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N-Methyl-d-aspartate (NMDA) receptor hyperfunction plays a key role in the pathological processes of depression and neurodegenerative diseases, whereas NMDA receptor hypofunction is implicated in schizophrenia. Considerable efforts have been made to target NMDA receptor function for the therapeutic intervention in those brain disorders. In this mini-review, we first discuss ion flux-dependent NMDA receptor signaling and ion flux-independent NMDA receptor signaling that result from structural rearrangement upon binding of endogenous agonists. Then, we review current strategies for exploring druggable targets of the NMDA receptor signaling and promising future directions, which are poised to result in new therapeutic agents for several brain disorders. [ABSTRACT FROM AUTHOR]

Background and objectives: Encephalitis is a devastating neurologic disorder with high morbidity and mortality. Autoimmune causes are roughly as common as infectious ones. N-methyl-D-aspartic acid receptor (NMDAR) encephalitis (NMDARE), characterized by serum and/or spinal fluid NMDAR antibodies, is the most common form of autoimmune encephalitis (AE). A translational rodent NMDARE model would allow for pathophysiologic studies of AE, leading to advances in the diagnosis and treatment of this debilitating neuropsychiatric disorder. The main objective of this work was to identify optimal active immunization conditions for NMDARE in mice. Methods: Female C57BL/6J mice aged 8 weeks old were injected subcutaneously with an emulsion of complete Freund's adjuvant, killed and dessicated Mycobacterium tuberculosis, and a 30 amino acid peptide flanking the NMDAR GluN1 subunit N368/G369 residue targeted by NMDARE patients' antibodies. Three different induction methods were examined using subcutaneous injection of the peptide emulsion mixture into mice in 1) the ventral surface, 2) the dorsal surface, or 3) the dorsal surface with reimmunization at 4 and 8 weeks (boosted). Mice were bled biweekly and sacrificed at 2, 4, 6, 8, and 14 weeks. Serum and CSF NMDAR antibody titer, mouse behavior, hippocampal cell surface and postsynaptic NMDAR cluster density, and brain immune cell entry and cytokine content were examined. Results: All immunized mice produced serum and CSF NMDAR antibodies, which peaked at 6 weeks in the serum and at 6 (ventral and dorsal boosted) or 8 weeks (dorsal unboosted) post-immunization in the CSF, and demonstrated decreased hippocampal NMDAR cluster density by 6 weeks post-immunization. In contrast to dorsally-immunized mice, ventrally-induced mice displayed a translationallyrelevant phenotype including memory deficits and depressive behavior, changes in cerebral cytokines, and entry of T-cells into the brain at the 4-week timepoint. A similar phenotype of memory dysfunction and anxiety was seen in dorsallyimmunized mice only when they were serially boosted, which also resulted in higher antibody titers. Discussion: Our study revealed induction method-dependent differences in active immunization mouse models of NMDARE disease. A novel ventrallyinduced NMDARE model demonstrated characteristics of AE earlier compared to dorsally-induced animals and is likely suitable for most short-term studies. However, boosting and improving the durability of the immune response might be preferred in prolonged longitudinal studies. [ABSTRACT FROM AUTHOR]

Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids' enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, consciousness impairment in patients with end‐stage renal disease (ESRD) has been paid more and more attention, but the cause and mechanism of consciousness state change is not clear. Methods: As the hippocampus played a crucial role in consciousness, we explored the pathological and electrophysiological changes in chronic kidney disease (CKD) mouse hippocampus. Results: Whole‐cell recordings in hippocampal neurons showed that miniature excitatory postsynaptic current (mEPSC) frequency decreased, but the amplitude was unaltered in CKD_8w mice. In addition, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor‐mediated EPSCs (AMPAR‐EPSCs) and N‐methyl‐D‐aspartic acid receptor‐mediated EPSCs (NMDAR‐EPSCs) in hippocampal Schaffer collateral‐CA1 synapses displayed a significant decline in CKD_8w mice. Although the ratio of AMPAR‐/NMDAR‐EPSCs did not change, the paired‐pulse ratio (PPR) in CKD_8w mice increased. Intriguingly, the mEPSC frequency and AMPAR‐/NMDAR‐EPSCs amplitudes were positively associated with body weight, and the mEPSC frequency was negatively correlated with serum creatinine in CKD_8w mice, indicating a potential correlation between cognition and nutritional status in patients with CKD. To confirm the above hypothesis, we collected the clinical data from multiple hemodialysis centers to analyze the correlation between cognition and nutritional status. Conclusion: Our analysis indicated that protein energy wasting (PEW) was a possible independent risk factor for consciousness dysfunction in maintenance hemodialysis (MHD) patients. Our results provided a more detailed mechanism underlying the cognitive impairment (CI) in ESRD patients at the synaptic level. Last but not least, our results showed that PEW was a probable new independent risk factor for CI in cases with ESRD. [ABSTRACT FROM AUTHOR]

Copyright of Revista de Toxicología is the property of Asociacion Espanola de Toxicologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A strict localization into the neural retina and the capacity to survive many pathogenic conditions are unique characteristics of Müller glia. Retinal damage induces cellular and molecular changes that place Müller cells as focal points to either protect or further impair neuronal function. This work evaluated the involvement of extracellular vesicles (EVs) in the transduction of high N-methyl-D-aspartate (NMDA) concentration signal between Müller glia-to-Müller glia as part of several factors and signal transduction mechanisms dictating either a gliotic (damaging) or regenerative process. These EVs were obtained, characterized, and quantified from control and NMDA-treated Müller cells using murine Müller cell primary cultures to evaluate the functional outcome of these preparations. The obtained results support the existence of different subpopulations of EVs that may induce a differential response. These EVs did not affect the viability, migration, and wound healing capacity of cultured Müller cells. However, the EVs obtained from NMDA-treated Müller cultures, but not from untreated cells, increased actin polymerization and induced the expression of the multipotency genes nestin and lin28. We propose that, upon a lesion paradigm, Müller-derived EVs may induce the spread of molecular changes in neighboring cells resulting in the formation of the characteristic glial retinal scar in mammalians or else trigger a neurogenic process in regenerative species. Summary Statement: Retinal Müller cells secrete extracellular vesicles that can be captured by other Müller cells. In response to a signal that may be deleterious for the retina, Müller glia-derived extracellular vesicles spread instructions to induce gene expression changes in other cells. [ABSTRACT FROM AUTHOR]

Depression, a mental disorder that plagues the world, is a burden on many families. There is a great need for new, fast-acting antidepressants to be developed. N-methyl-D-aspartic acid (NMDA) is an ionotropic glutamate receptor that plays an important role in learning and memory processes and its TMD region is considered as a potential target to treat depression. However, due to the unclear binding sites and pathways, the mechanism of drug binding lacks basic explanation, which brings great complexity to the development of new drugs. In this study, we investigated the binding affinity and mechanisms of an FDA-approved antidepressant (S-ketamine) and seven potential antidepressants (R-ketamine, memantine, lanicemine, dextromethorphan, Ro 25-6981, ifenprodil, and traxoprodil) targeting the NMDA receptor by ligand–protein docking and molecular dynamics simulations. The results indicated that Ro 25-6981 has the strongest binding affinity to the TMD region of the NMDA receptor among the eight selected drugs, suggesting its potential effective inhibitory effect. We also calculated the critical binding-site residues at the active site and found that residues Leu124 and Met63 contributed the most to the binding energy by decomposing the free energy contributions on a per-residue basis. We further compared S-ketamine and its chiral molecule, R-ketamine, and found that R-ketamine had a stronger binding capacity to the NMDA receptor. This study provides a computational reference for the treatment of depression targeting NMDA receptors, and the proposed results will provide potential strategies for further antidepressant development and is a useful resource for the future discovery of fast-acting antidepressant candidates. [ABSTRACT FROM AUTHOR]

Byline: Hongfei. Xue, Yushu. Jiang, Lingzhi. Qin, Xiaojuan. Wang, Milan. Zhang, Shuhua. Dai, Yongshi. Teng, Jiajia. Xu, Wei. Li Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a type of autoimmune encephalitis (AE) [...]

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune condition caused by reversible internalization of the NMDA receptor as the result of autoantibodies produced via an immunologic trigger. (1) The condition [...]

Background: Flexible fiberoptic bronchoscopy (FFB) for children is widely performed under sedation. Currently, the optimal sedation regimen remains unclear. Esketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which has stronger sedative and analgesic effects and exerts less cardiorespiratory depression than other sedatives. The purpose of this study was to evaluate whether a subanesthetic dose of esketamine as an adjuvant to propofol/remifentanil and spontaneous ventilation compared with control reduces the procedural and anesthesia-related complications of FFB in children. Materials and methods: Seventy-two children ≤ 12 years of age who were scheduled for FFB were randomly assigned, in a 1:1 ratio, to the esketaminepropofol/ remifentanil (Group S, n = 36) or to the propofol/remifentanil group (Group C, n = 36). All children were retained spontaneous ventilation. The primary outcome was the incidence of oxygen desaturation (respiratory depression). Perioperative hemodynamic variables, blood oxygen saturation (SPO2), endtidal partial pressure of carbon dioxide (PetCO2), respiratory rate (R), and the Bispectral index (BIS), induction time, procedural time, recovery time, the time to the ward from the recovery room, consumption of propofol and remifentanil during the procedure and the appearance of adverse events, including paradoxical agitation following midazolam administration, injection pain, laryngospasm, bronchospasm, PONV, vertigo, and hallucination were also compared. Results: The incidence of oxygen desaturation was significantly lower in Group S (8.3%) compared to Group C (36.1%, p = 0.005). The perioperative hemodynamic profile including SBP, DBP, and HR were more stable in Group S than that in Group C (p < 0.05). Consumption of propofol and remifentanil was lower in Group S than in Group C (p < 0.05). Furthermore, PAED scores, cough scores and injection pain were lower in the Group S than in Group C (p < 0.05). The recovery time of Group S was slightly longer than that of Group C (p < 0.05). Nobody happened paradoxical agitation following midazolam administration, PONV, vertigo, and hallucinations in both groups (p > 0.05). Conclusion: Our findings indicate that a subanesthetic dose of esketamine as an adjuvant to propofol/remifentanil and spontaneous respiration is an effective regimen for children undergoing FFB. Our findings will provide a reference for clinical sedation practice during these procedures in children. [ABSTRACT FROM AUTHOR]

Aims: N‐methyl‐D‐aspartic acid (NMDA) receptors play subunit‐specific role in central neuronal development. However, insights into the pharmacological modulation of NMDA receptors were mainly lack of subunit and synaptic selectivity. The purpose of the present study was to develop a novel strategy to rapidly recognize NMDA subunit 2A (NMDA‐2A) ligands from natural products and provide subunit‐selective drug candidates for Alzheimer's disease (AD). Methods: The recombinant NMDA‐2A containing a tag of epidermal growth factor receptor (EGFR) was expressed in Escherichia coli cells and immobilized on ibrutinib‐modified microspheres based on the specific reaction between EGFR and its inhibitor ibrutinib. A novel affinity stationary phase was synthesized to screen NMDA‐2A ligands from Gardenia jasminoides Ellis. Results: The immobilized receptor column exhibited excellent receptor selectivity and ligand‐binding activity. Crocetin was screened by using this method. In a cellular model of AD, the protein level of NMDA‐2A was significantly decreased compared with the control group, while treatment with crocetin significantly increased NMDA‐2A level in a concentration‐dependent manner, confirming that crocetin could bind to NMDA‐2A in vitro. Conclusion: In the present study, we developed a reliable method for the rapid identification of NMDA‐2A ligands from natural products, which may be used as a platform for new drug discovery to generate high‐quality drug candidates. [ABSTRACT FROM AUTHOR]

New-onset refractory status epilepticus (NORSE) is a rare entity referring refractory status epilepticus (SE) in a patient without a history of epilepsy or an apparent cause. Herein, we report on a 31-year-old young female of anti-N-methyl D-aspartate (NMDA) receptor encephalitis admitted with NORSE. Her complaints began a week ago with a fever, meaningless movements, restlessness, and talking to herself. She had a history of operation for ovarian teratoma 10 years ago. Electrocardiography, hemogram, biochemistry, and neuroimaging were normal. Due to recurrent seizures despite intravenous diazepam infusions, phenytoin infusion was introduced, reducing the duration and frequency of seizures. Electroencephalogram (EEG) revealed a generalized slow background activity with low voltage and delta waves in left hemisphere derivatives without any epileptiform discharge. Autoimmune encephalitis panel revealed a positive anti-NMDAR receptor antibody. Intravenous immunoglobulins were given for 5 days. She was improved clinically and did not have a recurrent seizure. The history of our case emphasizes the importance of EEG and CSF antibody tests to reach the underlying etiology in patients presenting with refractory SE and neuropsychiatric symptoms of an unknown cause. Application of a proper treatment promptly with this approach could prevent the potential morbidity and mortality in these patients. [ABSTRACT FROM AUTHOR]

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Objectives: The usage of caffeine, a psychostimulant that is included in many foods and drinks, is rising, especially among young people. Also, caffeine works as an ergogenic substance during exercise to improve performance, and strength. In this study, our aim was to investigate the effect of caffeine consumption and exercise on hippocampal learning and memory functions in early life. Methods: Postnatal 28 days old Wistar albino male rats (n = 28) were randomly divided into 4 groups; control group (C), caffeine group (Cf), exercise group (E), caffeine+exercise group (CfE). Caffeine was dissolved in drinking water (0.3 g/L) and the treadmill exercise was applied 3 days a week. Following, the rats were applied to Morris Water Maze Test (MWMT) and open field test. N-methyl-D-aspartate (NMDA) receptors NR2A, NR2B, and brain-derived neurotrophic factor (BDNF) gene expression levels were investigated in hippocampus tissue by RT-PCR. Results: In MWMT, there was no significant difference in terms of learning and memory functions and hippocampal gene expression levels of the groups (p > 0.05). In the open field test, the time spent in the center was decreased in the CfE group, and the number of entries to the center was decreased in the E and CfE groups compared to the control group (p < 0.05). Conclusions: We assumed that caffeine given with exercise application caused anxiety behavior but did not affect learning and memory. There is a need for new studies investigating the effect of caffeine on exercise with different doses and durations depending on age. [ABSTRACT FROM AUTHOR]

Background: Regulation of cerebral blood flow (CBF) directly influence brain functions and dysfunctions and involves complex mechanisms, including neurovascular coupling (NVC). It was suggested that the serine protease tissue-type plasminogen activator (tPA) could control CNV induced by whisker stimulation in rodents, through its action on N-methyl-d-Aspartate receptors (NMDARs). However, the origin of tPA and the location and mechanism of its action on NMDARs in relation to CNV remained debated. Methods: Here, we answered these issues using tPANull mice, conditional deletions of either endothelial tPA (VECad-CreΔtPA) or endothelial GluN1 subunit of NMDARs (VECad-CreΔGluN1), parabioses between wild-type and tPANull mice, hydrodynamic transfection-induced deletion of liver tPA, hepatectomy and pharmacological approaches. Results: We thus demonstrate that physiological concentrations of vascular tPA, achieved by the bradykinin type 2 receptors-dependent production and release of tPA from liver endothelial cells, promote NVC, through a mechanism dependent on brain endothelial NMDARs. Conclusions: These data highlight a new mechanism of regulation of NVC involving both endothelial tPA and NMDARs. [ABSTRACT FROM AUTHOR]

Objectives] To explore the antidepressant-like effects of PAFL and its potential mechanisms. [Methods] This study used PAFL in mice under various conditions and analyzed the results. The antidepressant-like effects of flavonoids from Pteridium aquilinum (PAFL) and its possible action mechanism were discussed. [Results] PAFL (5 mg/kg, i. p.) exhibited markedly antidepressant-like activities, which could be reversed by treatment with p-chlorophenylalanine (an inhibitor of 5-HT synthesis), haloperidol (a non-selective D2 receptor antagonist) and N-methyl-D-aspartic acid (an agonist at the glutamate site). Meanwhile, PAFL also effectively increased the hippocampus 5-HT, DA, and Glu levels of mice exposed to TST and FST. The LPS-induced antidepressant behavioral experiment showed that PAFL (1 and 5 mg/kg, i. p.) and fluoxetine (20 mg/kg, i. p.) effectively reduced the immobility time, and increase activity time in OFT. PAFL pretreatment significantly reduced IL-6 and TNF-a serum levels and improve the changes of hippocampal SOD and MDA oxidative stress indicators. Furthermore, PAFLpreconditioning could up-regulate BDNF and TikB contents in hippocampus and down-regulate IkB-q and NF-kB phosphorylation. [Conclusions] The antidepressant-like effects of PAFL might be mediated by the 5-HT, DAergic and Gluergic systems, and the mechanisms of anti-depressant effects of PAFL might be via the alterations of animal behaviors, hippocampus inflammation and neurotrophy, which might be attributed by the BDNF/TtkB/NF-kB signaling pathway. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gelsemium is a medicinal plant that has been used to treat various diseases, but it is also well-known for its high toxicity. Complex alkaloids are considered the main poisonous components in Gelsemium. However, the toxic mechanism of Gelsemium remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of Gelsemium toxicity. The alkaloid compounds and candidate targets of Gelsemium, as well as related targets of excitotoxicity, were collected from public databases. The crucial targets were determined by constructing a protein–protein interaction (PPI) network. Subsequently, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the bioprocesses and signaling pathways involved in the excitotoxicity corresponding to alkaloids in Gelsemium. Then, the binding affinity between the main poisonous alkaloids and key targets was verified by molecular docking. Finally, animal experiments were conducted to further evaluate the potential mechanisms of Gelsemium toxicity. A total of 85 alkaloids in Gelsemium associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of Gelsemium was mainly related to the protein phosphorylation reaction and plasma membrane function. There were also 164 pathways involved in the toxic mechanism, such as the calcium signaling pathway and MAPK signaling pathway. Molecular docking showed that alkaloids have high affinity with core targets, including MAPK3, SRC, MAPK1, NMDAR2B and NMDAR2A. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD50 values of female and male mice were 0.071 mg·kg−1 and 0.149 mg·kg−1, respectively. Furthermore, we found that N-methyl-D-aspartic acid (NMDA), a specific NMDA receptor agonist, could significantly increase the survival rate of acute humantenirine-poisoned mice. The results also show that humantenirine could upregulate the phosphorylation level of MAPK3/1 and decrease ATP content and mitochondrial membrane potential in hippocampal tissue, while NMDA could rescue humantenirine-induced excitotoxicity by restoring the function of mitochondria. This study revealed the toxic components and potential toxic mechanism of Gelsemium. These findings provide a theoretical basis for further study of the toxic mechanism of Gelsemium and potential therapeutic strategies for Gelsemium poisoning. [ABSTRACT FROM AUTHOR]

Propofol is widely used as a short-acting intravenous anaesthetic for the induction and maintenance of anaesthetic sedation. The application of propofol is expanding due to its advantages and the increasing demand for painless diagnosis and treatment. However, accumulating clinical and experimental evidence has shown that propofol can potentially be abused and is prone to causing addiction. To further understand the underlying mechanism of propofol addiction, our review places emphasis on explaining the roles of the mesolimbic, noradrenergic, and nitrergic systems in propofol addiction. We have focused on the role of the gamma-aminobutyric acid, glucocorticoid, N-methyl-D-aspartic acid, adenosine A2A, and corticotropin-releasing factor receptors in the mesolimbic system in forming and maintaining propofol addiction. Furthermore,wehave attempted to clarify the relationship between the dopaminergic pathway, extracellular signal-regulated kinase signalling pathway, and the ventral tegmental area-nucleus accumbens circuit in the mesolimbic system. [ABSTRACT FROM AUTHOR]

Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a broad range of disorders of the central nervous system. Despite significant progress in characterizing structure and transport mechanism of the transporter, the regulation of transport function through oligomerization remains to be understood. In the present work, association of two forms of GlyT1 into dimers and higher order oligomers was detected by coimmunoprecipitation. To investigate functional properties of dimers of a GlyT1 cysteine mutant L288C, we performed oxidative cross-linking of the positioned cysteine residues in extracellular loop 3 (EL3) near the extracellular end of TM6. By analyzing the effect of copper phenanthroline (CuP)-induced dimerization on transport function, cross-linking of L288C was found to inhibit transport activity. In addition, an intramolecular ion pair Lys286-Glu289 was revealed to be critical for stabilizing EL3 in a conformation that modulates CuP-induced dimerization and transport function of the GlyT1 L288C mutant. Furthermore, the influence of transporter conformation on GlyT1 L288C dimerization was investigated. The substrate glycine, in the presence of both Na+ and Cl−, significantly reduced oxidative cross-linking, suggesting a large-scale rotation of the bundle domain during substrate transport impairs interfacial interactions between L288C protomers. The present study provides new insights into structural and functional elements regulating GlyT1 transport activity through its dimerization or oligomerization. [ABSTRACT FROM AUTHOR]

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia's, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O's dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

A diallyl amine salt monomer bearing a β-CD substituent was cyclopolymerized for the first time. The reaction of 6-O-toluenesulfonyl-β-cyclodextrin [(C 6 H 10 O 5) 6 -(C 5 H 7)]-CH 2 OTs with diallylamine followed by protonation afforded the diallylamine salt monomer [(C 6 H 10 O 5) 6 -(C 5 H 7)]-CH 2 NH+(CH 2 CH=CH 2) 2 Cl−] (I). The cyclopolymerization of monomer I and its copolymerization with monomer [Me 2 N+(CH 2 CH=CH 2) 2 Cl−] (II), [−O 2 CCH 2 NH+(CH 2 CH=CH 2) 2 ] (III), [H 2 O 3 PCH 2 NH+(CH 2 CH=CH 2) 2 Cl−] (IV) or [HO 2 CCH 2 CH(CO 2 H)NH+(CH 2 CH=CH 2) 2 Cl−] (V) yielded a series of copolymers having residues of β-CD and glycine or methyl phosphonate or aspartic acid. Terpolymerization in the presence of SO 2 afforded polymers with alternating placements of the SO 2 units. The solution properties of the pH-responsive polyzwitterions, including their viscosity, were examined. The water-insoluble terpolymer I / V /SO 2 with 20 mol% β-CD residues removed the organic micropollutant 2-naphthol from an aqueous system via host/guest complexation. This work paves the way for the possible synthesis of cross-linked polymers that can simultaneously remove organic micropollutants and toxic metal ions (by complexation with the chelating glycine, aspartic acid, and aminomethyl phosphonate ligands) from contaminated aqueous systems. [Display omitted] [ABSTRACT FROM AUTHOR]

Byline: Sankar. Gorthi, Dulari. Gupta Background and Aims: The scope of treatment in Alzheimer's Disease has widened in recent times with FDA approval of new drugs. This review looks at [...]

Alcohol use disorder (AUD) is a global public health problem and is frequently comorbid with mental disorders, including anxiety and depression. Ferroptosis is an iron-dependent cell death, which is involved in the pathological process of various diseases such as neurodegenerative diseases, but the role of ferroptosis in the mediation of AUD and its induced mental disorders is unclear. In this study, we aimed to investigate whether ferroptosis was involved in alcohol-induced depressive and anxiety-like behaviors in mice. Following an 8-week period of intermittent alcohol exposure, the alcohol group showed noticeable depressive and anxiety-like behaviors. In addition, nissl staining revealed that alcohol exposure induced neuron damage in the hippocampus (Hip) and prefrontal cortex (PFC) of mice. The levels of synapse-related proteins were significantly reduced in the alcohol group. Iron staining demonstrated that alcohol increased the number of iron-positive staining cells. The protein expression of the transferrin receptor (TFRC) was increased, and the expression of glutathione peroxidase 4 (GPX4) was decreased, respectively, in the alcohol group. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly prevented alcohol-induced neuron damage and enhanced the expression of N-methyl-d-aspartic acid (NMDA) receptor 2B (NR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor 1 (GluA1) and GPX4 in vitro. These results indicated that alcohol exposure could induce depressive and anxiety-like behaviors, and that this effect may occur via activating ferroptosis. [ABSTRACT FROM AUTHOR]

The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug–drug interactions. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) and tumor necrosis factor (TNF)-α contribute to the pathogenesis of several ocular diseases. Previous studies have shown that MMP-9 activation plays an important role in capillary degeneration in injured retinas. In this study, we aimed to determine the roles of TNF-α in capillary degeneration and MMP-9 activation in the injured retina. In rats, retinal injury was induced by intravitreal injection of N-methyl-D-aspartic acid (NMDA, 200 nmol) at postnatal day 7. We examined (1) the effects of blocking MMP-9 and TNF-α signaling pathway on capillary degeneration, (2) changes in protein levels and distribution of MMP-9 and TNF-α, and (3) the interaction between MMP-9 and TNF-α in regulating the expression level of each protein in retinas of NMDA-injected eyes. Intravitreal injection of GM6001, an MMP inhibitor, or TNF-α neutralizing antibody (anti-TNF-α Ab) attenuated capillary degeneration in retinas of NMDA-injected eyes. Protein levels of TNF-α increased 2 h after NMDA injection, whereas those of MMP-9 increased 4 h after the injection. Anti-TNF-α Ab suppressed activation of MMP-9 in retinas of NMDA-injected eyes, whereas GM6001 diminished the TNF-α protein expression. Incubation of recombinant TNF-α with supernatants of homogenized retina increased protein levels and activity of MMP-9. These results suggest that TNF-α and MMP-9 collaboratively increase their expression levels in the retina following neurodegeneration, thus leading to retinal capillary degeneration. The cooperative interaction between MMP-9 and TNF-α could be involved in the exacerbation of retinal neurovascular degeneration. [ABSTRACT FROM AUTHOR]

There is a growing interest in the psychiatric properties of the dissociative anaesthetic ketamine, as single doses have been shown to have fast‐acting mood‐enhancing and anxiolytic effects, which persist for up to a week after the main psychoactive symptoms have diminished. Therefore, ketamine poses potential beneficial effects in patients with refractory anxiety disorders, where other conventional anxiolytics have been ineffective. Ketamine is a noncompetitive antagonist of the N‐methyl‐d‐aspartate (NMDA) glutamate receptor, which underlies its induction of pain relief and anaesthesia. However, the role of NMDA receptors in anxiety reduction is still relatively unknown. To fill this paucity in the literature, this systematic review assesses the evidence that ketamine significantly reduces refractory anxiety and discusses to what extent this may be mediated by NMDA receptor antagonism and other receptors. We highlight the temporary nature of the anxiolytic effects and discuss the high discrepancy among the study designs regarding many fundamental factors such as administration routes, complementary treatments and other treatments. [ABSTRACT FROM AUTHOR]

Most excitatory impulses received by neurons are mediated by ionotropic glutamate receptors (iGluRs). These receptors are located at the apex and play an important role in memory, neuronal development, and synaptic plasticity. These receptors are ligand-dependent ion channels that allow a wide range of cations to pass through. Glutamate, a neurotransmitter, activates three central ionotropic receptors: N-methyl-D-aspartic acid (NMDA), -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainic acid (KA). According to the available research, excessive glutamate release causes neuronal cell death and promotes neurodegenerative disorders. Arabidopsis thaliana contains 20 glutamate receptor genes (AtGluR) comparable to the human ionotropic glutamate (iGluRs) receptor. Many studies have proved that AtGL-rec genes are involved in a number of plant growth and physiological activities, such as in the germination of seeds, roots, abiotic and biotic stress, and cell signaling, which clarify the place of these genes in plant biology. In spite of these, the iGluRs, Arabidopsis glutamate receptors (AtGluR), is associated with the ligand binding activity, which confirms the evolutionary relationship between animal and plant glutamate receptors. Along with the above activities, the impact of mammalian agonists and antagonists on Arabidopsis suggests a correlation between plant and animal glutamate receptors. In addition, these glutamate receptors (plant/animal) are being utilized for the early detection of neurogenerative diseases using the fluorescence resonance energy transfer (FRET) approach. However, a number of scientific laboratories and institutes are consistently working on glutamate receptors with different aspects. Currently, we are also focusing on Arabidopsis glutamate receptors. The current review is focused on updating knowledge on AtGluR genes, their evolution, functions, and expression, and as well as in comparison with iGluRs. Furthermore, a high throughput approach based on FRET nanosensors developed for understanding neurotransmitter signaling in animals and plants via glutamate receptors has been discussed. The updated information will aid in the future comprehension of the complex molecular dynamics of glutamate receptors and the exploration of new facts in plant/animal biology. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder characterized by positive, negative, and cognitive symptoms. Cognitive symptoms are a kind of symptoms with high incidence and great impact on patients. There is no effective treatment in clinical practice. N-methyl-d-aspartic acid (NMDA) receptor hypofunction may be an important cause of cognitive symptoms. MK-801 (also named Dizocilpine), a noncompetitive antagonist of NMDA receptor, is often used to construct a model of NMDA receptor dysfunction. In terms of treatment, environmental enrichment (EE) as an environmental intervention can effectively improve the symptoms of cognitive impairment in rodents. In this paper, we first briefly introduce the background of cognitive symptoms and EE in schizophrenia, and then investigate the manifestations of MK-801 induced cognitive impairment, the improvement of EE on these cognitive impairments based on the MK-801 induced schizophrenia rodent models, and the possible mechanism of EE in improving cognitive symptoms. This article reviews the literature in recent years, which provides an important reference for MK-801 to construct a cognitive symptom model of schizophrenia and the mechanism of EE in improving cognitive symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) could effectively relieve the pain and depression in neuropathic pain (NP) patients. However, the specific treatment parameters and exact mechanism are still unclear. Our purpose is to observe the effects of rTMS on pain and despair‐like behaviour in chronic constriction injury (CCI) rats and explore its possible mechanism. Thirty‐two 8‐week‐old male Sprague–Dawley rats were randomly divided into four groups: sham operation group (S, n = 8), CCI group (n = 8), 1 Hz‐rTMS group (n = 8) and 10 Hz‐rTMS group (n = 8). The rTMS was applied to the left dorsal anterior agranular insular (AId) 1 week after the operation, once a day, 5 days/week for 4 consecutive weeks. Mechanical hyperalgesia, despair‐like behaviours and sciatic nerve function were used to evaluate the effects of rTMS. Besides, glucose metabolism, the metabotropic glutamate receptors 5 (mGluR5), N‐Methyl‐D‐Aspartic acid receptor type 2B (NMDAR2B), tumour necrosis factor‐α (TNF‐α), interleukin‐6 (Ll‐6) and interleukin‐1β (Ll‐1β) in AId were tested to explore the possible mechanism. Compared with 1 Hz‐rTMS, the rats of 10 Hz‐rTMS had higher the mechanical hyperalgesia, higher sugar preference and shorter swimming immobility time. Besides, the expressions of mGluR5, NMDAR2B, TNF‐α, Ll‐1β and Ll‐6 both in 1 Hz‐rTMS and 10 Hz‐rTMS groups were reduced compared with the CCI group; the 10 Hz‐rTMS group had a more decrease than that of 1 Hz‐rTMS. Furthermore, the [18]F‐FDG uptake was lower than that in the 1 Hz‐rTMS group. Compared with 1 Hz‐rTMS, 10 Hz‐rTMS could more effectively relieve mechanical hyperalgesia and reverse despair‐like behaviour in rats. The mechanism could be related to regulating mGluR5/NMDAR2B‐related inflammatory signalling pathways in the AId. [ABSTRACT FROM AUTHOR]

To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels, we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine receptors, perhaps because AMS is unstable at physiological pH. Here, we show that at pH 5, AMS is an efficacious agonist, eliciting in zebrafish α1 glycine receptors a maximum single-channel open probability of 0.85, much greater than that of β-alanine (0.54) or taurine (0.12), and second only to that of glycine itself (0.96). Thermodynamic cycle analysis of the efficacy of these closely related agonists shows supra-additive interaction between changes in the length of the agonist molecule and the size of the anionic moiety. Single particle cryo-electron microscopy structures of AMS-bound glycine receptors show that the AMS-bound agonist pocket is as compact as with glycine, and three-dimensional classification demonstrates that the channel populates the open and the desensitized states, like glycine, but not the closed intermediate state associated with the weaker partial agonists, β-alanine and taurine. Because AMS is on the cusp between full and partial agonists, it provides a new tool to help us understand agonist action in the pentameric superfamily of ligand-gated ion channels. [ABSTRACT FROM AUTHOR]

Kainate receptors (KARs) are glutamate receptors that participate in the postsynaptic transmission of information and in the control of neuronal excitability, as well as presynaptically modulating the release of the neurotransmitters GABA and glutamate. These modulatory effects, general follow a biphasic pattern, with low KA concentrations provoking an increase in GABA and glutamate release, and higher concentrations mediating a decrease in the release of these neurotransmitters. In addition, KARs are involved in different forms of long‐ and short‐term plasticity. Importantly, altered activity of these receptors has been implicated in different central nervous system diseases and disturbances. Here, we describe the pre‐ and postsynaptic actions of KARs, and the possible role of these receptors in disease, a field that has seen significant progress in recent years. [ABSTRACT FROM AUTHOR]

Objective: Neuropathic pain is a common secondary complication of spinal cord injury (SCI). N-methyl-D-aspartate (NMDA) receptor activation is critical for hypersensitivity in neuropathic pain. This activation requires the binding of both glutamate and the D-serine co-agonist to the NMDA glycine site. We evaluated the effects of D-serine on neuropathic pain after SCI and explored the underlying molecular mechanisms. Methods: Anesthetized rats underwent T9 spinal cord contusion (130 kdyn). D-serine (500 and 1,000 mg/kg) and MK-801 hydrogen maleate (2.0 mg/kg) were injected daily for 2 weeks, starting the day after SCI. Functional outcomes were assessed according to the Basso, Beattie, and Bresnahan scale, while histological outcomes were evaluated based on lesion volume and spared tissue area. Mechanical allodynia and thermal hyperalgesia were evaluated by measuring the withdrawal threshold of a von Frey filament and hot/cold plate latency. Western blotting was performed to determine the expression levels of Trpv1, Nav1.9, calcitonin gene-related peptide (CGRP), and ß-actin in damaged tissue. Results: The withdrawal threshold values and latency of the D-serine group were significantly lower than those of the noninjection group. The MK-801 group showed higher threshold values and latencies than the other groups. Western blotting showed increased Nav1.9 and Trpv1 levels and lower CGRP levels in the D-serine group, whereas the MK-801 group showed the opposite results. Conclusion: D-serine increases neuropathic pain after traumatic SCI by mediating the NMDA receptor. NMDA receptor antagonists alleviate neuropathic pain after traumatic SCI. [ABSTRACT FROM AUTHOR]