REDUCTION IN CNS INJURY BY MODIFICATION OF ISCHEMIC ENERGY METABOLISM

无氧代谢是中枢神经系统缺氧/缺血的特征。 能量是从厌氧糖酵解中获得的，尽管能量的量不是 足以维持中枢神经系统的代谢活动，以及 这一代谢途径的最终产物乳酸和 H+，可能会对从缺血中恢复的神经元造成额外的损伤。 我们使用了脊髓缺血模型来研究中枢神经系统缺血。 主要原因有两个：1)缺血对特异性脑损伤的影响 突触和神经元突起可以很好地表征在 电生理方法对脊髓的影响及2)缺血的影响 在运动和感觉功能方面，可以通过恢复来预测 诱发电位。初步数据显示乳酸盐有两个阶段 与脊髓缺血相关的蓄积。紧随其后 主动脉闭塞，脊髓乳酸浓度 随着丙酮酸的耗尽而增加。主动脉松解后 闭塞时，存在第二个短暂的乳酸蓄积期 脊髓，与脊髓丙酮酸增加有关 集中精神。缺血前脊髓代谢率和 血糖浓度降低缺血和缺血后 乳酸积聚。所有这些治疗干预措施都有改善 缺血后电生理恢复。代谢抑制 硫喷妥钠和亚低温等药物已被证明可以改善 脑缺血后的长期神经恢复。这项提案概述了 两种新疗法治疗缺血性乳酸中毒的研究。 第一个提议的治疗方法是增加能源的可获得性 酮体和短链脂肪酸等底物不能 被厌氧代谢。第二种建议的治疗方法是抑制 乳酸脱氢酶，催化 丙酮酸转化为乳酸。两种治疗方法对脊髓的影响 乳酸蓄积和对电生理功能的影响 学习。

Anaerobic metabolism is a characteristic feature of CNS hypoxia/ischemia. Energy is obtained from anaerobic glycolysis, although the amount is not sufficient to maintain the metabolic activity of the CNS, and accumulation of the end-products of this metabolic pathway, lactate and H+, may result in additional injury to neurons recovering from ischemia. We have used a model of spinal cord ischemia to study CNS ischemia processes for 2 major reasons: 1) The effect of ischemia on specific synaptic and neuronal processes can be very well characterized in the spinal cord by electrophysiological means and 2) The effects of ischemia in terms of motor and sensory function can be predicted by the recovery of evoked potentials. Preliminary data have shown two periods of lactate accumulation associated with spinal cord ischemia. Immediately after occlusion of the aorta, lactic acid concentration in the spinal cord increases, as pyruvate becomes depleted. After release of the aortic occlusion, there is a second transient period of lactate accumulation in the spinal cord, associated with an increase in spinal cord pyruvate concentration. Preischemia reduction in spinal cord metabolic rate and in blood glucose concentration reduce both the ischemic and postischemic lactate accumulation. All of these therapeutic interventions improve electrophysiological recovery after ischemia. The metabolic inhibiting agents, thiopental and hypothermia, have been demonstrated to improve long-term neurological recovery from ischemia. This proposal outlines an investigation of two additional treatments of ischemic lactic acidosis. The first proposed treatment is to increase the availability of energy substrates such as ketone bodies and short chain fatty acids that cannot be anaerobically metabolized. The second proposed treatment is to inhibit lactic dehydrogenase, the enzyme that catalyzes the conversion of pyruvate to lactate. The effects of these two treatments on spinal cord lactate accumulation and on electrophysiological function will be studied.