MAGNESIUM AND THE PATHOPHYSIOLOGY OF BRAIN INJURY

我们实验室最近的研究表明， 镁离子(Mg~(2+))在体内可能起重要的调节作用。 创伤性脑损伤的病理生理后遗症。镁 是大脑中调节细胞的关键离子 生物能量学和创伤后脑内镁离子浓度的变化 潜在地改变局部脑代谢、脑血管功能和 细胞内钙流量，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 在本申请中用于(1)表征细胞外和 实验性脑损伤后细胞内镁离子浓度变化(2) 确定镁离子缺乏是否改变创伤后结局和 脑损伤后维持镁离子稳态是否具有神经保护作用 伤害，(3)检查相互作用的药物疗法的疗效 镁离子稳态对脑损伤后的神经保护、复合体和 (4)确定多种药物疗法的益处是否 已知对脑损伤有效的是与康复有关的 组织中的镁离子和增强的生物能量状态。胞外 镁离子的浓度将随着时间的推移在流体- 大鼠冲击性脑损伤分级模型的建立 脑内微渗析和原子吸收光谱分析。 细胞内镁离子的变化将使用磷(P)进行评估 核磁共振(核磁共振)光谱。受伤后的变化 细胞外和细胞内的镁离子将与细胞内钙离子的变化有关 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)、组织病理损伤、神经学(运动)和认知(莫里斯 水迷宫)赤字。分子生物学技术将被用于 检查脑创伤后改变之间的关系 镁与热休克蛋白(HSP-72)的mRNA表达 即刻早期基因(IEG)c-fos/c-jun。为了开始确定 创伤后镁离子的去向，我们将测量镁 在血浆和脑脊液(CSF)中的浓度。我们还将 评估饮食限制后的镁离子缺乏是否会 影响创伤后转归及伤后是否给予镁离子治疗 将改善创伤后脑血管，代谢，组织病理学， 和行为功能。最后，还观察了黄连胶囊的治疗效果。 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Kynurenate将 评估它们对创伤后局部脑血流、代谢、神经元的影响 损害和行为功能。创伤后的“关键窗口” 药物干预的评估将使用最理想的 药物疗法的结合。总而言之，这些拟议的研究 有助于我们更好地理解 脑血管、代谢、组织学和行为损害的基础 与TBI相关联，并导致开发新的和更多 脑外伤治疗的有效治疗方法。

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.