MAGNESIUM AND THE PATHOPHYSIOLOGY OF BRAIN INJURY

镁与脑损伤的病理生理学

基本信息

批准号：
2702984
负责人：
TRACY K. MCINTOSH
金额：
$ 24.06万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 2000-04-30
项目状态：
已结题

项目摘要

Recent work from our laboratory has suggested that changes in the magnesium ion (Mg2+) may play an important role in mediating the pathophysiological sequelae of traumatic brain injury (TBI). Magnesium is a critical ion in the brain for the regulation of cellular bioenergetics and changes in brain Mg2+ concentrations after trauma can potentially alter regional brain metabolism, cerebrovascular function and intracellular calcium flux, thereby directly affecting post-traumatic neuronal susceptibility to damage. The objects of the studies outlined in this application are to (1) characterize changes in extracellular and intracellular concentrations of Mg2+ after experimental brain injury, (2) determine whether Mg2+ deficiency alters post-traumatic outcome and whether maintenance of Mg2+ homeostasis is neuroprotective after brain injury, (3) examine the efficacy of pharmacotherapies that interact with the Mg2+ homeostasis is neuroprotective after brain injury, complex, and (4) determine whether the beneficial effects of diverse pharmacotherapies known to be effective in brain injury are associated with the recovery of tissue Mg2+ and enhanced bioenergetics status. Extracellular concentrations of Mg2+ will be characterized over time after fluid- percussion (FP) brain injury of graded severity int he rat using intracerebral microdialysis and atomic absorption spectrophotometry. Changes in intracellular Mg2+ will be assessed using phosphorus (P) nuclear magnetic resonance (NMR) spectroscopy. Post-injury changes in extracellular and intracellular Mg2+ will be related to alterations in regional cerebral blood flow (rCBF, radiolabeled microspheres/iodoantipyrine autoradiography), cerebral bioenergetics (P NMR), histopathological damage, neurologic (motor), and cognitive (Morris Water Maze) deficits. Molecular biology techniques will be employed to examine the relationship between post-traumatic alterations in brain magnesium and expression of mRNA for heat-shock protein (HSP-72) and the immediate early genes (IEG) c-fos/c-jun. In order to begin to determine the fate of the magnesium ion following trauma, we will measure magnesium concentrations in plasma and cerebrospinal fluid (CSF). We will also evaluate whether Mg2+ deficiency following dietary restriction will affect post-traumatic outcome and whether post-injury treatment with Mg2+ will improve post-traumatic cerebrovascular, metabolic, histopathologic, and behavioral function. Finally, the therapeutic efficacy of the competitive NMDA antagonist CGS19755, the AMPA/KA receptor antagonist GYKk152466, the novel presynaptic glutamate release blocker BW619C89, and the NMDA-associated glycine receptor antagonist kynurenate will be evaluated for their effects on post-traumatic rCBF, metabolism, neuronal damage, and behavioral function. A "critical window" for post-traumatic pharmacologic intervention will be assessed using the most optimal combination of pharmacotherapies. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie cerebrovascular, metabolic, histologic, and behavioral damage associated with TBI and result in the development of new and more effective therapeutic approaches to the treatment of brain trauma.

我们实验室最近的工作表明，镁离子（Mg2+）可能在介导创伤性脑损伤（TBI）的病理生理后遗症。镁是大脑中调节细胞的关键离子生物能学和创伤后脑部 Mg2+ 浓度的变化可以可能改变区域脑代谢、脑血管功能和细胞内钙离子流动，从而直接影响创伤后神经元对损伤的易感性。概述的研究对象在本申请中的目的是（1）表征细胞外和实验性脑损伤后细胞内 Mg2+ 浓度，(2) 确定 Mg2+ 缺乏是否会改变创伤后结果以及脑后维持 Mg2+ 稳态是否具有神经保护作用损伤，（3）检查与相互作用的药物疗法的功效 Mg2+ 稳态在脑损伤后具有神经保护作用，复杂且 (4) 确定多种药物疗法是否有益已知对脑损伤有效并与恢复有关组织 Mg2+ 和增强的生物能状态。细胞外 Mg2+ 的浓度将在流体后随时间变化进行表征大鼠使用敲击（FP）严重程度的脑损伤脑内微透析和原子吸收分光光度法。将使用磷 (P) 评估细胞内 Mg2+ 的变化核磁共振（NMR）光谱。受伤后的变化细胞外和细胞内 Mg2+ 的变化与局部脑血流量（rCBF，放射性标记微球/碘安替比林放射自显影），脑生物能量学（P NMR）、组织病理学损伤、神经系统（运动）和认知（莫里斯水迷宫）赤字。将采用分子生物学技术检查大脑创伤后变化之间的关系镁和热休克蛋白 (HSP-72) mRNA 的表达以及立即早期基因 (IEG) c-fos/c-jun。为了开始确定创伤后镁离子的命运，我们将测量镁血浆和脑脊液（CSF）中的浓度。我们也会评估饮食限制后 Mg2+ 缺乏是否会导致影响创伤后结果以及是否使用 Mg2+ 进行创伤后治疗将改善创伤后脑血管、代谢、组织病理学、和行为功能。最后，治疗效果竞争性 NMDA 拮抗剂 CGS19755，AMPA/KA 受体拮抗剂 GYKk152466，新型突触前谷氨酸释放阻滞剂 BW619C89，以及 NMDA 相关甘氨酸受体拮抗剂犬尿酸盐将是评估其对创伤后 rCBF、代谢、神经元的影响损伤和行为功能。创伤后的“关键窗口” 将使用最优化的药物干预措施进行评估药物治疗的组合。总的来说，这些拟议的研究将增强我们对病理生理机制的理解是脑血管、代谢、组织学和行为损伤的基础与 TBI 相关并导致新的和更多的开发治疗脑外伤的有效治疗方法。