Age-dependent use of alternative cerebral substrates during metabolic depression

创伤性脑损伤(TBI)后的急性代谢变化定义为不分青红皂白地释放 钾和谷氨酸，脑局部葡萄糖代谢率一过性升高，随后 长期糖代谢抑制和三磷酸腺苷减少。在这段血糖低迷的时期 新陈代谢通过磷酸戊糖、自由基的产生和葡萄糖流量的增加 通过DMA损伤激活多聚ADP-核糖聚合酶(PARP)。PARP介导的DMA修复 进程需要NAD+。胞浆NAD+池的耗尽已被证明降低了GAPDH(一个关键的 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 成为一种不那么有利的能量底物。而葡萄糖仍然是大脑的主要代谢底物 在正常情况下，大脑有许多生理状态，在此期间大脑对葡萄糖的依赖 向酮体转移，酮体是唯一内源循环的替代底物，可以 显著补充大脑新陈代谢。最近，我们已经证明，外源性给药的R&GT；- 羟丁酸是由成人大脑代谢的，脑损伤导致的三磷酸腺苷下降得到缓解(Prins等人， 2004年)。我们的实验室还证明了生酮饮食在减少皮质醇含量方面的有效性。 出生后30天(PND30)和PND45的大鼠局灶性脑损伤后50%的挫伤体积(Prins等人 2005)。利用酮作为替代底物的可能性随着大脑的成熟而降低， 这表明较年轻的大脑具有更强的代谢这种底物的能力。中环 本项目的假设是脑损伤引起底物转运和葡萄糖生化的变化。 在CMRglc抑郁期间，加工促进替代底物的年龄相关新陈代谢。我们 相信使用酮体作为大脑代谢的替代底物提供了令人兴奋的 大脑发育中的局灶性脑损伤后的治疗潜力和迫切需要的治疗 创伤性脑损伤儿童的选择。

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.