THE INTERPLAY OF GLUTAMATE-ASPARTATE SIGNALING AND THE NITRIC OXIDE SYSTEM: MOLECULAR MECHANISMS, PHYSIOLOGICAL FUNCTIONS, PATHOLOGICAL CONSEQUENCES, AND THERAPEUTIC INTERVENTIONS
DOI:
https://doi.org/10.11603/mcch.2410-681X.2025.i4.15928Keywords:
Nitric Oxide (NO); Glutamate; NMDA-receptor; Excitotoxicity; neuronal NO synthase (nNOS).Abstract
Introduction. The interaction between the excitatory amino acid (EAA) system (L-glutamate, L-aspartate) and the nitric oxide (NO) system is a fundamental signaling cascade in mammals. It functions as a “double-edged sword”, defining the boundary between physiological adaptation and pathological damage. The Aim of the Study. To conduct a comprehensive, interdisciplinary analysis and to systematize current data on the molecular mechanisms, physiological and pathological roles, and therapeutic potential of the glutamate- NO signaling pathway. Results and Discussion. The central integrative event is the activation of the ionotropic NMDA-receptor (NMDAR), which triggers calcium-dependent NO synthesis by neuronal NO synthase (nNOS). Under physiological conditions, this cascade is essential for synaptic plasticity (LTP), neurovascular coupling, and peripheral regulation (e.g., in the GIT). However, its overactivation during ischemia, trauma, and neuroinflammation initiates the mechanism of excitotoxicity. This review provides a detailed analysis of key pathogenetic links: (1) the conversion of NO into the highly toxic peroxynitrite; (2) the role of inducible iNOS in neuroinflammation; (3) the phenomenon of nNOS “uncoupling” due to deficiency of its cofactor BH4; and (4) the critical role of the GluN2B-PSD-95- nNOS supramolecular complex as a “pro-death” signal target. The pathological role of the cascade in stroke, neurodegenerative diseases (Alzheimer’s, Parkinson’s), and the formation of chronic pain is discussed. Conclusions. The clinical failures of non-selective NMDAR antagonists are analyzed, justifying the shift in therapeutic strategies toward “fine-tuning” modulation. Promising approaches include selective GluN2B subunit antagonists, ONOO- scavengers, nNOS stabilizers, and innovative peptides that disrupt the pathological PSD-95/ nNOS interaction. Understanding this cascade remains a priority for developing new treatments for neurological and somatic disorders.
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