Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion. (6th January 2017)

• Record Type: Journal Article
• Authors: Kim, A Young; Jeong, Kyeong-Hoon; Lee, Jae Ho; Kang, Yup; Lee, Soo Hwan; Baik, Eun Joo
• Is Part Of: Neuroscience. Volume 340(2017)
• Page Start: 487
• Page End: 500
• Publication Date: 2017-01-06
• Subjects: AAT aspartate aminotransferase -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- GDH glutamate dehydrogenase -- I/R ischemia and reperfusion -- IOA iodoacetate -- OGD oxygen and glucose deprivation -- TCA tricarboxylic acid -- α-KG alpha-ketoglutarate -- EDTA ethylenediaminetetraacetic acid -- EGTA ethylene glycol tetraacetic acid -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- PBS phosphate-buffered saline -- FBS fetal bovine serum -- Ara-C cytosine arabinofuranoside -- PMSF phenylmethylsulfonyl fluoride -- βLA beta-lapachone -- BCH 2-aminobicyclo-(2, 2, 1)-heptane-2-carboxylic acid -- TTC 2, 3, 5-triphenyltetrazolium chloride; neuroprotection -- focal ischemia -- reperfusion -- energy metabolism -- glutamate dehydrogenase; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2016.11.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: In brain ischemia and reperfusion, α-ketoglutarate and ATP were severely depleted. Glutamate dehydrogenase catalyzes glutamate into α-ketoglutarate, finally producing intracellular ATP. Beta-lapachone stimulated the activation of mitochondrial glutamate dehydrogenase in energy-depleted conditions. Beta-lapachone provided glutamate dehydrogenase-mediated influx of α-ketoglutarate into the TCA cycle and production of ATP. Thus, the activation of glutamate dehydrogenase by BCH and beta-lapachone represents a potential neuroprotective strategy. 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.