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Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion

Authors
Kim, AY | Jeong, KH | Lee, JH  | Kang, Y  | Lee, SH  | Baik, EJ
Citation
Neuroscience, 340. : 487-500, 2017
Journal Title
Neuroscience
ISSN
0306-45221873-7544
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 alpha-ketoglutarate (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. Iodoacetate, an inhibitor of glycolysis, was also used in a model of energy failure, remarkably depleting ATP and alpha-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 mitochondrial 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.
MeSH

DOI
10.1016/j.neuroscience.2016.11.007
PMID
27845178
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Ajou Authors
강, 엽  |  백, 은주  |  이, 수환  |  이, 재호
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