title: 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 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.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
authors.forename: A Young
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Gachon University of Medicine and Science, Incheon 406-840, Republic of Korea.
authors.forename: Kyeong-Hoon
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
authors.forename: Soo Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Republic of Korea. Electronic address: eunjoo@ajou.ac.kr.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Baik
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009285:Naphthoquinones / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D009285:Naphthoquinones; D018696:Neuroprotective Agents; C014638:beta-lapachone; D005969:Glutamate Dehydrogenase
keywords: energy metabolism; focal ischemia; glutamate dehydrogenase; neuroprotection; reperfusion