A Novel Approach to Stroke Treatment: Acid-Sensing Iion Channel Inhibitors

描述（由申请人提供）：中风是美国第三大死亡原因，也是导致严重、长期残疾的主要原因。尽管近年来在确定脑缺血的细胞和分子反应方面取得了巨大进展，但我们的知识还不足以防止缺血性损伤。目前还没有一种神经保护剂通过临床试验。然而，我们确实知道钙的进入是缺血性脑损伤的主要特征。阻断钙的进入可防止中风时脑细胞死亡。在寻找缺血情况下脑损伤的其他效应器时，我们的注意力被最近发现的酸感离子通道（asic）家族所吸引。由于酸中毒是缺血性脑的核心和突出的代谢特征，并且ASIC具有Ca2+通透性，我们假设ASIC在缺血性脑损伤中的病理功能。这个离子通道家族的成员对酸性刺激有反应，因此会被缺血、酸中毒的中心特征激活，在这种情况下，会通量Ca2+。我们的同事和我们提供了最近的数据，包括Ca2+成像，显示ASIC通道以pH依赖的方式在原生神经元中通量Ca2+。我们已经证明，这种Ca2+通量被模拟缺血显著增强，并且这种Ca2+通量是谷氨酸独立的。asic在哺乳动物中枢神经系统中表达，在突触可塑性、学习和记忆中起作用。它们的普遍存在使它们在缺血情况下可能成为脑损伤的重要调节剂。ASIC阻断的发现是20年来首次发现一种新的、有效的机制来预防急性卒中中的钙毒性。本提案的目的是促进ASIC通道抑制剂的发展，以创造急性卒中治疗药物。公共卫生相关性：中风是美国第三大死亡原因，也是导致严重、长期残疾的主要原因。阻断钙的进入可防止中风时脑细胞死亡。ASIC阻断的发现是20年来首次发现一种新的、有效的机制来预防急性卒中中的钙毒性。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Although in recent years enormous progress has been made towards defining the cellular and molecular responses of the brain to ischemia, our knowledge is not yet adequate to protect against ischemic injury. No neuroprotective agents of demonstrable efficacy have yet passed clinical trials. However, we do know that calcium entry is the central feature of ischemic brain injury. Blockade of calcium entry prevents brain cell death during stroke. In a search for other effectors of brain injury in the setting of ischemia, our attention has been drawn to the recently discovered family of acid-sensing ion channels (ASICs). As acidosis is a central and prominent metabolic feature of ischemic brain and as ASICs are capable of Ca2+ permeability we have hypothesized a pathological function of ASIC's in ischemic brain injury. Members of this ion channel family respond to acidic stimuli and would therefore be activated by that central feature of ischemia, acidosis and in that setting, would flux Ca2+. Our colleagues and we have offered recent data, to include Ca2+ imaging, showing that ASIC channels flux Ca2+ in native neurons in a pH dependent manner. We have shown that this Ca2+ flux is markedly potentiated by modeled ischemia and that this Ca2+ flux is glutamate independent. ASICs are expressed throughout the mammalian central nervous system where they function in synaptic plasticity, learning and memory. Their ubiquitous presence makes them potentially important modulators of brain injury in the setting of ischemia. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke. The aim of this proposal is to advance the development of inhibitors of ASIC channels towards the creation of an acute stroke therapeutic. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Blockade of calcium entry prevents brain cell death during stroke. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke.