afford protection from NMDA receptor-mediated neurotoxicity. Our results demonstrate a new pathway for NO regulation of physiological function that is not via cGMP, but instead involves reactions with membrane-bound thiol groups on the NMDA receptor-channel complex.
When slices of young rat hippocampus were exposed briefly (2 min) to N-methyl-D-aspartate (NMDA), a rise in the levels of cyclic GMP took place. This response was dependent on NMDA concentration (EC50 approximately 30 microM) and the maximal elevations exceeded the unstimulated levels by 25-fold. The response to 100 microM NMDA was inhibited by two competitive antagonists of the conversion of arginine to nitric oxide, L-NG-methylarginine and L-NG-nitroarginine (IC50 approximately 6 microM and 100 nM respectively). The inhibitions produced by both antagonists were reduced or abolished when the incubation medium was supplemented with L-arginine (100-300 microM). Slices of adult hippocampus produced smaller increases (5-fold) in cyclic GMP levels in response to 100 microM NMDA than those found in the immature tissue, but the response could similarly be inhibited by NG-methylarginine. The results indicate that NMDA receptor activation in the hippocampus induces the generation of nitric oxide from arginine and that this novel intercellular messenger mediates the increases in cyclic GMP levels.
Nitric oxide (NO) is a recently discovered and highly unorthodox messenger molecule. Current evidence indicates that, in the CNS, NO is produced enzymatically in postsynaptic structures in response to activation of excitatory amino acid receptors. It then diffuses out to act on neighbouring cellular elements, probably presynaptic nerve endings and astrocyte processes. In several peripheral nerves, and quite possibly in parts of the CNS as well, NO might be formed presynaptically and thus act as a neurotransmitter. In both cases, a major action of NO is to activate soluble guanylate cyclase and so raise cGMP levels in target cells.
In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.
Compounds that antagonize neuronal excitation induced by dicarboxylic amino acids were tested in two animal models of epilepsy, namely sound-induced seizures in DBA/2 mice and threshold pentylenetetrazol seizures in Swiss mice. Sound-induced seizures could be prevented by intracerebroventricular injection of compounds that block excitation due to N-methyl-D-aspartic acid. The most potent such compound, 2-amino-7-phosphonoheptanoic acid, was anticonvulsant in both test systems when given either intraperitoneally or intracerebroventricularly. Specific antagonists of excitation that is caused by amino acids provide a new class of anticonvulsant agents.
7-Nitro indazole (7-NI) inhibits rat striatal, cerebellar, hippocampal, cerebral cortex and olfactory bulb nitric oxide synthase (NOS) in vitro with IC50 values of 0.68 +/- 0.01 microM, 0.64 +/- 0.03 microM, 1.53 +/- 0.05 microM, 0.93 +/- 0.04 microM and 1.05 +/- 0.02 microM respectively (n = 6). Intraperitoneal (i.p.) or oral administration of 7-NI (30 mg kg-1) to rats inhibited NOS enzyme activity measured ex vivo in all five brain regions (n = 5-6). NOS inhibition (maximal effect, 0.5 h post-injection) was transient with complete recovery at either 4 h (oral administration) or 24 h (i.p. administration). Repeated i.p. injection of 7-NI (30 mg kg-1, every 4 h for 20 h) inhibited NOS enzyme activity at 24 h by 51-61% in all brain regions. The relatively transient NOS inhibitory effect of 7-NI following parenteral administration should be taken into account when using this drug to evaluate the central effects of nitric oxide.
Although originally developed as a possible screen for antidepressants, the Porsolt forced swimming test has more recently been extensively used as a model for studying the involvement of the endocrine system in the acquisition and retention of behavioural responses. In previous studies we have shown that while adrenalectomised rats acquire the immobile response normally, they are unable to retain it on retest next day. In the present study we show that retention of the immobile response in the Porsolt swim test is impaired in intact rats given the nitric oxide (NO) inhibitor L-N-arginine methyl ester (L-NAME), in a dose- and time-dependent manner. At a dose of 50 mg/kg levels of immobility are similar to those in adrenalectomised animals, an effect reversed by the simultaneous administration of L-arginine (50 mg/kg). L-Arginine also reverses the behavioural effect of adrenalectomy, and L-NAME blocks the ability of dexamethasone or the kappa-selective opioid ketocyclazocine to reverse the effect of adrenalectomy on retention of the immobile response. We conclude that the kappa-opioid and glucocorticoid mediated pathways previously shown to independently facilitate retention are mediated by nitric oxide.
The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.
Nitric oxide signalling in the central nervous system
- J Boulton
- Cl
J, Boulton CL (1995) Nitric oxide signalling in the central nervous system. Annu Rev. Physiol. 57:683–706