ROLE OF MAGNESIUM IN THE PATHOPHYSIOLOGY OF BRAIN INJURY

头部损伤在美国是一个重要而独特的健康问题， 美国的 在头部创伤的幸存者中， 每一年都会经历残余的神经功能障碍， 神经缺陷似乎是由直接机械性 神经元通路中断，通过继发性或延迟性 这些机制是在几小时到几天内发展起来的， 创伤性的侮辱 虽然部分延迟的损害， 中枢神经系统（CNS）创伤性损伤后， 由于内源性的释放或激活， 自我毁灭因素， 对继发性损伤知之甚少， 基本上不令人满意。 我们实验室最近的研究表明 脑镁（Mg++）的下降可能是一个关键因素， 创伤性脑损伤的病理生理后遗症 因为Mg++对于所有ATP的产生和消耗都是必需的 反应，它调节细胞的生物能量状态，并发挥 相当大的控制多种多样的代谢和 离子通量途径 因此，组织中Mg++的变化可能是 连接明显无关的CNS损伤因素的共同机制 以及对特定治疗的反应。 拟议的研究 将研究Mg++在继发性高血压中的病理生理作用。 液压冲击脑外伤模型的脑损伤 在老鼠身上受伤 总细胞外和 脑损伤后细胞内游离镁离子浓度 将被表征并与时间进程和损伤相关 严重性。 镁的变化也将与 细胞生物能态（31 P NMR）的改变， 线粒体功能，以及其他脑阳离子的变化 Ca ~（++）、Na ~（++）、K ~（++）、Zn ~（++）含量和组织含水量。 镁缺乏（饮食限制）和镁的影响 补充神经化学、组织病理学和 将检查脑损伤后的神经行为结果。 到 评估镁门控兴奋性氨基酸的作用 (EAA)脑损伤中离子通道，细胞外和 脑损伤后测量的组织EAA变化， 非竞争性EAA受体拮抗剂MK-801和CGS-19755将 在有和没有Mg++补充的情况下， 治疗脑损伤的有效性。 这些研究将 扩展我们对基本病理生理学的理解， 导致不可逆组织损伤的机制， 创伤性脑损伤，并可能导致发展 有效的新的治疗方法，用于治疗脑 损伤

Head injuries pose a significant and unique health problem in the United States. Of people that survive head trauma, over 60,000 each year experience residual neurological dysfunction These neurological deficits appear to be caused by direct mechanical disruption of neuronal pathways and through secondary or delayed mechanisms that develop over a period of hours to days following the traumatic insult. Although part of the delayed damage to the central nervous system (CNS) after traumatic injury appears to result from the release or activation of endogenous autodestructive factors, the fundamental mechanisms underlying secondary injury are poorly understood and current therapies largely unsatisfactory. Recent work from our laboratory suggests that decline in brain magnesium (Mg++) may be a critical factor in the pathophysiological sequelae of traumatic brain injury. Because Mg++ is mandatory for all ATP producing and consuming reactions, it regulates cellular bioenergetic state and exerts considerable control over a large diversity of metabolic and ionic flux pathways. Changes in tissue Mg++ may therefore be a common mechanism linking apparently unrelated CNS injury factors and the response to specific treatments. The proposed studies will examine the pathophysiological role of Mg++ in secondary brain injury using a model of fluid-percussion traumatic brain injury in the rat. Changes in total, extracellular and intracellular free brain Mg++ concentrations after brain injury will be characterized and related to time course and injury severity. Magnesium changes will also be correlated with alterations in cellular bioenergetic state (31P NMR), mitochondrial function, as well as changes in other brain cation concentrations (Ca++, Na+, K+, Zn++) and tissue water content. The effect of Mg deficiency (dietary restriction) and Mg supplementation on neurochemical, histopathological and neurobehavioral outcome after brain injury will be examined. To evaluate the role of the magnesium-gated excitatory amino acid (EAA) ion channel in brain injury, changes in extracellular and tissue EAA changes to be measured after brain injury and noncompetitive EAA receptor antagonists MK-801 and CGS-19755 will be evaluated, with and without Mg++ supplementation, for their efficacy in the treatment of brain injury. These studies will expand our understanding of the fundamental pathophysiological mechanisms that contribute to irreversible tissue damage after traumatic brain injury, and may lead to the development of effective new therapeutic approaches for the treatment of brain injury.