Friese Manuel A, Craner Matthew J, Etzensperger Ruth, Vergo Sandra, Wemmie John A, Welsh Michael J, Vincent Angela, Fugger Lars
Medical Research Council Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Nat Med. 2007 Dec;13(12):1483-9. doi: 10.1038/nm1668. Epub 2007 Nov 11.
Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1-/- mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.
多发性硬化症是一种与轴突退变相关的神经炎症性疾病。神经元表达的质子门控酸敏感离子通道1（ASIC1）对Na⁺和Ca²⁺具有通透性，这些离子的过度积累与轴突退变有关。我们验证了ASIC1在中枢神经系统（CNS）炎症性病变中导致轴突退变的假说。诱导实验性自身免疫性脑脊髓炎（EAE）后，与野生型小鼠相比，Asic1基因敲除小鼠的临床缺陷明显减轻，轴突退变也减少。与酸中毒介导的损伤一致，EAE小鼠脊髓的pH测量显示组织酸中毒足以打开ASIC1。在体外神经外植体中也观察到了Asic1缺失与酸中毒相关的保护作用。氨氯地平是一种已获许可且临床安全的ASIC阻滞剂，在神经外植体和EAE中同样具有神经保护作用。尽管免疫细胞也表达ASIC，但这种表达不太可能解释Asic1失活的神经保护作用，因为野生型小鼠和Asic1基因敲除小鼠的CNS炎症相似。此外，从野生型小鼠过继转移T细胞并不影响Asic1缺失介导的保护作用。这些结果表明，ASIC1阻滞剂可能为多发性硬化症提供神经保护作用。
