缺血性酸中毒细胞生物学新概念
Robert Stone Dow 神经生物学实验室
Ca2+离子中毒是缺血性脑损伤主要原因，但在过去十多年里的卒中研究中，由于谷氨酸盐拮抗剂 未能显示神经脑保护作用，使得脑缺血时细胞内Ca2+离子含量增加的机制变得模糊起来。酸中毒是缺血的一个常见特征，在脑损伤中起了重要的作用，但其机制仍就未能很好地明确。最近，提出了一个缺血性酸中毒的细胞生物学新概念，即酸中毒激活Ca2+-酸性通透-感受离子通道(ASICs)，包括非依赖性谷氨酸盐感受器、ASIC阻滞剂抑制Ca2+-依赖性神经损伤。乏内源性ASICs细胞能拮抗酸性损伤，同时影响ASIC1a性Ca2+-通透敏感性。在缺血中，脑室内注射ASIC1a阻滞剂、或 干扰ASIC1a基因性缺血性损伤，实现脑保护作用。酸中毒脑损伤是通过Ca2+离子中毒的膜受体机制所致，此可作为卒中的一种新治疗方法。
A new understanding of the cell biology of ischemic acidosis
Roger Simon MD, Zhi-Gang Xiong, M.D., Ph.D
Robert Stone Dow Neurobiology Laboratories
Portland, Oregon
Ca2+ toxicity remains the central focus of ischemic brain injury. The mechanism bywhich toxic Ca2+ loading of cells occurs in brain ischemia however has become less clear over the past decade as multiple human trials of glutamate antagonists have failed to show effective neuroprotection in stroke. Acidosis is a common feature of ischemia and is assumed to play a critical role in brain injury, however the mechanism(s) remain ill-defined. A new understanding of the cell biology of ischemic acidosis is that acidosis activates Ca2+-permeable Acid-Sensing Ion Channels (ASICs), inducing glutamate receptor-independent, Ca2+-dependent neuronal injury inhibited by ASIC blockers. Cells lacking endogenous ASICs are resistant to acid injury, while transfection of Ca2+-permeable ASIC1a establishes sensitivity. In focal ischemia, intracerebroventricular injection of ASIC1a blockers, or knockout of the ASIC1a gene protects the brain from ischemic injury. Thus acidosis injures the brain via membrane receptor based mechanisms with resultant toxicity of [Ca2+]i, disclosing new potential therapeutic targets for stroke., 百拇医药
Ca2+离子中毒是缺血性脑损伤主要原因，但在过去十多年里的卒中研究中，由于谷氨酸盐拮抗剂 未能显示神经脑保护作用，使得脑缺血时细胞内Ca2+离子含量增加的机制变得模糊起来。酸中毒是缺血的一个常见特征，在脑损伤中起了重要的作用，但其机制仍就未能很好地明确。最近，提出了一个缺血性酸中毒的细胞生物学新概念，即酸中毒激活Ca2+-酸性通透-感受离子通道(ASICs)，包括非依赖性谷氨酸盐感受器、ASIC阻滞剂抑制Ca2+-依赖性神经损伤。乏内源性ASICs细胞能拮抗酸性损伤，同时影响ASIC1a性Ca2+-通透敏感性。在缺血中，脑室内注射ASIC1a阻滞剂、或 干扰ASIC1a基因性缺血性损伤，实现脑保护作用。酸中毒脑损伤是通过Ca2+离子中毒的膜受体机制所致，此可作为卒中的一种新治疗方法。
A new understanding of the cell biology of ischemic acidosis
Roger Simon MD, Zhi-Gang Xiong, M.D., Ph.D
Robert Stone Dow Neurobiology Laboratories
Portland, Oregon
Ca2+ toxicity remains the central focus of ischemic brain injury. The mechanism bywhich toxic Ca2+ loading of cells occurs in brain ischemia however has become less clear over the past decade as multiple human trials of glutamate antagonists have failed to show effective neuroprotection in stroke. Acidosis is a common feature of ischemia and is assumed to play a critical role in brain injury, however the mechanism(s) remain ill-defined. A new understanding of the cell biology of ischemic acidosis is that acidosis activates Ca2+-permeable Acid-Sensing Ion Channels (ASICs), inducing glutamate receptor-independent, Ca2+-dependent neuronal injury inhibited by ASIC blockers. Cells lacking endogenous ASICs are resistant to acid injury, while transfection of Ca2+-permeable ASIC1a establishes sensitivity. In focal ischemia, intracerebroventricular injection of ASIC1a blockers, or knockout of the ASIC1a gene protects the brain from ischemic injury. Thus acidosis injures the brain via membrane receptor based mechanisms with resultant toxicity of [Ca2+]i, disclosing new potential therapeutic targets for stroke., 百拇医药