Evidence that the Loss of the Voltage‐Dependent Mg²⁺ Block at the N‐Methyl‐D‐Aspartate Receptor Underlies Receptor Activation During Inhibition of Neuronal Metabolism

Abstract

In this study, the importance of the Mg2+ blockade of the N-methyl-D-aspartate (NMDA) receptor during metabolic stress was examined in embryonic day 13 chick retina. Retina exposed to mild conditions of metabolic stress (i.e., blockade of glycolysis with 1 mM iodoacetate for 30 min) underwent acute histological somal and neuritic swelling and an increase in gamma-aminobutyric acid (GABA) release into the medium. These acute signs of metabolic stress were eliminated by NMDA antagonists present during pharmacological blockade of glycolysis, occurred in the absence of a net increase in extracellular glutamate or aspartate, and were not affected by the presence or absence of Ca2+ in the incubation medium. One possible explanation for the activation of NMDA receptors in the absence of an increase in extracellular ligand is that NMDA sensitivity during metabolic stress may be governed at the receptor level. Depolarization of membrane potential during metabolic stress may result in the loss of the Mg2+ blockade from the NMDA receptor channel, resulting in an increased potency for glutamate. To test this, the dose-response characteristics for NMDA, glutamate, and kainate in the presence or absence of extracellular Mg2+ and the effects of Mg2+ on metabolic inhibition were examined. The potency for NMDA- or glutamate-mediated acute toxicity was enhanced two- to fivefold in the absence of Mg2+. Omission of Mg2+ greatly decreased the minimal concentration of agonist needed to produce acute excitotoxicity; 25 versus 5 microM for NMDA and 300 versus 10 microM for glutamate in 1.2 or zero Mg2+, respectively. Elevating external Mg2+ to 20 mM completely protected against NMDA-mediated acute toxic effects. In contrast, varying external Mg2+ had no effect on kainate-induced toxicity. Acute toxicity caused by inhibition of metabolism was not potentiated in the absence of Mg2+ but was attenuated by elevating extracellular Mg2+. The protective effect of Mg2+ during metabolic inhibition was not additive with NMDA antagonists, suggesting that the action of Mg2+ was at the level of the NMDA receptor. These findings are consistent with the hypothesis that the Mg2+ block is lifted during metabolic inhibition and may be the primary event resulting in NMDA receptor activation.

Excitotoxicity and Glaucoma

“…Several studies have shown increases in the expression of glutamine synthetase [78] after pressure elevation [81,82], whereas others have reported decreases. Thus, it remains controversial whether elevated IOP alters glial cell glutamate metabolism as a potential mechanism of retinal excitotoxicity [83].…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…Сульфат магния (MgSO 4 ) стал активно рассматри-ваться в качестве нейропротектора при ГИППГМ благо-даря своей способности смягчать эксайтотоксическое повреждение путем связывания ионных каналов NMDA-глу таматных рецепторов магнием и блокировки поступле-ния внутрь кальция [130]. Помимо этого, магний умень-шает вторичное воспаление, связанное с повреждением мозга, стабилизирует клеточные мембраны и ингибирует свободные радикалы, а также улучшает сердечно-сосу-дистую стабильность [131][132][133].…”

Excitotoxic Injury to Retinal Ganglion Cells

“…1). For this reason, when RGCs become chronically depolarized, excitotoxic levels of NMDA channel activity can occur even in the presence of otherwise "normal" levels of extrtacellular glutamate (Zeevalk & Nicklas, 1992). The loss of voltagedependent magnesium block can be experimentally approximated by perfusion with magnesium-free solution.…”