Argon: long term effects after transient middle artery occlusion; the role of ERK 1/2 activation; the effect on regional cerebral glucose metabolism on neuronal viability

稀有气体氙、氩和氦最初被认为是化学惰性的，但它们一再表现出非凡的生物特性。氙是一种众所周知的麻醉剂，并且在各种神经损伤模型中被证明是一种有效的神经保护剂。与氙相比，氩气在药效学上有许多不同之处。特别是，它的镇静特性的缺乏实际上可能是有利的，因为它允许给药患者神经损伤而不忽视他们的实际神经状态。第二个显著的区别是成本和随之而来的管理方便性：氩气是大气中含量第三丰富的元素，比氙气的成本效益高100倍左右，可以很容易地应用于围手术期和重症监护病房。最重要的是，我们的团队最近证明了氩气在体外创伤性和缺血性脑损伤模型中具有神经保护作用。因此，我们在短暂性大脑中动脉闭塞（tMCAO）的体内模型中测试了氩气在脑缺血期间的神经保护潜力。我们能够证明在再灌注24小时后，总体受损脑容量和神经功能缺损显著减少。最终，我们能够在体外证明氩气通过上游激酶MEK增强小胶质细胞ERK 1/2的活性。在这项拨款申请的范围内，我们将在一个完善的tMCAO模型中研究氩气的长期影响。具体来说，我们将评估氩气对脑损伤炎症和再生反应的影响以及细胞外信号调节激酶（ERK）激活的作用。此外，我们将通过使用各种已建立的示踪剂进行放射自显影，研究氩气是否调节区域脑葡萄糖代谢率（rCMRglc）和神经元活力。

Originally thought to be chemically inert, the noble gases xenon, argon and helium have repeatedly exhibited remarkable biological properties. Xenon is a well known anaesthetic and, has demonstrated in various models of neuronal injury, an effective neuroprotectant. Compared to xenon, argon presents a number of pharmacodynamic distinctions. In particular, its lack of sedative properties may actually be advantageous as it allows administration to patients with neurological injury without overlooking their actual neurological status. A striking second difference involves cost and consequent ease of administration: Argon, the third most abundant element in our atmosphere and about one hundred-fold more cost effective than xenon, may be easily applied perioperatively and in intensive care units. Most important, our group has recently demonstrated that argon conveys neuroprotective effects in in vitro models of traumatic and ischemic brain injury. In consequence, we tested the neuroprotective potential of argon when applied during cerebral ischemia in an in vivo model of transient middle cerebral artery occlusion (tMCAO). We were able to demonstrate a significant reduction in overall damaged brain volume and neurologic deficit twenty-four hours after reperfusion. Ultimately, we were able to demonstrate that argon enhanced ERK 1/2 activity in microglia via the upstream kinase MEK in vitro. Within the scope of this grant application we will examine the long term effects of argon in a well established tMCAO model. Specifically, we will assess the effect of argon on the inflammatory and regenerative response to brain injury and the role of extracellular signal-regulated kinase (ERK) activation. Furthermore, we will study whether argon modulates regional cerebral metabolic rate of glucose (rCMRglc) and neuronal viability by employing various established tracers for autoradiography.