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Acid-sensing channels as novel target for brain ischemia

酸感应通道作为脑缺血的新靶点

基本信息

批准号：
7812567
负责人：
ZHIGANG XIONG
金额：
$ 39.43万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-10-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812567
关键词：
ASIC channel Acidosis Acids Adverse effects Aggressive behavior Amiloride Animal Model Animal Testing Animals Behavior Brain Brain Ischemia Brain region Cell Culture Techniques Cells Cerebellum Chemosensitization Clinical Clinical Trials Clinical Trials Design Collaborations Comorbidity Data Development Dose Drug Administration Routes Equation Equilibrium Excitatory Amino Acid Antagonists Experimental Models Failure Free Radical Scavengers Functional disorder Future Genes Glucose Glutamate Receptor Glutamates Goals Health Planning Hippocampus (Brain)Human Hyperactive behavior Imaging Techniques In Vitro Infarction Inhibitory Concentration 50 Injection of therapeutic agent Injury International Intervention Intracranial Hemorrhages Intramuscular Intravenous Ions Ischemia Ischemic Brain Injury Ischemic Neuronal Injury Ischemic Stroke Mediating Membrane Membrane Potentials Modeling Morbidity - disease rate Mus Neuroglia Neuronal Injury Neurons Neuroprotective Agents Oligodendroglia Oregon Oxygen Pathway interactions Patients Pattern Peptides Perfusion Peritoneal Permeability Pharmaceutical Preparations Play Preclinical Drug Evaluation Primates Property Proteins Protocols documentation Public Health Receptor Activation Regulation Rodent Rodent Model Role Route Safety Saints Small Interfering RNA Solutions Stroke Surface System Testing Therapeutic Therapeutic Intervention Time Toxic effect Toxin Translating Variant Venoms Widow abstracting analog base benzamil cell injury clinically relevant deprivation desensitization disability effective therapy extracellular human subject in vivo inhibitor/antagonist ion channel blocker knock-down knockout gene mortality mouse model neuroprotection new therapeutic target novel patch clamp pre-clinical preclinical study prevent response small molecule stroke therapy success voltage white matter injury

项目摘要

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.

摘要/项目摘要缺血性中风是死亡率和发病率的主要病程，而且最常见的长期残疾的常见原因。不幸的是，仍然没有有效的对中风患者的治疗，除非使用时间有限的溶栓药物温多姆和潜在的颅内出血副作用。它已经被公认为几十年来，细胞内的钙离子积累，特别是通过谷氨酸受体的激活，以及由此产生的钙毒性，在缺血性脑损伤。然而，最近使用谷氨酸拮抗剂和最近的自由基清除剂，未能显示出对缺血的保护作用受伤。尽管多种因素可能共同导致了试验表明，谷氨酸非依赖性钙负荷途径(S)可能起到同样的作用缺血时钙离子毒性的影响。事实上，我们最近在神经细胞培养和全动物缺血模型已经证明，酸敏感离子的激活通道(ASIC)和随后的钙离子进入是酸中毒的主要原因。介导的谷氨酸受体非依赖性缺血性脑损伤。在培养的小鼠中皮层神经元，降低pH激活阿米洛利敏感的ASIC电流。在大多数神经元、ASIC对钙离子具有通透性，并激活这些通道诱导细胞内钙离子浓度([钙]i)升高。通过以下方式激活ASIC 神经细胞与酸性溶液的短暂孵育诱导时间依赖性细胞损伤电压门控钙通道和谷氨酸受体阻滞剂的存在。这然而，酸诱导的谷氨酸非依赖性神经元损伤可通过阻断来抑制 ASICs，通过降低细胞外[Ca~(2+)]，或通过ASIC1基因敲除。在体内小鼠脑缺血模型、ASIC1阻断或ASIC1基因敲除缩小脑梗塞体积。这些发现有力地表明，ASIC可能代表着新的人类中风的治疗靶点。我们的目标是将我们令人兴奋的发现扩展到动物细胞向人脑神经元转化探讨ASICs在酸中毒中的作用人脑组织神经元的缺血性损伤。我们的中心假设是人脑神经元表达ASIC。ASICs的激活诱导细胞内钙离子积聚，它与酸中毒介导的谷氨酸非依赖性神经元损伤有关。成功这些研究是将ASIC作为人类新靶点的重要一步中风疗法。