Non-competitive NMDA Receptor Antagonist Research Articles

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

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

NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood–brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators.

Is anti-NMDA receptor encephalitis real? II. Therapeutic challenges

The first part of the review challenges the diagnostic concept of anti-NMDA receptor encephalitis (ANMDARE). The second part focuses on analyzing current therapeutic approaches. It is demonstrated that the use of antipsychotics or immunosuppressants poses the risk of severe complications, potentially leading to fatal outcomes, in the near or distant future. Comparing clinical and neurobiological effects associated with antibodies to the GluN1 subunit of the glutamate N-methyl-D-aspartate receptors (NMDAR1-AB) and the administration of subanesthetic doses of the non-competitive NMDA receptor antagonist Ketamine highly suggests a neuroprotective, health-promoting role of NMDAR1-AB, which should not be suppressed but rather potentiated. Benzodiazepines and electroconvulsive therapy (ECT) remain the treatment of choice for acute polymorphic hyperkinetic psychoses.

NMDA Receptor Antagonist Memantine Ameliorates Experimental Autoimmune Encephalomyelitis in Aged Rats.

Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4+ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes' mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

A Behavioral and Electroencephalographic Study of Anesthetic State Induced by MK-801 Combined with Haloperidol, Ketamine and Riluzole in Mice.

Ketamine is an intravenous anesthetic that acts as a channel blocker on the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor subtype. MK-801 is the most potent compound among noncompetitive NMDA receptor antagonists. Ketamine induces loss of the righting reflex (LORR) in rodents, which is one of the indicators of unconsciousness, whereas high doses of MK-801 produce ataxia, but not LORR. In contrast, we previously reported that MK-801 combined with a low dose of the dopamine receptor antagonist haloperidol-induced LORR in mice. To assess a neurophysiologically distinct brain state and demonstrate unconsciousness, electroencephalograms (EEG) need to be examined together with LORR. Therefore, we herein investigated EEG changes after the systemic administration of MK-801 alone or in combination with haloperidol, and compared them with those induced by ketamine, the glutamate release inhibitor riluzole, and the γ-aminobutyric acid type A receptor agonist propofol. All drugs were intraperitoneally administered to adult male ddY mice (n = 168). General anesthesia was evaluated based on the righting reflex test. Animals who exhibited no righting for more than 30 seconds were considered to have LORR. In a separate group of mice, EEG of the primary visual cortex was recorded before and after the administration of MK-801 (3.0 mg/kg) alone or in combination with haloperidol (0.2 mg/kg), ketamine (150 mg/kg), riluzole (30 mg/kg), or propofol (240 mg/kg). The waveforms recorded were analyzed using EEG power spectra and spectrograms. The high dose of MK-801 alone did not induce LORR, whereas MK-801 combined with haloperidol produced LORR in a dose-dependent manner. Ketamine, riluzole, and propofol also dose-dependently induced LORR. In the EEG study, MK-801 alone induced a significant increase in δ power, while MK-801 plus haloperidol exerted similar effects on not only δ, but also θ and α power during LORR, suggesting that increases in δ, θ, and α power were necessary for LORR. The results obtained on MK-801 plus haloperidol were similar to those on ketamine in the behavioral and EEG studies, except for an increase in γ power by ketamine during LORR. Propofol significantly increased δ, θ, α, and β power during LORR. However, the EEG results obtained using riluzole, which produced a unique pattern of lower amplitude activity spanning most frequencies, markedly differed from those with the other drugs. This study revealed differences in EEG changes induced by various sedatives. The results obtained on MK-801 alone and MK-801 plus haloperidol suggest the importance of dopamine transmission in maintaining the righting reflex.

Impaired enzymatic antioxidant defense in erythrocytes of rats with ammonia-induced encephalopathy: role NMDA receptors

Hepatic encephalopathy (HE), a medical term that deals with a neuropsychiatric disorder seen in patients with severe hepatic dysfunction, has been known for more than a century, however, pathogenetic mechanisms underlying cerebral dysfunction during conditions of liver disease are still not entirely understood. There is a consensus that an accumulation of ammonia in brain as a result of impaired detoxification capacity of the liver or the appearance of a portosystemic shunt is a primary cause of HE. Current evidence suggests that ammonia toxicity is mediated by hyperactivation of glutamate receptors, mainly N-methyl-D-aspartate receptors (NMDA-R) and affects many processes of aerobic metabolism that provides energy for a myriad of specific functions and viability of nerve cells. Recent reports on the presence of functional NMDA receptors in erythrocytes and deviations from normal ranges in many blood test parameters that was indicative of impaired hemodynamics and reduced carrying capacity for oxygen in erythrocytes in most patients with HE implicate the relationship between “erythrocyte damage” and cerebral dysfunction. In order to understand how, during hyperammonemia, disturbances in energy metabolism in brain that needs a constant supply of a high level of oxygen in the blood lead to encephalopathy, it is necessary to reveal ammonia-induced disorders in energy metabolism and antioxidant defense system of erythrocytes and explore the potential role of ammonia in reduced brain oxygenation. To detect the said missing link, the activities of erythrocyte antioxidant enzymes and concentrations of GSH, GSSG and H2O2 were measured in animals with hyperammonemia by using MK-801, a powerful noncompetitive NMDA receptor antagonist. It was found that the accumulation of ammonia in the blood of animals with hyperammonemia occurs within rat erythrocytes in large amounts and makes these cells which do not contain enzymes for the removal of ammonia, more susceptible to a prooxidant environment of ammonia created during oxidative stress that was completely or partially inhibited with the help of MK-801. Data obtained provide a support to identification of extra risk factors in cognitive disorders and in the prediction of unfavorable outcome with hypoperfusion in patients with elevated concentrations of ammonia in the blood.

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist-induced behavioral disruptions in male and female mice.

Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.

Influence of the dose of ketamine used on schizophrenia-like symptoms in mice: A correlation study with TH, GAD67, and PPAR-γ

Schizophrenia is a chronic, debilitating mental illness that has not yet been completely understood. In this study, we aimed to investigate the effects of different doses of ketamine, a non-competitive NMDA receptor antagonist, on the positive- and negative-like symptoms of schizophrenia. We also explored whether these effects are related to changes in the immunoreactivity of GAD67, TH, and PPAR-γ in brain structures. To conduct the study, male mice received ketamine (20–40 mg/kg) or its vehicle (0.9 % NaCl) intraperitoneally for 14 consecutive days. We quantified stereotyped behavior, the time of immobility in the forced swimming test (FST), and locomotor activity after 7 or 14 days. In addition, we performed ex vivo analysis of the immunoreactivity of GAD, TH, and PPAR-γ, in brain tissues after 14 days. The results showed that ketamine administration for 14 days increased the grooming time in the nose region at all tested doses. It also increased immobility in the FST at 30 mg/kg doses and decreased the number of rearing cycles during stereotyped behavior at 40 mg/kg. These behavioral effects were not associated with changes in locomotor activity. We did not observe any significant alterations regarding the immunoreactivity of brain proteins. However, we found that GAD and TH were positively correlated with the number of rearing during the stereotyped behavior at doses of 20 and 30 mg/kg ketamine, respectively. GAD was positively correlated with the number of rearing in the open field test at a dose of 20 mg/kg. TH was inversely correlated with immobility time in the FST at a dose of 30 mg/kg. PPAR-γ was inversely correlated with the number of bouts of stereotyped behavior at a dose of 40 mg/kg of ketamine. In conclusion, the behavioral alterations induced by ketamine in positive-like symptoms were reproduced with all doses tested and appear to depend on the modulatory effects of TH, GAD, and PPAR-γ. Conversely, negative-like symptoms were associated with a specific dose of ketamine.

Impaired Enzymatic Antioxidant Defense in Erythrocytes of Rats with Ammonia-Induced Encephalopathy: Role of NMDA Receptors.

Hepatic encephalopathy (HE), a neuropsychiatric disorder developing in patients with severe hepatic dysfunction, has been known for more than a century. However, pathogenetic mechanisms of cerebral dysfunction associated with liver disease are still poorly understood. There is a consensus that the primary cause of HE is accumulation of ammonia in the brain as a result of impaired liver detoxification capacity or the portosystemic shunt. Current evidence suggests that ammonia toxicity is mediated by hyperactivation of glutamate receptors, mainly N-methyl-D-aspartate receptors (NMDARs), and affects brain aerobic metabolism, which provides energy for multiple specific functions and neuronal viability. Recent reports on the presence of functional NMDARs in erythrocytes and the data on the deviations of blood parameters from their normal ranges indicate impaired hemodynamics and reduced oxygen-carrying capacity of erythrocytes in most patients with HE, thus suggesting a relationship between erythrocyte damage and cerebral dysfunction. In order to understand how hyperammonemia (HA)-induced disturbances in the energy metabolism in the brain (which needs a constant supply of large amounts of oxygen in the blood) lead to encephalopathy, it is necessary to reveal ammonia-induced impairments in the energy metabolism and antioxidant defense system of erythrocytes and to explore a potential role of ammonia in reduced brain oxygenation. To identify the said missing link, the activities of antioxidant enzymes and concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and H2O2 were measured in the erythrocytes of rats with HA that were injected with the noncompetitive NMDAR antagonist MK-801. We found that in rats with HA, ammonia was accumulated in erythrocytes (cells lacking ammonia removal enzymes), which made them more susceptible to the prooxidant environment created during oxidative stress. This effect was completely or partially inhibited by MK-801. The data obtained might help to identify the risk factors in cognitive disorders and facilitate prediction of unfavorable outcomes of hypoperfusion in patients with a blood elevated ammonia concentration.

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.

The Highs and Lows of Memantine-An Autophagy and Mitophagy Inducing Agent That Protects Mitochondria.

Memantine is an FDA-approved, non-competitive NMDA-receptor antagonist that has been shown to have mitochondrial protective effects, improve cell viability and enhance clearance of Aβ42 peptide. Currently, there are uncertainties regarding the precise molecular targets as well as the most favourable treatment concentrations of memantine. Here, we made use of an imaging-based approach to investigate the concentration-dependent effects of memantine on mitochondrial fission and fusion dynamics, autophagy and mitochondrial quality control using a neuronal model of CCCP-induced mitochondrial injury so as to better unpack how memantine aids in promoting neuronal health. GT1-7 murine hypothalamic cells were cultured under standard conditions, treated with a relatively high and low concentration (100 µM and 50 µM) of memantine for 48 h. Images were acquired using a Zeiss 780 PS1 platform. Utilising the mitochondrial event localiser (MEL), we demonstrated clear concentration-dependent effects of memantine causing a protective response to mitochondrial injury. Both concentrations maintained the mitochondrial network volume whilst the low concentration caused an increase in mitochondrial number as well as increased fission and fusion events following CCCP-induced injury. Additionally, we made use of a customised Python-based image processing and analysis pipeline to quantitatively assess memantine-dependent changes in the autophagosomal and lysosomal compartments. Our results revealed that memantine elicits a differential, concentration-dependent effect on autophagy pathway intermediates. Intriguingly, low but not high concentrations of memantine lead to the induction of mitophagy. Taken together, our findings have shown that memantine is able to protect the mitochondrial network by preserving its volume upon mitochondrial injury with high concentrations of memantine inducing macroautophagy, whereas low concentrations lead to the induction of mitophagy.

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine’s therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within 1 hr after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine’s effects on animals’ behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.

Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice.

Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 administration at effective (50mg/kg) or subeffective (1mg/kg) dosesby intragastric route (ig). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1pmol/site, intracerebroventricular, icv, a selective agonist of the NMDA receptors), D-serine (30µg/site, icv, a co-agonist at the NMDA receptor), arcaine (1mg/kg, intraperitoneal, ip, an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5µg/site, icv, an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF1 (50mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 with low doses of MK-801 (0.001mg/kg, ip, a non-competitive NMDA receptor antagonist) or ketamine (0.1mg/kg, ip, a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus.

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

Analysis of the Involvement of NMDA Receptors in Analgesia and Hypothermia Induced by the Activation of TRPV1 Ion Channels.

NMDA glutamate receptors play an important role in normal and pathophysiological nociception. At the periphery, they can interact with TRPV1 ion channels. The blockade of TRPV1 ion channels decreases NMDA-induced hyperalgesia, and NMDA receptor antagonists suppress the pain response to the TRPV1 agonist capsaicin. Since TRPV1 ion channels and NMDA receptors can functionally interact at the periphery, it would be interesting to investigate the possibility that they interact in the CNS. A single subcutaneous injection of 1 mg/kg of capsaicin was found to raise the thermal pain threshold in the tail flick test in mice, which reproduces the spinal flexion reflex, owing to the ability of capsaicin to cause long-term desensitization of nociceptors. Preventive administration of either noncompetitive NMDA receptor antagonists (high-affinity MK-801 20 μg/kg and 0.5 mg/kg subcutaneously; low-affinity hemantane 40 mg/kg intraperitoneally) or the selective TRPV1 antagonist BCTC (20 mg/kg intraperitoneally) inhibit the capsaicin-induced increase in the pain threshold. Capsaicin (1 mg/kg, subcutaneous injection) induces transient hypothermia in mice, which is brought about by hypothalamus-triggered vegetative reactions. This effect is prevented by BCTC but not by the noncompetitive NMDA receptor antagonists.

Unsubstantiated use of Selective serotonin reuptake inhibitors as an alternative for the treatment of depression

Unsubstantiated use of Selective serotonin reuptake inhibitors as an alternative for the treatment of depression

Recent Developments in Tacrine-based Hybrids as a Therapeutic Option for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial, irreversible, and age-related neurodegenerative disorder among the elderly. AD attracts attention due to its complex pathogenesis, morbidity and mortality rates, and the limitations of drugs used in the treatment of AD. Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are used in the clinic. While tacrine, donepezil, galantamine, and rivastigmine are cholinesterase inhibitors, memantine is a non-competitive NMDA receptor antagonist. However, these drugs could not delay the progress of AD. The traditional clinical approach which is the one drug-one target concept is not entirely effective in the treatment of AD. Also, it is of high-priority to develop potent and novel anti-AD drugs by the design concept of multitarget directed ligands (MTDLs) which combine pharmacophores interacting with different pathways in AD. This article provides an overview of the noteworthy structural modifications made to tacrine to develop novel candidates for anti-Alzheimer drugs. Due to the complex pathology of AD, multifunctional tacrine-based ligands targeting different hallmarks, β-amyloid, tau protein, N-methyl-Daspartate receptor, cholinesterases, monoamine oxidases, secretases, have been studied. Here, tacrinebased derivatives including heterocyclic structures such as dihydroxypyridine, chromene, coumarin, pyrazole, triazole, tetrahydroquinolone, dipicolylamine, arylisoxazole were reported with promising anti-AD effects compared to tacrine. In vitro and in vivo assays showed that new tacrine-based hybrids, which are selective, neuroprotective, and non-hepatotoxic, might be considered as remarkable anti-AD drug candidates for further clinical studies.

Effects of memantine on mania-like phenotypes exhibited by Drosophila Shaker mutants.

Increased glutamate levels and electrolytic fluctuations have been observed in acutely manic patients. Despite some efficacy of the non-competitive NMDA receptor antagonist memantine (Mem), such as antidepressant-like and mood-stabilizer drugs in clinical studies, its specific mechanisms of action are still uncertain. The present study aims to better characterize the Drosophila melanogaster fly Shaker mutants (SH), as a translational model of manic episodes within bipolar disorder in humans, and to investigate the potential anti-manic properties of Mem. Our findings showed typical behavioral abnormalities in SH, which mirrored with the overexpression of NMDAR-NR1 protein subunit, matched well to glutamate up-regulation. Such molecular features were associated to a significant reduction of SH brain volume in comparison to Wild Type strain flies (WT). Here we report on the ability of Mem treatment to ameliorate behavioral aberrations of SH (similar to that of Lithium), and its ability to reduce NMDAR-NR1 over-expression. Our results show the involvement of the glutamatergic system in the SH, given the interaction between the Shaker channel and the NMDA receptor, suggesting this model as a promising tool for studying the neurobiology of bipolar disorders. Moreover, our results show Mem as a potential disease-modifying therapy, providing insight on new mechanisms of action.

Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation

BackgroundAs a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms. MethodsTo mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue. ResultsCP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus. ConclusionsOur results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression.

Prenatal ketamine exposure impairs prepulse inhibition via arginine vasopressin receptor 1A-mediated GABAergic neuronal dysfunction in the striatum

Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.