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（由申请人提供）：中风是美国第三大死亡原因，也是严重长期残疾的主要原因。虽然近年来在确定脑对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保护免受缺血性损伤。目前还没有有效的神经保护剂通过临床试验。然而，我们知道钙离子进入是缺血性脑损伤的中心特征。阻断钙进入可防止中风期间脑细胞死亡。在寻找缺血性脑损伤的其他效应物时，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的中心和突出的代谢特征，并且由于ASIC能够具有Ca2+渗透性，因此我们假设ASIC在缺血性脑损伤中的病理功能。该离子通道家族的成员对酸性刺激有反应，因此会被局部缺血、酸中毒的中心特征激活，并在这种情况下，会流动Ca2+。我们的同事和我们提供了最近的数据，包括Ca2+成像，表明ASIC通道以pH依赖性方式在天然神经元中流动Ca2+。我们已经表明，这种Ca2+流量显着增强模型缺血，这种Ca2+流量是谷氨酸盐的独立。ASIC在整个哺乳动物中枢神经系统中表达，在那里它们在突触可塑性、学习和记忆中起作用。它们的普遍存在使它们成为缺血环境中脑损伤的潜在重要调节剂。ASIC阻断剂的发现是20年来首次发现一种新的有效机制来预防急性中风中的钙毒性。该提案的目的是推进ASIC通道抑制剂的开发，以创建急性中风治疗药物。公共卫生相关性：在美国，中风是第三大死亡原因，也是严重、长期残疾的主要原因。阻断钙进入可防止中风期间脑细胞死亡。ASIC阻断剂的发现是20年来首次发现一种新的有效机制来预防急性中风中的钙毒性。