GLUTAMATE DEHYDROGENASE AS A NEUROPROTECTIVE TARGET AGAINST BRAIN ISCHEMIA AND REPERFUSION

Abstract

Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alphaketoglutarate (alpha-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. Here, we tested whether the modulation of GDH activity can rescue ischemia/reperfusion-induced neuronal death in an in vivo mouse model of middle artery occlusion and an in vitro oxygen/glucose depletion model. lodoacetate, an inhibitor of glycolysis, was also used in a model of energy failure, remarkably depleting ATP and a-KG. To stimulate GDH activity, the GDH activator 2-aminobicyclo-(2,2,1)-heptane-2 -carboxylic acid and potential activator beta-lapachone were used. The GDH activators restored alpha-KG and ATP levels in the injury models and provided potent neuroprotection. We also found that beta-lapachone increased glutamate utilization, accompanied by a reduction in extracellular glutamate. Thus, our hypothesis that mitochondria' GDH activators increase alpha-KG production as an alternative energy source for use in the TCA cycle under energy-depleted conditions was confirmed. Our results suggest that increasing GDH-mediated glutamate oxidation represents a new therapeutic intervention for neurodegenerative disorders, including stoke. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.