Effects Of NMDA Receptor Antagonists Research Articles

Low-Affinity NMDA Receptor Antagonist Hemantane in a Topical Formulation Attenuates Arthritis Induced by Freund's Complete Adjuvant in Rats.

N-methyl-D-aspartate (NMDA) receptors that are expressed by T-cells modulate T-cell proliferation, cytotoxicity and cell migration toward chemokines. Several studies have shown an anti-inflammatory effect of NMDA receptor antagonists. This study compares the effect of the noncompetitive low-affinity NMDA receptor antagonist N-(2-adamantyl)-hexamethyleneimine hydrochloride (hemantane) in a topical formulation (gel) with the cyclooxygenase (COX) inhibitor diclofenac in a topical formulation (gel) in rats with arthritis induced by Freund's Complete Adjuvant (FCA). On day 14 after an FCA injection into the left hind paw, rats with contralateral hind paw edema were selected for further investigation (29/65). They were treated with 5% hemantane gel or 1% diclofenac gel applied locally to hind paws daily for 2 weeks starting 14 days after the FCA injection. Rats with arthritis were examined hind paw edema, hyperalgesia, and motor deficits; their body weight and hematological parameters were recorded. The rats were euthanized on day 28, followed by histological examination of the ankle joint (HE stain). Rats with arthritis exhibited hind paw inflammation and hyperalgesia, motor deficits, changes of hematological parameters, reduced weight gain and spleen hypertrophy. Histological examination of the ankle joint revealed degenerative-dystrophic lesions of the cartilaginous tissue, proliferative inflammation of the synovium, edema and lymphocytic/macrophage infiltration of periarticular tissues. Hemantane gel reduced hind paw edema, pain, motor deficits and histological signs of inflammation; its effect was comparable to diclofenac gel. Hemantane gel alleviates FCA-induced arthritis in rats, and its effect is comparable to diclofenac gel.

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells.

Type 2 diabetes mellitus (T2DM) remains one of the most pressing health issues facing modern society. Several antidiabetic drugs are currently in clinical use to treat hyperglycaemia, but there is a need for new treatments that effectively restore pancreatic islet function in patients. Recent studies reported that both murine and human pancreatic islets exhibit enhanced insulin release and β-cell viability in response to N-methyl-D-aspartate (NMDA) receptor antagonists. Furthermore, oral administration of dextromethorphan, an over-the-counter NMDA receptor antagonist, to diabetic patients in a small clinical trial showed improved glucose tolerance and increased insulin release. However, the effects of NMDA receptor antagonists on the secretion of the incretin hormone GLP-1 was not tested, and nothing is known regarding how NMDA receptor antagonists may alter the secretion of gut hormones. This study demonstrates for the first time that, similar to β-cells, the NMDA receptor antagonist MK-801 increases the release of GLP-1 from a murine L-cell enteroendocrine model cell line, GLUTag cells. Furthermore, we report the 3′ mRNA expression profiling of GLUTag cells, with a specific focus on glutamate-activated receptors. We conclude that if NMDA receptor antagonists are to be pursued as an alternative, orally administered treatment for T2DM, it is essential that the effects of these drugs on the release of gut hormones, and specifically the incretin hormones, are fully investigated.

Effects of NMDA receptor antagonists on behavioral economic indices of cocaine self-administration

BackgroundCurrently, there are no FDA-approved medications for the treatment of psychostimulant (e.g., cocaine) use disorders. Because the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor is an important mediator of addiction-like behaviors, the goal of the current study was to determine if the GluN2B-selective antagonist Ro 63–1908 is efficacious in attenuating cocaine self-administration. MethodsAdult Sprague Dawley rats (24 males and 11 females) were implanted with indwelling catheters and were trained to self-administer cocaine (0.75 mg/kg/inf). Rats were then trained in a threshold procedure, in which the dose of cocaine decreased across six 6-min blocks (0.75, 0.27, 0.08, 0.03, 0.01, 0.003 mg/kg/inf). This procedure allowed for the quantification of behavioral economic indices of drug self-administration. Following training in the threshold procedure, rats were treated with the GluN2B-selective antagonist Ro 63–1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Rats also received treatments of the NMDA receptor channel blocker MK-801 (0, 0.01, 0.03, 0.06 mg/kg; s.c.). ResultsBlocking NMDA receptors decreased initial intake (i.e., consumption during the first block), although Ro 63–1908 and MK-801 increased area under the curve (global measure of demand) and decreased demand elasticity, an effect observed primarily in males. Neither drug affected demand intensity (i.e., consumption of cocaine at a minimally constrained price). ConclusionsWhile blocking the NMDA receptor decreases initial intake of cocaine, NMDA receptor antagonists make cocaine more inelastic with increasing price. These results suggest that NMDA receptor antagonists can exacerbate addiction-like behaviors during self-administration during extinction-like conditions that are observed in later blocks of the threshold procedure.

Opposing effects of NMDA receptor antagonists on early life stress-induced aggression in mice.

Rates of childhood trauma are high amongst violent offenders who frequently recidivate. Few clinical options are available to treat excessive and recurring violent aggression associated with childhood trauma. Those that do exist are largely ineffective and often replete with side effects. One promising pharmacological target is the glutamate binding N-methyl- d-aspartate receptor (NMDAR). Clinically available NMDAR antagonists have proven successful in mitigating violent and aggressive behavior associated with a host of psychiatric diseases and have both immediate and long-term effects on nervous system function and behavior. This study examined the impact of three NMDAR antagonists on long-lasting aggression brought on by early-life stress: MK-801, memantine, and ketamine. We find that social isolation early in adolescence followed by acute traumatic stress in the form of noncontingent foot shock (FS) late in adolescence works in tandem to promote long-lasting excessive aggression in mice when measured 1 week later. Systemic injections of MK-801 and memantine 30 min before FS suppressed the long-lasting attack behavior induced by our early life stress induction protocol. Systemic injections of ketamine, on the other hand, significantly enhanced the long-lasting attack behavior when injected before FS. These findings indicate that MK-801, memantine, and ketamine have distinct and opposing effects on early life stress-induced aggression, suggesting these drugs may be mechanistically distinct. This study identifies memantine as a promising pharmacological treatment for aggressive behavior associated with early life stress and demonstrates the need for greater care when using glutamate receptor antagonists to treat aggression.

Computational investigation of phytochemicals from Withania somnifera (Indian ginseng/ashwagandha) as plausible inhibitors of GluN2B-containing NMDA receptors

N-Methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Owing to dearth of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies acting like salutary agents is a dynamic expanse of investigation to contest neurodegenerative disease. Withania somnifera (W. somnifera) has been used since antiquity as a nerve tonic and nootropic agents in Ayurveda, an old Indian system of medicine. In the present study, we have explored phytochemicals from Ayurvedic herb W. somnifera as an inhibitor of NMDA receptor-mediated excitotoxicity through allosteric reticence of the GluN1-GluN2B encompassing NMDARs by dint of molecular docking and dynamics studies. Thus, steering and constraining GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. Out of the curtained phytochemicals, chlorogenic acid revealed significant docking scores of –8.856 and –8.645 kcal/mol and free binding energies of –49.84 and –50.67 kcal/mol in Chain AB and Chain CD of NMDARs, respectively. Chlorogenic acid in AB chain forms four hydrogen bonding with Glu110, Arg115, Leu135 and Asp136 amino acid residues and five hydrogen bond with Glu106, Ala107, Ile133, Ile335and Arg155 amino acid residues of CD chain. To further validate the interaction of top scored molecule chlorogenic acid, molecular dynamics study of 100 ns was carried out. It indicated that the protein–ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. In silico pharmacokinetic predictions of the screened phytochemicals were within the defined range described for human use. Communicated by Ramaswamy H. Sarma

Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations

BackgroundATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AimWe aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. MethodsA retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. ResultsPatients (age 2.5–20 years) had symptom onset at an early age (6 days–1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks–4.8 years) with some improvements reported in all five. ConclusionsOur observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure–function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.

Perspectives for Treating Alzheimer’s Disease: A Review on Indigeous Plants for Alzheimer Disease

Alzheimer’s disease (AD) is one of the most common forms of dementia. The salient pathological hallmarks of AD are extracellular accumulation of amyloid β peptide (Aβ) forming senile plaques (SP), the aggregates of intracellular neurofibrillary tangles (NFTs) and microglial changes in the brain. N-Methyl-D-aspartate receptor (NMDAR), a member of ionotropic glutamate receptor (iGluR), plays an indispensable mantle in maintaining calcium homeostasis and synaptic plasticity. Activation of NMDAR requires co-binding of glycine and glutamate along with postsynaptic depolarization. Upon activation it facilitates the entry of calcium ion into the neurons. The GluN2B subunit of NMDAR has been involved into the direct interaction with Aβ and tau protein and also in the activation of microglia, thus leading to pathophysiology of AD. N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Owing to dearth of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies acting like salutary agents is a dynamic expanse of investigation to contest neurodegenerative disease. In this review we have delved deep into different NMDA antagonist and their pivotal role in preventing Aβ-mediated synaptic plasticity and their potential role as therapeutic target to curtail AD.

Studying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivatives

NMDA receptors were proven to play a significant role in the processes of epileptogenesis. Experimental data indicate a significant anticonvulsant effect of NMDA receptor antagonists, but the use of the studied NMDA ligands remains limited due to their low efficiency and toxic effects. The aim of the study was to investigate the anticonvulsant effect of new ligands of the glutamate NMDA receptor complex imidazole-4,5-dicarboxylic acid (IDA) derivatives on a model of NMDA-induced convulsions in mice. The tested agents (IEM2258 and IEM2248) were injected into the lateral ventricles of a waking mouse brain at doses of 0.10.5 mmol in 5 l 15 minutes before the convulsant (NMDA). Valproic acid was used as a comparator drug. The results of the study showed that IDA derivatives exhibit anticonvulsant activity of various degrees of severity. A pronounced anticonvulsant effect was established for IEM2258 at a dose of 0.4 mmol: a significant reduction in the duration of convulsions (compared to the previous dose of the tested substance) and a total absence of NMDA-induced deaths. IEM2248 showed anticonvulsant activity at a dose of 0.2 mmol, in 100% of cases preventing fatal outcomes and completely protecting animals from the convulsions. Thus, the data obtained in this study showed dose-dependent anticonvulsant effect of new IDA derivatives (IEM2258 and IEM2248) due to the blockade of the NMDA receptor complex, that indicates the promising aspect for the development of these agents and further searching for effective and safe anticonvulsants among this pharmacological class.

The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the rat auditory thalamocortical pathway

Efficient sensory processing requires that the brain maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. According to the predictive coding framework there are two mechanisms underlying the MMN: repetition suppression and prediction error. MMN has been found to be reduced in individuals with schizophrenia, an effect believed to be underpinned by glutamate N-methyl-d-aspartate receptor (NMDA-R) dysfunction. In the current study, we aimed to test how the NMDA-R antagonist, MK-801 in the anaesthetized rat, affected repetition suppression and prediction error processes along the auditory thalamocortical pathway. We found that low-dose systemic administration of MK-801 differentially affect thalamocortical responses, namely, increasing thalamic repetition suppression and cortical prediction error. Results demonstrate an enhancement of neuronal mismatch, also confirmed by large scale-responses. Furthermore, MK-801 produces faster and stronger dynamics of adaptation along the thalamocortical hierarchy. Clearly more research is required to understand how NMDA-R antagonism and dosage affects processes contributing to MMN. Nonetheless, because a low dose of an NMDA-R antagonist increased neuronal mismatch, the outcome has implications for schizophrenia treatment.

Effects of Antagonists of Different Types of NMDA Receptor on Evoked Responses of Pyramidal Neurons in Rat Cerebral Cortex Slices

Despite the extensive pharmacology of NMDA receptors, the use of drugs able to decrease their overactivation in CNS pathologies is limited. One reason for this may be lack of knowledge of the effects of NMDA receptor antagonists on the functional properties of neurons, as a significant quantity of data has been obtained in in vitro models, which do not completely reproduce real pathophysiological processes. The present study addressed the effects of NMDA receptor antagonists with different mechanisms of action on the properties of pyramidal neuron responses in the prefrontal cortex of the rat brain. The competitive antagonist APV (50 μM) and the ion channel blocker memantine (100 μM) were inactive against evoked EPSP. In conditions of suppression of inhibitory transmission with picrotoxin (50 μM), extracellular stimulation evoked epileptiform responses with prolonged membrane depolarization and generation of a burst of action potentials. APV limited the duration and amplitude of these responses. Memantine acquired activity only when magnesium was excluded from the extracellular medium. Memantine’s lack of effect can be explained in terms of competition for the magnesium ion binding site in the channel cavity. These studies show that prediction of the systemic effects of blockers on neuron function and excitability requires use of in vitro models in which NMDA receptors are activated in the presence of a physiological magnesium concentration and without clamping of the membrane potential.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice.

Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.

Cocaine-induced Changes in the Expression of NMDA Receptor Subunits

Cocaine use disorder is manifested by repeated cycles of drug seeking and drug taking. Cocaine exposure causes synaptic transmission in the brain to exhibit persistent changes, which are poorly understood, while the pharmacotherapy of this disease has not been determined. Multiple potential mechanisms have been indicated to be involved in the etiology of co-caine use disorder. The glutamatergic system, especially N-methyl-D-aspartate (NMDA) receptors, may play a role in sever-al physiological processes (synaptic plasticity, learning and memory) and in the pathogenesis of cocaine use disorder. The composition of the NMDA receptor subunits changes after contingent and noncontingent cocaine administration and after drug abstinence in a region-specific and time-dependent manner, as well as depending on the different protocols used for co-caine administration. Changes in the expression of NMDA receptor subunits may underlie the transition from cocaine abuse to dependence, as well as the transition from cocaine dependence to cocaine withdrawal. In this paper, we summarize the cur-rent knowledge regarding neuroadaptations within NMDA receptor subunits and scaffolding proteins observed following voluntary and passive cocaine intake, as well as the effects of NMDA receptor antagonists on cocaine-induced behavioral changes during cocaine seeking and relapse.

Does Self-Reported or Behavioral Impulsivity Predict Subjective Response to Low-Dose Alcohol?

Subjective response to alcohol and impulsivity are both independent predictors of alcohol use and may be related risk factors for alcohol use disorders (AUDs). Recent findings suggest that more impulsive individuals may experience higher risk subjective response patterns at moderate-to-high doses of alcohol. However, whether these relationships are observable early in a drinking occasion remains an open question. This study examined multiple measures of impulsivity in relation to subjective response following low-dose alcohol. Eighty-seven non-treatment-seeking heavy drinkers were enrolled in a placebo-controlled alcohol administration study testing the effects of NMDA receptor antagonist, Memantine. Baseline impulsivity assessments included the Cued Go/No-Go Task, Experiential Discounting Task, and Barratt Impulsiveness Scale, Version 11 (BIS-11). Following consumption of low-dose alcohol aimed to increase blood alcohol concentration (BAC) to 0.03%, subjective stimulation and sedation were measured using the Biphasic Alcohol Effects Scale. Models were tested to relate impulsivity measures to subjective response with a post hoc exploratory model exploring boredom as an alternate predictor. Increases in stimulation and sedation were observed following low-dose alcohol, but were not predicted significantly by impulsivity measures. Although greater impulsivity on the BIS-11 was a trend-level predictor of increased sedation, post hoc analyses suggested these results were an artifact of boredom. Although impulsivity did not predict subjective response to low-dose alcohol, the results suggest that small amounts of alcohol can produce a range of subjective effects, even among heavy drinkers. Future studies would benefit by examining subjective response across a range of BACs among both light and heavy drinkers.

Влияние антагонистов NMDA рецепторов разных типов на вызванные ответы пирамидных нейронов в срезах коры мозга крысы

The use of NMDA receptor antagonists for the treatment of CNS diseases is currently limited. This may be due to the lack of knowledge about the effects of antagonists on the functional properties of neurons since in vitro models do not fully reproduce the real pathophysiological processes. We studied the effects of NMDA receptor antagonists on properties of pyramidal neuron responses in the rat prefrontal cortex. A competitive antagonist APV (50 µM) and an ion channel blocker memantine (100 µM) did not produce significant effects on evoked EPSP. When the inhibitory transmission was suppressed by picrotoxin (50 µM), the extracellular stimulation caused prolonged membrane depolarization and generation a series of action potentials. APV decreased duration and amplitude of such responses. Memantine was active only when magnesium was excluded from the extracellular environment. The lack of effects of memantine can be explained by its competition with magnesium for the binding site within the ion channel. This work demonstrates that in order to predict the systemic effects of blockers on the functions of neurons and their excitability, it is necessary to use in vitro models in which the activation of NMDA receptors occurs in the presence of physiological concentrations of magnesium and without clamping of membrane potential.

THE ROLE OF MAGNESIUM DEFICIENCY AND ITS SUPPLEMATION IN DISEASES OF CENTRAL NERVOUS SYSTEM. REVIEW

Relevance. Anti-depressant effects of NMDA receptor antagonists have been proven, a close association between low levels of magnesium in the blood and depression. Therefore, in recent years, antidepressant properties of magnesium are actively studied in animal experiments. Objective: To review modern literary sources about the role of magnesium deficiency in the pathogenesis of diseases of the central nervous system. Materials and methods. Searching for a depth of 12 years at Scopus, Google Scholar. Results. The results of experimental and clinical researches pointed out on association between low level of magnesium in hair, liquor, brain with higher risk of development dementia, depression and anxiety. An additional supplementation with magnesium in patients associates with decreasing risk of ischemic stroke and dementia, in pregnancy – provides neuroprotection of fetus, in case of depression increases effectiveness of antidepressants, in brain injury associates with faster recovery of cognitive functions, in migraines - with decreasing in the frequency of attacks and improvement of the quality patients’ lives, in case of neuroleptic therapy - with the possibility of delayed appearance or absence of manifestations of drug parkinsonism. These changes are explained by antagonistic effects of magnesium on glutamate receptors, decreasing oxidative stress intensity as well as neural cell apoptosis. Conclusion. Magnesium plays an important neuroprotective role.

201. Measuring Dissociative Effects of NMDA Receptor Antagonists in the Treatment of Depression

201. Measuring Dissociative Effects of NMDA Receptor Antagonists in the Treatment of Depression

P.1.h.014 - Differences in effects of NMDA receptor antagonists in BARR2-KO mice

P.1.h.014 - Differences in effects of NMDA receptor antagonists in BARR2-KO mice

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making.

Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study

N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases.

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10mg/kg) and MK-801 (0.32mg/kg) depressed all behaviour. Ketoprofen (1.0mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists.