REDUCTION IN CNS INJURY BY MODIFICATION OF ISCHEMIC ENERGY METABOLISM

无氧代谢是CNS缺氧/缺血的特征。 能量是从无氧糖酵解中获得的，尽管量不是 足以维持CNS的代谢活性，以及 这种代谢途径的终产物乳酸盐的积累， H+可导致从缺血恢复的神经元的额外损伤。 我们用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 突触和神经元的过程可以很好地表征， 脊髓的电生理手段和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， 与脊髓缺血相关的蓄积。后立即 主动脉闭塞脊髓乳酸浓度 增加，因为丙酮酸被耗尽。主动脉开放后 闭塞时，有第二个短暂的乳酸积累期， 脊髓，与脊髓丙酮酸盐的增加有关 浓度.缺血前脊髓代谢率降低， 血糖浓度降低缺血和缺血后 乳酸积累所有这些治疗干预措施都能改善 缺血后电生理恢复。代谢抑制 药物硫喷妥钠和低温，已被证明可以改善 从局部缺血中恢复神经功能。该提案概述了 缺血性乳酸酸中毒的两种额外治疗方法的研究。 第一个建议的治疗方法是增加能源的可用性 底物如酮体和短链脂肪酸， 被厌氧代谢。第二种治疗方法是抑制 乳酸脱氢酶是一种催化 丙酮酸转化为乳酸。这两种治疗方法对脊髓的影响 乳酸积累和对电生理功能的影响 研究了

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.