Age-dependent use of alternative cerebral substrates during metabolic depression

代谢性抑郁症期间替代性脑基质的年龄依赖性使用

基本信息

批准号：
7663688
负责人：
Mayumi Lynn Prins
金额：
$ 20.6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7663688
关键词：
15 year old Acute Address Adolescent Adult Affect Alzheimer&apos s Disease Animals Antioxidants Apoptosis Area Behavioral Biochemical Biochemical Pathway Biochemical Process Biochemistry Biological Assay Bite Brain Brain Hypoxia-Ischemia Brain Injuries Budgets Cause of Death Cell Culture Techniques Cells Cerebrum Child Childhood Complement Cortical Contusions Critiques DNA Damage DNA Repair Data Disease model Effectiveness Enzymes Evaluation Fasting Free Radicals Glucose Glucose Transporter Glycolysis Hippocampus (Brain)Hydroxybutyrates Image Immunohistochemistry Infusion procedures Injury Intervention Ketone Bodies Ketones Ketoses Ketosis Laboratories Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Modeling Motor NADH NMR Spectroscopy Outcome Outcome Measure Oxidation-Reduction Oxidative Stress Parkinson Disease Pathway interactions Patients Pentosephosphate Pathway Phase Physiological Poly(ADP-ribose) Polymerases Potassium Glutamate Principal Investigator Process Production Pyruvate Pyruvates Rattus Reading Recovery Recovery of Function Reporting SLC2A1 gene Slice Text Thalamic structure Therapeutic Time Tissue Extracts Traumatic Brain Injury United States Up-Regulation Venous Western Blotting Work Writing age group age related brain tissue cell injury cognitive recovery depression disability feeding functional outcomes functional status glucose metabolism glucose transport human tissue improved ketogenic diet ketogentic meetings neuroprotection oxidative DNA damage oxidative damage postnatal repaired response ribose-5-phosphate uptake

项目摘要

The acute metabolic changes after traumatic brain injury (TBI) are defined by the indiscriminate release of potassium and glutamate, transient elevation in local cerebral metabolic rate of glucose followed by prolonged glucose metabolic depression and reduction of ATP. During this period of depressed glucose metabolism there is an increase flux of glucose through the pentose phosphate, free radical production and activation of poly ADP-ribose polymerase (PARP) via DMA damage. The PARP-mediated DMA repair process requires NAD+. Depletion of the cytosolic NAD+ pool has been shown to decrease GAPDH (a key enzyme in the glycolytic pathway) activity. Under conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. While glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts towards ketone bodies, which are the only endogenously circulating alternative substrate that can significantly supplement cerebral metabolism. Recently, we have shown that exogenously administered R>- hydroxybutyrate is metabolized by the adult brain and TBI-induced decrease in ATP is alleviated (Prins et al., 2004). Our laboratory has also demonstrated the effectiveness of the ketogenic diet in reducing cortical contusion volume by 50% following focal TBI among postnatal day 30 (PND30) and PND45 rats (Prins et al 2005). The potential to utilize ketones as an alternative substrate decreases with cerebral maturation, suggesting that the younger brain possesses a greater ability to metabolize this substrate. The central hypothesis of this project is that TBI-induced changes in substrate transport and glucose biochemical processing promote age-dependent metabolism of alternative substrates during CMRglc depression. We believe that the use of ketone bodies as an alternative cerebral metabolic substrate offers exciting therapeutic potential following focal TBI in the developing brain and offers desperately needed treatment options for children with TBI.

创伤性脑损伤（TBI）后的急性代谢变化是由不加区别地释放钾和谷氨酸，局部脑葡萄糖代谢率短暂升高，随后长期葡萄糖代谢抑制和 ATP 减少。在这段血糖低迷的时期新陈代谢过程中，葡萄糖通过磷酸戊糖的通量增加，自由基产生，通过 DMA 损伤激活聚 ADP-核糖聚合酶 (PARP)。 PARP介导的DMA修复过程需要NAD+。细胞质 NAD+ 池的耗尽已被证明会减少 GAPDH（一个关键因素）糖酵解途径中的酶）活性。在糖酵解代谢受损的情况下，葡萄糖成为不太有利的能源底物。虽然葡萄糖仍然是主要的脑代谢底物正常情况下，有许多生理状态期间大脑对葡萄糖的依赖转向酮体，酮体是唯一可以内源循环的替代底物显着补充脑代谢。最近，我们已经证明外源性施用 R>- 羟基丁酸由成人大脑代谢，TBI 引起的 ATP 减少得到缓解（Prins 等人， 2004）。我们的实验室还证明了生酮饮食在减少皮质激素方面的有效性。出生后 30 天 (PND30) 和 PND45 大鼠局灶性 TBI 后挫伤体积减少 50%（Prins 等 2005）。利用酮作为替代底物的潜力随着大脑的成熟而降低，这表明年轻的大脑具有更强的代谢这种底物的能力。中央该项目的假设是 TBI 引起底物转运和葡萄糖生化的变化在 CMRglc 抑制期间，加工促进替代底物的年龄依赖性代谢。我们相信使用酮体作为替代脑代谢底物提供了令人兴奋的结果发育中大脑局部 TBI 后的治疗潜力，并提供急需的治疗患有 TBI 的儿童的选择。