MAGNESIUM AND THE PATHOPHYSIOLOGY OF BRAIN INJURY

我们实验室最近的工作表明， 镁离子（Mg 2+）可能在介导 创伤性脑损伤（TBI）的病理生理后遗症。 镁 是大脑中调节细胞功能的关键离子 生物能量学和创伤后脑Mg 2+浓度的变化可以 可能改变局部脑代谢、脑血管功能， 细胞内钙流，从而直接影响创伤后 神经元对损伤的敏感性。 概述的研究对象 在本申请中是（1）表征细胞外 实验性脑损伤后细胞内Mg 2+浓度，（2） 确定Mg 2+缺乏是否会改变创伤后结果， 维持Mg 2+稳态是否具有脑损伤后的神经保护作用 （3）检查药物治疗的有效性， Mg 2+稳态在脑损伤后具有神经保护作用，复杂， (4)确定各种药物治疗的有益效果 已知对脑损伤有效， 组织Mg 2+和增强的生物能量学状态。 细胞外 Mg 2+浓度将在流体- 撞击（FP）脑损伤的严重程度分级在他的大鼠使用 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Mg 2+的变化 核磁共振（NMR）光谱。 受伤后的变化 细胞外和细胞内Mg 2+将与 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 核磁共振）、组织病理学损伤、神经（运动）和认知（莫里斯 水迷宫）缺陷。 分子生物学技术将用于 研究创伤后大脑变化与 镁和热休克蛋白（HSP-72）的mRNA表达， 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。 我们还将 评估饮食限制后镁2+缺乏是否 影响创伤后结局以及是否用Mg 2+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，观察了 竞争性NMDA拮抗剂CGS 19755，AMPA/KA受体拮抗剂 GYKk 152466，新型突触前谷氨酸释放阻滞剂BW 619 C89，和 NMDA-相关甘氨酸受体拮抗剂犬尿烯酸盐将 评价其对创伤后rCBF、代谢、神经元 损伤和行为功能。 创伤后的“关键窗口” 药物干预将使用最佳的 药物治疗的组合。 综合起来，这些拟议的研究 将增强我们对病理生理机制的理解， 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发展 有效的治疗方法来治疗脑外伤。

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.