NMDA Glutamate Receptors Research Articles

D-glutamate and Gut Microbiota in Alzheimer's Disease.

Background: An increasing number of studies have shown that the brain–gut–microbiota axis may significantly contribute to Alzheimer’s disease (AD) pathogenesis. Moreover, impaired memory and learning involve the dysfunction neurotransmission of glutamate, the agonist of the N-methyl-d-aspartate receptor and a major excitatory neurotransmitter in the brain. This systematic review aimed to summarize the current cutting-edge research on the gut microbiota and glutamate alterations associated with dementia. Methods: PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, and Cochrane Systematic Reviews were reviewed for all studies on glutamate and gut microbiota in dementia published up until Feb 2020. Results: Several pilot studies have reported alterations of gut microbiota and metabolites in AD patients and other forms of dementia. Gut microbiota including Bacteroides vulgatus and Campylobacter jejuni affect glutamate metabolism and decrease the glutamate metabolite 2-keto-glutaramic acid. Meanwhile, gut bacteria with glutamate racemase including Corynebacterium glutamicum, Brevibacterium lactofermentum, and Brevibacterium avium can convert l-glutamate to d-glutamate. N-methyl-d-aspartate glutamate receptor (NMDAR)-enhancing agents have been found to potentially improve cognition in AD or Parkinson’s disease patients. These findings suggest that d-glutamate (d-form glutamate) metabolized by the gut bacteria may influence the glutamate NMDAR and cognitive function in dementia patients. Conclusions: Gut microbiota and glutamate are potential novel interventions to be developed for dementia. Exploring comprehensive cognitive functions in animal and human trials with glutamate-related NMDAR enhancers are warranted to examine d-glutamate signaling efficacy in gut microbiota in patients with AD and other neurodegenerative dementias.

Sympathomotor activation by midbrain locomotor neurons is mediated through glutamate release in the rostral ventrolateral medulla

Our pilot data showed that a portion of neuronal cells in the mecencephalic locomotor region (MLR) sends axonal projections to the rostral ventrolateral medulla (RVLM) (MLR‐RVLM pathway), being capable of eliciting sympathomotor activation in rats. Here, we examined the effect of ionotropic glutamate receptor blockade in rat RVLM on sympathomotor activation by the MLR‐RVLM pathway. Male rats received microinjections bilaterally in the RVLM with a retrograde adeno‐associated virus that encoded a channelrhodopsin with green fluorescence protein. Under anesthesia, 473 nm wavelength laser illumination of the MLR after administration in the RVLM with a cocktail of AP5 and CNQX, NMDA and AMPA glutamate receptor blockers, respectively, elicited 29% less (P < 0.05) renal sympathoexcitation than that after saline administration. Likewise, under decerebration without anesthesia, ventral root fiber excitation in response to MLR photostimulation seen after saline administration in the RVLM was suppressed to a 35% extent (P < 0.05) by preliminarily administration of the glutamate receptor blockers. These observations suggest that glutamatergic neurons in the MLR‐RVLM pathway function in generating central command function.Support or Funding InformationSupported by JSPS KAKENHI 18H03151 (S. Koba).

Molecular docking studies of N-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives as potential modulators of glutamate receptors

Introduction: The virtual target-oriented screening is a necessary stage of modern drug-design. In the present study, the affinity of pyridazine derivatives for the most promising antiparkinsonian biotargets – I–III groups of metabotropic and ionotropic NMDA-glutamate receptors – was evaluated.
 Materials and methods: Docking of the studied ligands to the active sites of biotargets – mGluR5, mGluR3, mGluR8, NMDA GluN2B – was performed using AutoDockVina. Base of the preparation of ligands and proteins – AutoDock­Tools-1.5.6. A Discovery Studio Visualizer 2017/R2 was used to visualize the interpretation of the results.
 Results and discussion: A high degree of the affinity is predicted for group III of the metabotropic mGlu8 receptors – binding energy from -5.0 to -8.7 kcal/mol, compared to -6.1 kcal/mol of that of the reference drug (L-AP4), as well as for the ionotropic NMDA GluN2B receptors –binding energy from -8.7 to -11.6 kcal/mol, compared to -11.3 kcal/mol of that of ifenprodil.
 Conclusion: The prospects of the searching for glutamate receptor modulators in a number of n-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives are proved. Some aspects of the structure-affinity relationship are discussed.

Memantine treatment prevents okadaic acid induced neurotoxicity at the systemic and molecular levels

The present study was designed to investigate the effects of okadaic acid intracerebroventricular (ICV) injection on memory function and expression level of α7 subunit of nicotinic acetylcholine receptor (nAChR) and NR2B subunit of NMDA glutamate receptors in the hippocampus, as well as effect of the antidementic drug memantine on okadaic acid induced changes at systemic and molecular levels in rats. Okadaic acid was dissolved in artificial cerebrospinal fluid (aCSF) and injected ICV 200 ng/10 μl. Vehicle control received 10 μl of aCSF ICV bilaterally. Control and okadaic acid injected rats were divided into two subgroups: treated i.p. with saline or memantine (5 mg/kg daily for 13 days starting from the day of okadaic acid injection). Rats were trained in the dual-solution plus-maze task that can be solved by using place or response strategies. The Western immunoblotting was used to determine relative amount of hippocampal receptors protein levels. Obtained data revealed that okadaic acid ICV injected rats were severely impaired at acquiring the place version of the maze accompanied by significant decline in hippocampal α7 subunit of nACh receptors protein levels. Memantine treatment can prevent okadaic acid induced impairment of hippocampal-dependent spatial memory and accompanied by modulation of the expression level of α7 subunit of nACh and NR2B subunit of NMDA receptors in the hippocampus. Thus, our results support the presumption that α7 nACh receptors may play an important role in the cognitive enhancer effects of memantine and emphasize the role of cholinergic-glutamatergic interactions in memory.

Glutamate receptors from diverse animal species exhibit unexpected structural and functional diversity.

The identification of AMPA, kainate and NMDA glutamate receptor subtypes by Watkins and colleagues underlies much of our understanding of excitatory synaptic transmission in the central nervous system of animals. Ongoing large scale genome sequencing projects in species for which physiological analysis of receptor function is challenging are resulting in identification of numerous eukaryotic glutamate receptor ion channels in the animal kingdom of life. On the basis of sequence similarity, these are frequently classified into the three vertebrate subtypes, initially identified using subtype selective ligands. Recent work reveals unexpected ligand binding profiles for these newly identified glutamate receptors, for example, kainate receptors on which NMDA acts as a competitive antagonist, and high affinity homomeric glycine activated glutamate receptors. Structural studies reveal that only subtle changes in the ligand binding domain, often identified only in retrospect, underlie different patterns of ligand binding, and that the biology of glutamate receptors is more complex than first anticipated.

Regulation of NMDA glutamate receptor functions by the GluN2 subunits.

The N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate the flux of calcium (Ca2+ ) into the post-synaptic compartment. Ca2+ influx subsequently triggers the activation of various intracellular signalling cascades that underpin multiple forms of synaptic plasticity. Functional NMDARs are assembled as heterotetramers composed of two obligatory GluN1 subunits and two GluN2 or GluN3 subunits. Four different GluN2 subunits (GluN2A-D) are present throughout the central nervous system; however, they are differentially expressed, both developmentally and spatially, in a cell- and synapse-specific manner. Each GluN2 subunit confers NMDARs with distinct ion channel properties and intracellular trafficking pathways. Regulated membrane trafficking of NMDARs is a dynamic process that ultimately determines the number of NMDARs at synapses, and is controlled by subunit-specific interactions with various intracellular regulatory proteins. Here we review recent progress made towards understanding the molecular mechanisms that regulate the trafficking of GluN2-containing NMDARs, focusing on the roles of several key synaptic proteins that interact with NMDARs via their carboxyl termini.

The NMDA Receptor Channel Blockers Memantine and IEM-1921 Decrease the Duration of Status Epilepticus in Wistar and Krushinskii–Molodkina Rats in a Lithium-Pilocarpine Model

Chronic experiments on Wistar and Krushinskii–Molodkina rats, which have an inherited predisposition to audiogenic convulsions, addressed the effects of preliminary administration of memantine and IEM-1921 – NMDA glutamate receptor channel blockers – on brain electrical activity on development of status epilepticus (SE) induced by pilocarpine. Electrograms were recorded from the hippocampus, caudate nucleus, and the somatosensory, visual, and auditory areas of the cortex. The nature and sequence of changes in the phases of SE identifi ed from electrogram patterns were not altered by blockers. In addition, the latent period of the onset of epileptiform activity on the EEG after administration of pilocarpine to Wistar rats decreased almost two-fold (to 10–15 min) after administration of memantine (5 mg/kg) or IEM-1921 (5 mg/kg). In Krushinskii–Molodkina rats, the latent period of development of epileptiform activity was initially shorter (13 ± 2 min) and was not altered by use of blockers. The mean durations of SE after administration of memantine to Wistar and Krushinskii–Molodkina rats were 2 and 3 times, respectively, shorter than without blocker, while durations were reduced seven-fold by IEM-1921. NMDA receptor blockers also signifi cantly weakened behavioral motor convulsions, decreasing the intensity of convulsions from 8 to 4 points on the Pinel and Rovner [1978] scale. These data provide evidence that blockade of NMDA receptors did not prevent the typical development of pilocarpine-induced SE, though duration was signifi cantly reduced.

Dantrolene : From Malignant Hyperthermia to Alzheimer's Disease.

Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of Ryanodine Receptor (RyR) by dantrolene decreases the abnormal calcium release from the Sarcoplasmic Reticulum (SR) or Endoplasmic Reticulum (ER), where RyR is located. Recently, emerging researches on dissociated cells, brains slices, live animal models and patients have demonstrated that altered RyR expression and function can also play a vital role in the pathogenesis of Alzheimer's Disease (AD). Therefore, dantrolene is now widely studied as a novel treatment for AD, targeting the blockade of RyR channels or another alternative pathway, such as the inhibitory effects of NMDA glutamate receptors and the effects of ER-mitochondria connection. However, the therapeutic effects are not consistent. In this review, we focus on the relationship between the altered RyR expression and function and the pathogenesis of AD, and the potential application of dantrolene as a novel treatment for the disease.

The Effect of Memantine Administration on Anxiety Maintenance in Stressed Male Wistar Rats

Background: Anxiety is considered as a chronic stress complication. The role of N-methyl-D-aspartate (NMDA) glutamate receptors located in basolateral amygdala (BLA) in stress-induced anxiety is hypothesized. Objectives: It is unknown how NMDA glutamate receptors located in BLA affect maintenance of chronic stress-induced anxiety. This study investigated the role of these receptors in maintaining anxiety induced by electric foot shock in male Wistar rats. Methods: Animals were subjected to stress based on the following protocol: Seven days after bilateral cannulation in BLA, they experienced seven sessions of stress (one session/day). Before each stress session, the animals received different doses of memantine (1, 2.5, and 5 mg/kg) peripherally, or (0.1, 1 and 5 μg/kg) in BLA. Six days after stress termination, the animals were tested for maintenance of anxiety using an open field paradigm. Moreover, the animals’ brains were removed for further assessment of brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Results: The stressed animals showed anxiety six days after stress termination. Moreover, chronic peripheral and central memantine injection by itself showed both anxiolytic and anxiogenic properties six days after drug administration termination in the non-stressed animals. Memantine preadministration, both peripherally and centrally, reduced the stress-induced maintenance of anxiety in the stressed animals. The BDNF assessment revealed that stress and memantine did not change hippocampal BDNF level six days after drug or stress termination. Conclusions: Inhibition of NMDA receptors in BLA can inhibit maintenance of stress-induced anxiety, which is not related to hippocampal BDNF level. In addition, chronic memantine injection induces anxiety.

Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory.

Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS-Glud1 -/- mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l-serine and d-serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal-prefrontal cortex circuitry. Finally, hippocampus-dependent contextual fear retrieval was deficient in CNS-Glud1 -/- mice, and c-Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion-dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal-prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity-induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.

Interaction between leptin and glutamatergic system on food intake regulation in neonatal chicken: role of NMDA and AMPA receptors

Objective: The aim of the current study was to determine the possible interaction of the central leptin and Glutamatergic systems on feeding behavior in neonatal 3-hours food deprived (FD3) broilers chickens.Methods: In experiment 1, FD3 chicken received intracerebroventricular (ICV) injection of control solution (group i) and 2.5, 5 and 10 µg of Leptin (groups ii–iv). In experiment 2, FD3 chicken were ICV injected with (group i) control solution and groups ii–iv with 2.5, 5 and 10 nmol of AG-490 (JAK2 antagonist). In experiment 3, injections were (i) control solution, (ii) Leptin (10 µg), (iii) AG-490 (2.5 nmol) and (iv) Leptin + AG-490. In experiment 4, broiler chickens were ICV injected with (i) control solution, (ii) Leptin (10 µg), (iii) MK-801 (NMDA glutamate receptors antagonist; 15 nmol) and (iv) Leptin + MK-801. Experiments 5–9 were similar to experiment 1, except chicken were ICV injected with CNQX (AMPA receptor antagonist, 390 nmol), UBP-302 (Kainate receptor antagonist, 390 nmol), AIDA (mGluR1 antagonist, 2 nmol), LY341495 (mGluR2 antagonist, 150 nmol) and UBP1112 (mGluR3 antagonist, 2 nmol) instead of MK-801. Then, food intake was measured until 120 min after injection.Results: ICV injection of leptin (2.5, 5 and 10 µg) significantly decreased food intake in a dose dependent manner (p < 0.05). Also, ICV injection of the JAK2 antagonist (2.5, 5 and 10 nmol) had hyperphagic effect in chicken (p < 0.05). Co-administration of leptin + AG-490, partially decreased leptin-induced hypophagia in broiler chicken (p < 0.05). In addition, co-injection of leptin + MK-801 significalty inhibited leptin-induced hypophagia in neonatal chicken (p < 0.05). Also, co-administration of leptin + CNQX partially attenuated hypophagic effect of leptin in chicken (p < 0.05).Conclusion: The results of present study suggest that leptin has hypophagic effect in neonatal chicken and this effect is probably mediated via NMDA and AMPA glutamatergic receptors.

Gut neurotoxin p-cresol induces differential expression of GLUN2B and GLUN2A subunits of the NMDA receptor in the hippocampus and nucleus accumbens in healthy and audiogenic seizure-prone rats.

Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subunits is observed in several brain disorders and pathological conditions. Recently, we have shown that intraperitoneal injection of the gut neurotoxin p-cresol induces autism-like behavior and accelerates seizure reactions in healthy and epilepsy-prone rats, respectively. In this study, we evaluated the expression of GLUN2B and GLUN2A NMDAR subunits, and assessed the activity of cAMP-response element binding protein (CREB) and Rac1 in the hippocampi and nucleus accumbens of healthy and epilepsy-prone rats following p-cresol administration. We have found that subchronic intraperitoneal injection of p-cresol induced differential expression of GLUN2B and GLUN2A between the two brain regions, and altered the GLUN2B/GLUN2A ratio, in rats in both groups. Moreover, p-cresol impaired CREB phosphorylation in both brain structures and stimulated Rac activity in the hippocampus. These data indicate that p-cresol differently modulates the expression of NMDAR subunits in the nucleus accumbens and hippocampi of healthy and epilepsy-prone rats. We propose that these differences are due to the specificity of interactions between dopaminergic and glutamatergic pathways in these structures.

Inflammation, insulin resistance and the pathophysiology of depression: implications for novel antidepressant developments

This review summarises the impact of chronic low grade inflammation as a causative factor in the pathophysiology of major depression. Evidence is presented to show that proinflammatory cytokines both directly, and indirectly by increasing hypercortisolaemia, desensitise insulin receptors and thereby decrease the transport of glucose into the brain (the diabetic brain). In addition, the proinflammatory cytokines activate the tryptophan-kynurenine pathway which results in the synthesis of the NMDA-glutamate receptor agonist quinolinic acid. This acts as a neurotoxin and facilitates neuronal apoptosis. As metabolic changes initiated by low grade inflammation underlie the pathophysiology of depression, drugs which attenuate the inflammatory cascade may present an approach to the novel development of antidepressants. The review concludes with a summary of drugs which might be considered for their novel therapeutic activity. Key points: 1. Chronic low grade inflammation commonly occurs in major depression and contributes to adverse changes in brain energy metabolism by decreasing insulin receptor function and thereby reducing glucose transport into the brain. 2. Low grade inflammation initiates an increase in the tryptophan-kynurenine pathway which enhances the NMDA-glutamate receptor function and thereby increases neuronal apoptosis. As many of the pathophysiological changes in depression result from dysfunctional brain metabolism caused by chronic low grade inflammation, it is concluded that drugs targeting the inflammatory pathways may offer new possibilities for the development of novel antidepressants.

Изменение поведения и экспрессии генов ионотропных рецепторов глутамата в мозге взрослых крыс после неонатальных введений бактериального липополисахарида

A large number of studies indicate the role of early-life experience, in particular neonatal infections, in the formation of a high level of anxiety later in life. Changes in NMDA and AMPA glutamate receptor subunit composition that result in the violation of receptor functional activity may comprise the mechanism behind the behavioral impairments. Our work aimed to investigate exploratory and anxiety-like forms of behavior of adult rats that were treated with lipopolysaccharide (LPS) during the 3rd week of postnatal development at neuroinflammation-inducing doses. Levels of gene expression of NMDA receptor subunits (Grin1, Grin2a, Grin2b) and AMPA receptor subunits (Gria1, Gria2) in the medial prefrontal cortex, ventral and dorsal areas of the hippocampus were assessed by qRT-PCR. Our study on Wistar male rats revealed that the administration of LPS at doses of 25 and 50 μg/kg on P15, P18, P21 increased the expression of proinflammatory cytokine mRNA (interleukin-1β and tumor necrosis factor) in the hippocampus 2 h post treatment. Elevated expression of Grin2b, Gria1, Gria2 genes in the ventral hippocampus was observed 3 months after the administration of 50 μg/kg LPS compared with saline-treated control rats. Gria2 gene expression was found to be increased in the dorsal hippocampus 3 months after 25 μg/kg LPS injections in comparison with the controls. These changes were accompanied by impaired exploratory behavior of adult LPS-treated rats in the Open field test and a decreased level of anxiety in the Elevated plus maze. Taken together, our results substantiate early-life inflammation as a cause of prolonged changes in the hippocampal expression of genes of NMDA and AMPA receptor subunits and have an impact on related forms of behavior.

N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy.

N-Acetylcysteine, one of the most prescribed antioxidant drugs, enhances pain threshold in rodents and humans by activating mGlu2 metabotropic glutamate receptors. Here, we assessed the analgesic activity of N-acetylcysteine in the streptozotocin model of painful diabetic neuropathy and examined the effect of N-acetylcysteine on proteins that are involved in mechanisms of nociceptive sensitization. Mice with blood glucose levels ≥250 mg/dl in response to a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg) were used for the assessment of mechanical pain thresholds. Systemic treatment with N-acetylcysteine (100 mg/kg, i.p., either single injection or daily injections for seven days) caused analgesia in diabetic mice. N-acetylcysteine-induced analgesia was abrogated by the inhibitors, sulfasalazine (8 mg/kg, i.p.), erastin (30 mg/kg, i.p.), and sorafenib (10 mg/kg, i.p.), or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). Repeated administrations of N-acetylcysteine in diabetic mice reduced ERK1/2 phosphorylation in the dorsal region of the lumbar spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK inhibitor, PD0325901 (25 mg/kg, i.p.), the TRPV1 channel blocker, capsazepine (40 mg/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate receptor antagonists (memantine, 25 mg/kg, plus MTEP, 5 mg/kg, both i.p.). These findings offer the first demonstration that N-acetylcysteine relieves pain associated with diabetic neuropathy and holds promise for the use of N-acetylcysteine as an add-on drug in diabetic patients.

Anesthetic care for patients with anti-NMDA receptor encephalitis.

Introduction:Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, an autoimmune disorder resulting from antibodies directed against the NMDA (glutamate) receptor, is the second most frequent cause of immune-mediated encephalitis. To date, the information related to the anesthetic care of children with this disorder is limited to anecdotal reports.Methods:We reviewed the anesthetic care of six patients with anti-NMDA receptor encephalitis who underwent 21 procedures at our institution from 2014 through 2019.Results:The study cohort included six patients, ranging in age from 2 to 18 years, who required anesthetic care during 21 procedures. Airway management included a laryngeal mask airway (n = 8), endotracheal intubation (n = 12), and native airway with spontaneous ventilation (n = 1). Intravenous (IV) induction with propofol was used in 17 procedures for five patients, including three that required rapid sequence intubation using rocuronium or succinylcholine. Inhalation induction with sevoflurane in nitrous oxide (N2O)/oxygen (O2) was chosen for two procedures in two patients. A combination of both induction techniques was used for two patients in two procedures. Maintenance anesthesia was accomplished with a volatile agent, predominantly sevoflurane, for 18 of the 21 procedures; propofol infusion for one procedure; and single dose of propofol was used for two short procedures. N2O was not used for maintenance anesthesia in any of the encounters. None of the patients exhibited adverse events, including hemodynamic instability, thermoregulatory problems, or respiratory events perioperatively. Postoperatively, there was no observed deterioration in clinical status attributed to anesthetic care.Discussion:Multisystem involvement in anti-NMDA receptor encephalitis includes memory loss, behavior irregularity, psychosis, arrhythmias, blood pressure (BP) instability, and hypoventilation. In our study cohort, we noted no intraoperative issues and deterioration in clinical status following the use of volatile anesthetic agents, opioids, dexmedetomidine, and propofol for general anesthesia (GA) or sedation. As ketamine, xenon, and N2O mediate their anesthetic effects, primarily, through antagonism of NMDA receptors, theoretical concerns suggest that they should be avoided.

Lekovi u lečenju demencija - unapred izgubljena bitka?

Alzheimer's disease (AD), the most common cause of dementia, is growing health, social and economic issue because of the increasing number of sufferers, limited efficacy of available treatment options, and high total healthcare costs. It is clinically characterized by cognitive and behavioral impairments, both of which need to be treated appropriately to improve patients' quality of life and their caregivers as well. Currently, available anti-dementia medications provide only modest and transient cognitive benefits. Donepezil, rivastigmine and galantamine (cholinesterase inhibitors) are indicated for the symptomatic management of mild to moderately severe AD, while memantine (NMDA glutamate receptors antagonist) is recommended for moderate-to-severe AD. A special focus on behavioral symptoms (e.g. anxiety, depression, aggression) management is required as they cause great suffering in patients/caregivers. The use of medications that can impair cognitive function, such as drugs with anticholinergic activity, should be avoided in patients with dementia. Additionally, interventions that could delay or prevent dementia onset in some subjects are focused on minimizing modifiable risk factors (hypertension, diabetes, depression) and maximizing protective factors (physical activity, healthy diet, leisure, and social activities). The treatment of AD remains a challenge.

Stress-Induced Spatial Memory Deficit Reversed by Basolateral Amygdala NMDA Receptor Inhibition in Male Wistar Rats.

Introduction:The present study investigated the role of the Basolateral Amygdala (BLA) N-methyl-D-aspartate (NMDA) receptors in stress-induced spatial memory disturbance among the male Wistar rats.Methods:The male Wistar rats (Average weight =200 g) were cannulated bilaterally in the BLA, and entered the study (n=6–8) after one week. They received seven electro–foot-shock stress sessions on seven consecutive days. Memantine (0.1, 1, and 5 μg/rat) or saline (0.5 μL/ rat) was injected into the BLA, five minutes before each stress session. The control groups received the same doses of memantine and no stress. After the end of the stress sessions, blood samples were taken from all animals to evaluate their plasma corticosterone. Also, the spatial learning and memory of the study animals were evaluated using the Barnes maze method. The animals experienced five consecutive days of training on the maze for spatial learning. On the sixth day, their spatial memory was evaluated on the maze. Time, distance, the number of errors, and the taking strategy for reaching the target hole were considered as the parameters for the spatial learning and memory evaluation.Results:Stress increases the plasma corticosterone level, while memantine preadministration reduces the stress effects. Besides, stress increases the time and distance to the target hole and the number of errors. Stress changed the animals’ strategy from serial to random type. However, the intra-BLA memantine reversed all the disturbances induced by the stress.Conclusion:This study indicated that the BLA glutamate NMDA receptors modulate the effect of stress on spatial learning and memory deficit.

Cellular mechanisms of neuroimmune interaction in multiple sclerosis: ionotropic glutamate receptors of T-lymphocytes

Using flow cytometry and real-time RT-PCR, we studied the effect of the blockade of glutamate NMDA receptors on the quantitative distribution of IFNγ- and IL-4-producing CD4+ and CD8+ T-lymphocytes and the expression of transcription factor of genes T-bet and GATA-3 in immune cells derived from healthy individuals and multiple sclerosis patients (MS). From the results of the study, it follows that blockade of NMDA receptors leads to a decrease in the proportion of studied effector subpopulations of T-lymphocytes, as well as differential modulation of gene expression of transcription factors (TBX21, GATA3). The severity of the negative effect of receptor blockade differs in different subpopulations of CD4+ and CD8+ T cells, which leads to a shift in the cytokine balance towards “proinflammatory” type 1 T-cells, to a greater extent in patients with MS. Thus, glutamate can regulate the Th1/Th2 and Tc1/Tc2 сytokine balance by modulating the activity of NMDA receptors of T lymphocytes in MS.

Effects of glutamate-related drugs on anxiety and compulsive behavior in rats with obsessive-compulsive disorder

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). We examined the effects and potential mechanism of glutamate-related drugs on compulsive behavior in quinpirole (QNP)-sensitized rats, to deepen our understanding of the link between OCD and glutamate.Method: This study systematically compared the effects of the partial NMDA agonist D-Cycloserine and the NMDA antagonist NVP-AAMO77, Ro25-6981 on compulsive behavior using the elevated zero maze, open field, and marble burying tests in QNP-induced OCD model.Results: The competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists NVP-AAMO77 (5 mg/kg) and Ro25-6981 (5 mg/kg) significantly inhibited anxiety-like and compulsive behavior in rats. And D-Cycloserine at all doses showed significant suppression on anxiety-like and marble-burying behavior. Glutamic acid (Glu) levels, reflecting changes in the glutamatergic neurotransmission, were significantly decreased in rat hippocampus of the NVP-AAMO77 and D-Cycloserine-treated group compared to the saline-treated group. The levels of other amino acids were unaffected. Moreover, NVP-AAMO77 significantly decreased the expression of the subunit NR2A of the NMDAR, and Ro25-6981 suppressed the level of the subunit NR2B of the NMDAR, while D-Cycloserine decreased both the subunit NR2A and NR2B of the NMDAR.Conclusion: Collectively, these findings suggest a functional role of NMDARs in anxiety and compulsive behaviors, with NMDARs inhibition promoting anxiolytic-like and anti-compulsive responses. These findings suggest that D-cycloserine, NVP-AAMO77, and Ro25-6981 could be useful drugs for the treatment of OCD, which may be due to the suppression of NR2A- or NR2B- containing NMDAR.