GLUTAMATE DEHYDROGENASE AS A NEUROPROTECTIVE TARGET AGAINST BRAIN ISCHEMIA AND REPERFUSION
- Authors
- Kim, A. Young; Jeong, Kyeong-Hoon; Lee, Jae Ho; Kang, Yup; Lee, Soo Hwan; Baik, Eun Joo
- Issue Date
- 6-Jan-2017
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- neuroprotection; focal ischemia; reperfusion; energy metabolism; glutamate dehydrogenase
- Citation
- NEUROSCIENCE, v.340, pp.487 - 500
- Journal Title
- NEUROSCIENCE
- Volume
- 340
- Start Page
- 487
- End Page
- 500
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6480
- DOI
- 10.1016/j.neuroscience.2016.11.007
- ISSN
- 0306-4522
- 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.
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