A Model of Glutamate Neurotoxicity and Mechanisms of the Development of the Typical Pathological Process

Abstract

A glutamate model of stroke was analyzed from the standpoint of the development of a typical pathological process that is thought to occur when major regulatory mechanisms are violated. The analysis made it possible to isolate the main mechanisms that underlie a transition from normal physiological processes to common pathological changes. This review considers a generalizing concept of how the pathological process develops. Following the concept, the typical pathological process is based on nonspecific distortion of cyclic regulatory processes and arises when reactive nitrogen species (RNS) and reactive oxygen species (ROS) increase simultaneously. Once RNS and ROS concentrations are beyond the regulatory capabilities of biochemical antioxidant systems, nitric oxide and superoxide anion radical cycles are disrupted. In the context of the concept, damage to cell membranes and subcellular structures in glutamate toxicity arises because the above alterations lead to the generation of nitrogen dioxide, which is a highly reactive compound, is involved in free radical chain reactions, and oxidizes the main biochemical components of living organisms: DNA/RNA (guanines primarily), fatty acids (unsaturated fatty acids that are components of phospholipid membranes), and proteins (the SH groups of sulfur-containing amino acids and the OH groups of tyrosine residues to produce nitrotyrosine). The concept agrees well with the ideas that every disease starts with a failure of regulatory mechanisms (R. Virkhov) and that dysregulatory pathology forms its basis (G.N. Kryzhanovsky). The mechanisms of the toxic effects of glutamate- and NO-generating compounds as a model of stroke made it possible to suggest methods to reduce their damaging effects. The methods have already been used as part of therapy for ischemic and hemorrhagic strokes, hemorrhages, and head injuries.