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대뇌 허혈과 재관류 손상에서의 glutamate dehydrogenase활성에 의한 신경세포보호
- Author(s)
- 김아영
- Advisor
- 백은주
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2017-02
- Language
- kor
- Alternative Abstract
- Energy metabolism in the brain is important during normal function and in pathological conditions, especially stroke. Although glucose is a main obligatory substrate, the brain can use other energy substrates, including monocarboxylic acid, ketone bodies, amino acids, and fatty acids during glucose restriction. In particular, glutamate is the most abundant excitatory amino acid, and 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 cycle intermediate alpha-ketoglutarate (α-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. Here, it is examined 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. It was also found that beta-lapachone increased glutamate utilization, accompanied by a reduction in extracellular glutamate. In addition, the glutamate consumed by beta-lapachone was supplied from glutamine with phosphate-activated glutaminase (PAG) reaction. Thus, the hypothesis that mitochondrial GDH activators increase α-KG production as an alternative energy source for use in the tricarboxylic acid cycle under energy-depleted conditions was confirmed. The results suggest that increasing GDH-mediated glutamate oxidation represents a new therapeutic intervention for neurodegenerative disorders, including stoke.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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