Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5737559 | Neuroscience | 2017 | 14 Pages |
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 (α-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 α-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 α-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 α-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.
Keywords
2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acidPBSFBSBCHHEPESAATOGDPMSFα-KGEGTATCAGAPDHTTCGDH2,3,5-triphenyltetrazolium chloride4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidI/RAra-CAspartate aminotransferasealpha-ketoglutarateEDTAethylene glycol tetraacetic acidEthylenediaminetetraacetic acidtricarboxylic acidischemia and reperfusionFocal ischemiaReperfusionfetal bovine serumphenylmethylsulfonyl fluorideEnergy metabolismNeuroprotectionOxygen and glucose deprivationPhosphate-buffered salineglutamate dehydrogenaseglyceraldehyde-3-phosphate dehydrogenaseIodoacetateIoA
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Authors
A Young Kim, Kyeong-Hoon Jeong, Jae Ho Lee, Yup Kang, Soo Hwan Lee, Eun Joo Baik,