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

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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.