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The role of norepinephrine at synapses. Norepinephrine is synthesized in a multistep process. Tyrosine is converted to L-DOPA via the activity of tyrosine hydroxylase (TH). L-DOPA is then decarboxylated via DOPA decarboxylase into dopamine. Dopamine via dopamine betahydroxylase (DBH) is then converted to norepinephrine (NE). NE is released at synapses where it can bind to α-adrenergic receptors or β-adrenergic receptors on postsynaptic neurons to modulate neuronal firing or modulate adrenergic neurons signaling. NE excess can be eliminated via the activity of monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). NE can also be recycled back to presynaptic neurons via the NE transporters (NET).
Source publication
Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer’s disease. Cholinergic neurons are widely distributed in brain regions that pl...
Contexts in source publication
Context 1
... noradrenergic system regulates many physiological processes such as visceral, cognitive, behavioral, motor control, and attention [80]. Figure 2 illustrates the role of NE in the brain at synapses. ...
Context 2
... noradrenergic system regulates many physiological processes such as visceral, cognitive, behavioral, motor control, and attention [80]. Figure 2 illustrates the role of NE in the brain at synapses. Figure 2. The role of norepinephrine at synapses. ...
Similar publications
RationaleIn addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine...
Citations
... Disturbances in the cholinergic system are also thought to account for neuronal and cognitive deficits in neurological diseases such as Alzheimer's, although the cholinergic alterations in Co-induced neurotoxicity have not been fully described. Patients with Alzheimer's disease have been shown to exhibit severe degeneration of cholinergic neurons and deficiency of acetylcholine (Ach), an excitatory neurotransmitter involved in cognition, memory and learning [12]. The amounts of Ach available in cholinergic neurons is regulated by enzymes including choline acetyl transferase (ChAT) and acetylcholinesterase (AchE) which modulate the synthesis and degradation of Ach, respectively. ...
Cobalt (Co) toxicity has been reported to produce central nervous system and gastrointestinal abnormalities. This study assessed the therapeutic effect of cholecalciferol (Cho) supplementation against damages caused by sub-acute (14-day) cobalt chloride (CoCl2) exposure in the brain and intestines. Thirty-five male Wistar rats were divided equally into five groups: Group I (control) received no treatment; Group II received oral CoCl2 (100 mg/kg) only; Groups III, IV, and V received 1000, 3000 and 6000 IU/kg of cholecalciferol, respectively by oral gavage, and concurrently with CoCl2. Cobalt-treated rats showed neuronal vacuolation and presence of pyknotic nuclei in the cerebral cortex and hippocampus, depletion of Purkinje cells in the cerebellum, as well as inflammation and congestion in the intestinal mucosa. Cobalt also increased brain and intestinal hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations, while simultaneously reducing glutathione (GSH) content, superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities. Further, CoCl2 induced increases in brain acetylcholinesterase (AchE) activity and serum zonulin (ZO-1) levels. Conversely, Cho administration suppressed CoCl2-induced damages in the brain and intestines by reducing lipid peroxidation and increasing the activities of antioxidant enzymes. Remarkably, Cho produced stimulation of brain choline acetyltransferase (ChAT) and suppression of AchE activity, along with dose-dependent reduction in serum levels of ZO-1, intestinal fatty acid-binding protein (iFABP) and nitric oxide. In conclusion, the protective role of cholecalciferol against cobalt-induced toxicity occurred via modulation of cholinergic, intestinal permeability and antioxidant pathways. The results may prove significant in the context of the role of gut-brain connections in neuroprotection.
... Acetylcholine is an excitatory neurotransmitter that is involved in memory performance and other higher-order EFs. By regulating acetylcholine synthesis and release, the central cholinergic nervous system controls acetylcholine levels [48]. In the case of the early loss of BF neurons, the cholinergic control balance in microglia may be disrupted, resulting in the overabundance of proinflammatory activated microglia. ...
Purpose
We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients’ apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed.
Methods
Structural magnetic resonance imaging data were collected. Patients’ demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients’ neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance.
Results
Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R² = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R² = 0.095 and 0.042 for EMCI and LMCI, respectively) function.
Conclusions
Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.
... Acetylcholinesterase inhibitors are associated with improved cognition in these patients, confirming the cholinergic hypothesis in AD pathology. Also, nicotinic and muscarinic receptors for acetylcholine are low in AD patients [37]. ...
... Basic forebrain cholinergic neurons (BFCNs) are a key component of the cholinergic system and are involved in learning and memory abilities of the brain. Moreover, BFCNs are the main source of acetylcholine (ACh)-a major excitatory neurotransmitter in the central cholinergic nervous system [5,8]. Based on recent clinical data, AD patients exhibited degeneration and reduction of cholinergic neurons, and severe ACh deficiency, which ultimately leads to the development of abnormal phosphorylation of tau protein, inflammation of nerve cells, cell death, and other pathological phenomena [5]. ...
Alzheimer’s disease (AD) is a chronic disease that is multifactorial. Its underlying cause and mechanisms are yet to be fully understood and numerous research are underway to develop more effective drug candidates. This research explores the synthesis of an indazole-containing novel drug targeting AD, particularly by inhibiting cholinesterase activity. Among the 17 indazole derivatives synthesized in this study, compound 4q was demonstrated to have potent and selective butyrylcholinesterase (BChE) inhibitory activity. Molecular docking simulations revealed that the binding of 4q with BChE was through hydrophobic and polar interactions. It was also found to easily permeate through the blood-brain-barrier via an in vitro model and is non-toxic when tested against SH-SY5Y cells.
... В мозге существует большое количество нейротрансмиттеров, но важнейшим из них является ацетилхолин, так как он отвечает за возбуждение одноименных нейронов в переднем мозге и гиппокампе, которые отвечают за обучение и память. Эти два отдела мозга связаны между собой синаптическими связями, которые в зависимости от стадии деменции могут утрачиваться, что приводит к ухудшению памяти [10,17]. Важной задачей является поддерживание высокого уровня ацетилхолина на высоком уровне, что обеспечивается приемом антихолинэстеразных лекарственных средств, таких как: ривастигмин, галантамин и донепезил. ...
Currently, about 50 million people suffer from Alzheimer's disease, and this number will only increase over time. There are only four clinically approved drugs to treat this pathology, which include acetylcholinesterase inhibitors (Rivastigmine, Donepezil, and Galantamine) and one N-methyl-D-aspartic acid receptor antagonist (memantine). Although these drugs have a therapeutic effect by improving the cognitive, functional, and behavioral characteristics of patients, they still relieve symptoms of the disease rather than manifest the links of pathogenesis, including -amyloid precursor protein and hyperphosphorylated tau protein formed during the cleavage of amyloid precursor protein. This group of drugs also has a number of undesirable effects on the gastrointestinal tract, cardiovascular system and nervous activity. In this regard, new drugs are being developed now, directed against -amyloid and affecting to reduce its production, aggregation, not allowing it to form plaques, the use of immunization method. There is also hyperphosphorylated tau protein, which is either not allowed to form or is immunized against. In addition to these methods, there are no less interesting ways to fight, such as the use of heat shock inducers, to activate the necessary chaperone family, or to reduce neuroinflammation by inhibiting tumor necrosis factors and using nutraceuticals. But, unfortunately, a large number of drugs cannot yet pass all 3 stages of clinical trials while maintaining their original therapeutic properties and without acquiring undesirable effects. That said, many drugs are either the basis for future drugs or are still participating in clinical trials themselves, showing encouraging results.
... Cholinergic dysfunction is one of the key pathological features of AD. The neurotransmitter acetylcholine (ACh) is generally involved in various cognitive processes, including attention, learning, and memory [5,6]. The neurotransmitter ACh hydrolysis through the action of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). ...
... Intermediate 5 was prepared by the reaction of compound 3 with pyridin-3-ylmethanamine (4) in the presence of N,Ndiisopropylethylamine (DIPEA) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3tetramethyluronium tetrafluoroborate (TBTU) in DMF. Compound 7a-s was also obtained by the reaction of 2-aryl-N-(pyridin-3-ylmethyl)quinoline-4-carboxamide (5) with alkyl/aryl halide (6) in acetonitrile at room temperature. FTIR, 1 H NMR, 13 C NMR, and elemental analysis characterized all synthesized compounds. ...
... Brown solid; Yield: 93 %; MP = 218-220 • C IR (KBr, v max ) 3300 (NH), 3020 (CH Aromatic), 2975 (CH Aliphatic) 1675 (C=O) Cm − 1 ; 1 H NMR (400 MHz, DMSO-d 6 6.01 (s, 2H, CH 2 ), 4.84 (d, J = 5.6 Hz, 2H, CH 2Amide ), 3.87 (s, 3H, OMe). 13 13 ...
Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Unfortunately, there is no effective treatment for this condition, so there is a growing interest in developing new anti-AD agents. In this research project, a series of phenyl-quinoline derivatives were designed as potential anti-AD agents. These derivatives were substituted at two different positions on benzyl and phenyl rings. The structures of the derivatives were characterized using techniques such as IR spectroscopy, 1 H NMR, 13 C NMR, and elemental analysis. During the in vitro screening, the derivatives were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was observed that most of the derivatives showed higher selectivity against BChE compared to AChE. Among the derivatives, analog 7n (with a methoxy group at R 1 and a 4-bromine substituent at R 2 exhibited the highest potency, with a 75-fold improvement in the activity compared to the positive control. Importantly, this potent analog demonstrated no toxicity at the tested concentration on SH-SY5Y cells, indicating its potential as a safe anti-AD agent. The level of GSK-3β was also reduced after treatments with 7n at 50 μM. Overall, this study highlights the design and evaluation of phenyl-quinoline derivatives as promising candidates for developing novel anti-AD agents.
... BuChE is a non-selective cholinesterase that can degrade ACh and butyrylcholine, making it a substitute for AChE, which specifically catalyzes ACh. Normal cholinergic signal transduction related to learning and memory depends on ACh [26,27], and one of the hallmarks of AD is ACh deficiency [24]. The use of cholinesterase inhibitors (AChEIs) can increase the concentration of ACh and are currently the only clinical drugs approved for the therapy of AD patients [28]. ...
This study assessed the halophyte species Limonium spathulatum (Desf.) as a possible source of natural ingredients with the capacity to inhibit enzymes related to relevant human health disorders and food browning. Extracts using food-grade solvents such as water and ethanol were prepared by maceration from dried L. spathulatum leaves. They were evaluated for in vitro inhibition activity of enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), α-glucosidase, tyrosinase and lipase, related to Alzheimer’s disease, type-2-diabetes mellitus, skin hyperpigmentation, and obesity, respectively. These extracts were also appraised for in vitro acute toxicity on tumoral and non-tumoral cell lines and their chemical composition by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS). The extracts were more effective towards BChE than AChE. The best results were obtained with the hydroethanolic and water extracts, with IC50 values of 0.03 mg/mL and 0.06 mg/mL, respectively. The hydroethanolic extract had the highest capacity to inhibit α-glucosidase (IC50: 0.04 mg/mL), higher than the positive control used (acarbose, IC50 = 3.14 mg/mL). The ethanol extract displayed the best inhibitory activity against tyrosinase (IC50 = 0.34 mg/mL). The tested samples did not inhibit lipase and exhibited low to moderate cytotoxic activity against the tested cell lines. The hydroethanolic extract had a higher diversity of compounds, followed by the ethanol and water samples. Similar molecules were identified in all the extracts and were mainly hydroxybenzoic acids, hydroxycinnamic acids, and flavonoids. Taken together, these results suggest that L. spathulatum should be further explored as a source of bioactive ingredients for the food, cosmetic, and pharmaceutical industries.
... The pathophysiological mechanisms leading to its onset are not certain. Cumulative evidence indicates that neurotransmitter dysfunction, an event that occurs in the initial stages of the disease, might lead to memory loss and accumulation of pathological proteins [51]. Degeneration of LC neurons and their noradrenergic projections to the neocortex and hippocampus occurs already in MCI patients, and this loss intensifies with the progression of the disease [17,19,52,53]. ...
Simple Summary
Noradrenaline is a crucial neurotransmitter produced by a group of neurons in the locus coeruleus and plays a significant role in regulating various physiological processes, including attention, arousal and stress responses. Alzheimer’s disease is a progressive and devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation in the brain of abnormal protein aggregates, such as amyloid-beta, tau and TDP-43, leading to the deterioration of neurons and cognitive decline. Studies have shown that the noradrenergic system is severely affected by Alzheimer’s disease. This depletion of noradrenaline levels has been associated with the cognitive decline and behavioral symptoms observed in Alzheimer’s patients. In this study, we showed that administering increasing doses of a selective noradrenergic immunotoxin caused dose-dependent working memory impairments and accumulation of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217 in the cortex and hippocampus of developing rats. These findings suggest that boosting noradrenergic activity may have beneficial effects on cognitive functions and slow down disease progression. However, further research is needed to fully comprehend the complex relationship between noradrenaline, cognitive function and the aberrant accumulation of proteins in Alzheimer’s disease and to develop effective treatments based on these findings.
Abstract
Noradrenaline (NA) depletion occurs in Alzheimer’s disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.
... Effective therapies for AD, either to prevent or mitigate its symptoms [61], are still notoriously absent or scarce. The pharmacological therapies that are currently available can be categorized according to their main aim, i.e., whether they purport to prevent/delay disease onset and progression or to mitigate symptoms. ...
Alzheimer disease (AD) is the most prevalent form of dementia among elderly people. Owing to its varied and multicausal etiopathology, intervention strategies have been highly diverse. Despite ongoing advances in the field, efficient therapies to mitigate AD symptoms or delay their progression are still of limited scope. Neuroplasticity, in broad terms the ability of the brain to modify its structure in response to external stimulation or damage, has received growing attention as a possible therapeutic target, since the disruption of plastic mechanisms in the brain appear to correlate with various forms of cognitive impairment present in AD patients. Several pre-clinical and clinical studies have attempted to enhance neuroplasticity via different mechanisms, for example , regulating glucose or lipid metabolism, targeting the activity of neurotransmitter systems, or addressing neuroinflammation. In this review, we first describe several structural and functional aspects of neuroplasticity. We then focus on the current status of pharmacological approaches to AD stemming from clinical trials targeting neuroplastic mechanisms in AD patients. This is followed by an analysis of analogous pharmacological interventions in animal models, according to their mechanisms of action.
... pH plays an important role in maintaining the proper conformation of an enzyme because enzyme activity is dependent on the ionization state of the amino acids in the active site. 35 The influence of the pH on the I p was investigated in a series of 10 mM PBS (pH from 5.0 to 8.0) including 2.0 μM ACh. As can be seen from Fig. 3C the maximum value of the I p was at pH 7.0. ...
This work offered an electrochemical biosensor for acetylcholine (ACh) detection using the bi-enzyme functionalized nanofiber composites-modified glassy carbon electrode (GE). The nanofiber composites (AuNPs@GCS) prepared by electrospinning and electrodeposition techniques, were systematically characterized from micromorphology, active groups, actual areas, and impedance, and were used to simultaneously decorate the acetylcholinesterase (AChE) and choline oxidase (ChOx). Bi-enzyme functionalized AuNPs@GCS (AChE-ChOx/AuNPs@GCS) electrode demonstrated superior loading capacity and stability, and when used for ACh analysis, the detection limit was 0.067 nM, outperforming previous sensors for linear range and LOD. After systematic methodological evaluation and feasibility verification, this biosensor had good stability, specificity, and reproducibility. In human serum samples, the results detected by the biosensor were compared with results tested by Enzyme-linked immunosorbent assay. T test was performed for statistical comparisons and p value more than 0.05 was considered no statistical significance. It indicated that this biosensor had a good application prospect in the ACh actual sample detection. This work also provided an efficient and accurate method for quantitative detection of neurotransmitters in complex biological samples.
