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

惰性气体Xe、Ar和He最初被认为是化学惰性气体，但它们一再显示出显著的生物特性。氙气是一种众所周知的麻醉剂，在各种神经元损伤模型中已证明是一种有效的神经保护剂。与氙气相比，Ar呈现出许多药效学上的区别。特别是，它缺乏镇静特性实际上可能是有利的，因为它允许对神经损伤患者进行给药，而不会忽视他们的实际神经状态。第二个显著的差异涉及成本和随之而来的管理简单性：Ar是我们大气中第三丰富的元素，成本效益大约是氙气的100倍，可以很容易地在围手术期和重症监护病房中使用。最重要的是，我们的团队最近在创伤和缺血性脑损伤的体外模型中证明了Ar具有神经保护作用。因此，我们在短暂性大脑中动脉闭塞(TMCAO)的活体模型中测试了在脑缺血期间应用Ar时的神经保护潜力。我们能够证明，在再灌注24小时后，受损的脑体积和神经功能缺陷显著减少。最终，我们能够证明，在体外，Ar通过上游激酶MEK增强小胶质细胞中ERK1/2的活性。在这项赠款申请的范围内，我们将在一个成熟的tMCAO模型中研究Ar的长期影响。具体地说，我们将评估Ar对脑损伤的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放射自显影示踪剂来研究Ar是否调节局部脑葡萄糖代谢率(RCMRglc)和神经元活性。

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.