ROLE OF MAGNESIUM IN THE PATHOPHYSIOLOGY OF BRAIN INJURY

头部损伤是一个重大而独特的健康问题 美国。在头部创伤中幸存下来的人中，超过6万人 每年都会经历这些残留的神经功能障碍 神经缺陷似乎是由直接机械性损伤引起的。 神经元通路的中断，通过继发性或延迟性 在接下来的几个小时到几天内发展起来的机制 伤痕累累的侮辱。虽然延迟损坏的一部分 创伤后的中枢神经系统(CNS)似乎 内源性激素释放或激活的结果 自杀性因素，潜在的基本机制 继发性损伤知之甚少，目前的治疗方法 很大程度上不能令人满意。我们实验室最近的研究表明 大脑中镁(镁++)的下降可能是一个关键因素 在创伤性脑损伤的病理生理后遗症中。 因为所有ATP的生产和消费都必须使用镁离子 反应，它调节细胞的生物能量状态，并施加 相当大程度上控制了新陈代谢和 离子通量路径。因此，组织中镁离子的变化可能是一种 明显无关的中枢神经系统损伤因子之间的共同机制 以及对特定治疗的反应。建议进行的研究 将研究镁离子在继发性脑损伤中的病理生理作用 液压冲击性脑损伤模型的建立 对大鼠的损伤。总的、胞外的和 脑损伤后脑细胞内游离镁离子浓度的变化 将表现为与时间进程和伤病有关的特征 严肃性。镁的变化也将与 细胞生物能量状态的改变(31P核磁共振)， 线粒体功能以及脑内其他阳离子的变化 钙离子、钠离子、钾离子、锌离子浓度和组织含水量。 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。至 评价镁门控兴奋性氨基酸的作用 (EAA)离子通道在脑损伤中的作用、细胞外和细胞外的变化 脑损伤后组织EAA的变化及临床意义 非竞争性兴奋性氨基酸受体拮抗剂MK-801和CGS-19755将 在补充和不补充镁离子的情况下，对其进行评估 治疗颅脑损伤的疗效观察。这些研究将 扩大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 脑部疾病的有效治疗新途径 受伤。

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.