Acid-sensing channels as novel target for brain ischemia

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Abstract/Project Summary Ischemic stroke is a leading course of mortality and morbidity, and the most common reason for long-term disabilities. Unfortunately there is still no effective treatment for stroke patients other than the use of thrombolitics which have limited time windom and potential side effect of intracranial hemorrhage. It has been well-recognized for several decades that that intracellular Ca2+ accumulation, particularly through glutamate receptor activation, and the resultant Ca2+ toxicity, play an important role in ischemic brain injury. However, the recent clinical trials using glutamate antagonists and most recently free radical scavengers, have failed to show protection against ischemic injury. Although multiple factors may have contributed together to the failure of the trials, it is likely that glutamate-independent Ca2+ loading pathway(s) equally contribute to the Ca2+ toxicity in ischemia. Indeed, our recent studies in neuronal cell culture and in whole animal models of ischemia have demonstrated that activation of acid-sensing ion channels (ASICs), and subsequent Ca2+ entry are largely responsible for acidosis- mediated, glutamate receptor-independent ischemic brain injury. In cultured mouse cortical neurons, lowering pH activates amiloride-sensitive ASIC currents. In the majority of these neurons, ASICs are permeable to Ca2+, and activation of these channels induces increased concentration of intracellular Ca2+ ([Ca2+]i). Activation of ASICs by brief incubation of neurons with acidic solutions induces time-dependent cell injury in the presence of blockers for voltage-gated Ca2+ channels and the glutamate receptors. This acid-induced, glutamate-independent neuronal injury is, however, inhibited by blocking the ASICs, by reducing the extracellular [Ca2+], or by ASIC1 gene knockout. In in vivo mouse model of ischemia, ASIC1 blockade or ASIC1 gene knockout dramatically reduced infarct volume. These findings strongly suggest that ASICs may represent novel therapeutic targets for human stroke. Our objective is to extend our exciting findings in animal cells to human brain neurons to explore the role of ASICs in acidosis-mediated ischemic injury of human brain neurons. Our central hypothesis is that human brain neurons express ASICs. Activation of ASICs induces intracellular Ca2+ accumulation, which is involved in acidosis-mediated, glutamate-independent neuronal injury. Success of these studies is an important step for establishing ASICs as novel targets for human stroke therapy.