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Biomolecules
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NMDA Receptor in Health and Diseases: 2nd Edition
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NMDA Receptor in Health and Diseases: 2nd Edition

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 7391

Special Issue Editor

Prof. Dr. Motohiro Okada

E-Mail Website
Guest Editor
Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan
Interests: epilepsy; schizophrenia; exocytosis; tripartite synaptic transmission

Special Issue Information

Dear Colleagues,

A pathologically hyperactivated NMDA receptor leads to an excitotoxicity reaction via the enhancement of cation inflow and the redox response; however, clinically NMDA receptor blocker generates severe adverse effects similar to the positive and negative symptoms of schizophrenia. It has been accepted that functional abnormalities of NMDA receptors contribute to the pathogenesis and pathophysiology of various neurodegenerative diseases and psychiatric disorders, such as schizophrenia, mood disorders, autism spectrum disorder, intellectual disability, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, stroke and brain ischemia. Especially, NMDA receptor inhibitor is recently established to be novel agents for the treatment of antidepressant-resistant depression. The purpose of this Special Issue, “NMDA receptors in health and disease”, will introduce the fields associated with NMDA receptors, explore advances and disadvantages in the role of NMDA receptors in diseases and disorders of the CNS, and discuss their possibilities as pharmacological tools to regulate glutamatergic transmission in several psychiatric disorders and neurodegenerative diseases associated with NMDA receptors. We invite authors to submit original research and review articles related to any of these aspects.

Prof. Dr. Motohiro Okada
Guest Editor

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Published Papers (4 papers)

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Research

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16 pages, 2825 KiB  
Article
Inhibition of NMDA Receptor Activation in the Rostral Ventrolateral Medulla by Amyloid-β Peptide in Rats
by Md Sharyful Islam, Chih-Chia Lai, Lan-Hui Wang and Hsun-Hsun Lin
Biomolecules 2023, 13(12), 1736; https://doi.org/10.3390/biom13121736 - 2 Dec 2023
Cited by 2 | Viewed by 1922
Abstract
N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (Aβ) is linked to the pathogenesis of Alzheimer’s disease (AD). Cerebro- and cardiovascular diseases might be the [...] Read more.
N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (Aβ) is linked to the pathogenesis of Alzheimer’s disease (AD). Cerebro- and cardiovascular diseases might be the risk factors for developing AD. The present study examines the acute effects of soluble Aβ on the function of NMDA receptors in rats RVLM. We used the magnitude of increases in the blood pressure (pressor responses) induced by microinjection of NMDA into the RVLM as an index of NMDA receptor function in the RVLM. Soluble Aβ was applied by intracerebroventricular (ICV) injection. Aβ1-40 at a lower dose (0.2 nmol) caused a slight reduction, and a higher dose (2 nmol) showed a significant decrease in NMDA-induced pressor responses 10 min after administration. ICV injection of Aβ1-42 (2 nmol) did not affect NMDA-induced pressor responses in the RVLM. Co-administration of Aβ1-40 with ifenprodil or memantine blocked the inhibitory effects of Aβ1-40. Immunohistochemistry analysis showed a significant increase in the immunoreactivity of phosphoserine 1480 of GluN2B subunits (pGluN2B-serine1480) in the neuron of the RVLM without significant changes in phosphoserine 896 of GluN1 subunits (pGluN1-serine896), GluN1 and GluN2B, 10 min following Aβ1-40 administration compared with saline. Interestingly, we found a much higher level of Aβ1-40 compared to that of Aβ1-42 in the cerebrospinal fluid (CSF) measured using enzyme-linked immunosorbent assay 10 min following ICV administration of the same dose (2 nmol) of the peptides. In conclusion, the results suggest that ICV Aβ1-40, but not Aβ1-42, produced an inhibitory effect on NMDA receptor function in the RVLM, which might result from changes in pGluN2B-serine1480 (regulated by casein kinase II). The different elimination of the peptides in the CSF might contribute to the differential effects of Aβ1-40 and Aβ1-42 on NMDA receptor function. Full article
(This article belongs to the Special Issue NMDA Receptor in Health and Diseases: 2nd Edition)
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Review

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21 pages, 611 KiB  
Review
Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia
by Ruri Okubo, Motohiro Okada and Eishi Motomura
Biomolecules 2024, 14(9), 1128; https://doi.org/10.3390/biom14091128 - 6 Sep 2024
Viewed by 1181
Abstract
For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and [...] Read more.
For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR. Full article
(This article belongs to the Special Issue NMDA Receptor in Health and Diseases: 2nd Edition)
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10 pages, 1423 KiB  
Review
Role of NMDA Receptor in High-Pressure Neurological Syndrome and Hyperbaric Oxygen Toxicity
by Alice Bliznyuk and Yoram Grossman
Biomolecules 2023, 13(12), 1786; https://doi.org/10.3390/biom13121786 - 13 Dec 2023
Cited by 1 | Viewed by 1734
Abstract
Professional divers exposed to pressures greater than 11 ATA (1.1 MPa) may suffer from high-pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus and patients and medical attendants undergoing hyperbaric oxygen therapy (HBOT) face the risk of CNS hyperbaric oxygen toxicity (HBOTx) [...] Read more.
Professional divers exposed to pressures greater than 11 ATA (1.1 MPa) may suffer from high-pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus and patients and medical attendants undergoing hyperbaric oxygen therapy (HBOT) face the risk of CNS hyperbaric oxygen toxicity (HBOTx) at oxygen pressure above 2 ATA (0.2 MPa). Both syndromes are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits, and N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in provoking them. Various NMDAR subtypes respond differently under hyperbaric conditions. The augmented currents observed only in NMDAR containing GluN2A subunit increase glutamatergic synaptic activity and cause dendritic hyperexcitability and abnormal neuronal activity. Removal of the resting Zn2+ voltage-independent inhibition exerted by GluN2A present in the NMDAR is the major candidate for the mechanism underlying the increase in receptor conductance. Therefore, this process should be the main target for future research aiming at developing neuroprotection against HPNS and HBOTx. Full article
(This article belongs to the Special Issue NMDA Receptor in Health and Diseases: 2nd Edition)
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17 pages, 2151 KiB  
Review
A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine
by Kouji Fukuyama, Eishi Motomura and Motohiro Okada
Biomolecules 2023, 13(9), 1288; https://doi.org/10.3390/biom13091288 - 23 Aug 2023
Cited by 5 | Viewed by 1812
Abstract
Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical [...] Read more.
Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-β-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine. Full article
(This article belongs to the Special Issue NMDA Receptor in Health and Diseases: 2nd Edition)
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