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

治疗中风的新方法：酸敏感离子通道抑制剂

• 批准号: 7616402
• 负责人: ROGER Pancoast SIMON
• 金额: $ 11.83万
• 依托单位: VIROGENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616402
• 关键词: ASIC channel; Acidosis; Acids; Advanced Development; Affect; Amiloride; Apoptotic; Attention; Brain; Brain Injuries; Calcium; Cause of Death; Cell Death; Cell Death Process; Cells; Cerebral Ischemia; Clinical Trials; Data; Effectiveness; Excitatory Amino Acid Antagonists; Family; Glutamates; Human; Image; In Vitro; Infarction; Injury; Ion Channel; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knowledge; Learning; Mediating; Memory; Metabolic; Modeling; Molecular; Necrosis; Nervous System Physiology; Neuraxis; Neurons; Neuroprotective Agents; Neurotoxins; Paper; Permeability; Play; Process; Publishing; Research; Rodent Model; Role; Stimulus; Stroke; Structure; Synaptic plasticity; System; Tarantula Venoms; Therapeutic; Toxic effect; United States; Venoms; acute stroke; analog; base; brain cell; disability; editorial; effective therapy; in vitro Model; in vivo; inhibitor/antagonist; member; novel strategies; perpetrators; phrases; prevent; public health relevance; response; synthetic peptide

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.

描述(申请人提供)：中风是美国第三大致死原因，也是导致长期严重残疾的主要原因。尽管近年来在确定大脑对缺血的细胞和分子反应方面取得了巨大的进展，但我们的知识还不足以保护大脑免受缺血损伤。目前还没有能证明疗效的神经保护剂通过临床试验。然而，我们确实知道钙内流是缺血性脑损伤的中心特征。阻止钙离子进入可防止中风时脑细胞死亡。在寻找脑缺血环境中脑损伤的其他效应因子的过程中，我们的注意力被最近发现的酸敏感离子通道(ASIC)家族所吸引。由于酸中毒是缺血性脑损伤的主要代谢特征，而ASIC具有钙离子通透性，因此我们推测ASIC在缺血性脑损伤中的病理作用。这个离子通道家族的成员会对酸刺激做出反应，因此会被缺血、酸中毒的中心特征激活，在这种情况下，会流动钙离子。我们的同事和我们提供了包括钙离子成像在内的最新数据，表明ASIC通道以一种pH依赖的方式在天然神经元中运送钙离子。我们已经证明，这种钙离子流量在模拟的缺血中显著增强，并且这种钙离子流量是不依赖谷氨酸的。ASIC在哺乳动物的中枢神经系统中表达，它们在突触可塑性、学习和记忆中发挥作用。它们的普遍存在使它们在脑缺血时可能成为脑损伤的重要调节器。ASIC阻滞剂的发现是20年来首次发现一种新的、有效的机制来预防急性中风的钙毒性。这项建议的目的是促进ASIC通道抑制剂的开发，以创造一种急性卒中疗法。公共卫生相关性：在美国，中风是第三大死亡原因，也是导致严重、长期残疾的主要原因。阻止钙离子进入可防止中风时脑细胞死亡。ASIC阻滞剂的发现是20年来首次发现一种新的、有效的机制来预防急性中风的钙毒性。