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通过不加选择的释放来定义的钾和谷氨酸，葡萄糖局部脑代谢率的短暂升高，然后是长时间的葡萄糖代谢抑郁症和ATP的减少。在这一降低葡萄糖的时期代谢通过五磷酸戊糖，自由基产生和通过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+。胞质NAD+池的耗竭已显示可减少GAPDH（钥匙糖酵解途径中的酶。在糖酵解代谢受损的条件下成为不太有利的能量基材。葡萄糖仍然是主要的大脑代谢底物在正常情况下，大脑对葡萄糖的依赖有许多生理状态向酮体转移，这是唯一可以循环的替代基板的酮体显着补充大脑代谢。最近，我们已经表明了外源给药的R> - 羟基丁酸被成人大脑代谢，TBI诱导的ATP降低被减轻（Prins等，，， 2004）。我们的实验室还证明了生酮饮食在减少皮质的有效性在产后第30天（PND30）和PND45大鼠之间的局灶性TBI之后，挫伤量增加了50％（Prins等人 2005）。利用酮作为替代底物的潜力随着脑成熟而降低，表明年轻的大脑具有更大的代谢能力来代谢这种底物。中央该项目的假设是TBI诱导的底物转运和葡萄糖生化的变化加工促进CMRGLC抑郁症期间替代底物的年龄依赖性代谢。我们相信使用酮体作为替代性大脑代谢底物提供令人兴奋的在发育中的大脑中局灶性TBI之后的治疗潜力，并提供迫切需要的治疗 TBI儿童的选择。