TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis
TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis
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DOI：
10.1038/nm.3015
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发表时间：
2012-12-01
期刊：
影响因子：
82.9
通讯作者：
Friese, Manuel A.
中科院分区：
文献类型：
--
作者：
Schattling, Benjamin;Steinbach, Karin;Friese, Manuel A.
在多发性硬化症（中枢神经系统（CNS）的炎性疾病）中，轴突和神经元损失是不可逆的神经功能残疾的主要原因。然而，哪些分子在炎症条件下导致轴突和神经元损伤仍然很大程度上未知。在这里，我们表明，瞬时受体电位melastatin 4（TRPM 4）阳离子通道是至关重要的，在这个过程中。TRPM 4在小鼠和人神经元胞体中表达，但它也在小鼠实验性自身免疫性脑脊髓炎（EAE）和人多发性硬化组织中的炎性CNS病变中的轴突中表达。使用抗糖尿病药物格列本脲缺乏或药理学抑制TRPM 4导致EAE中轴突和神经元变性减少，临床疾病评分减弱，但这不会改变EAE相关的免疫功能。此外，Trpm 4（-/-）小鼠神经元在体外被保护免受炎症效应机制如兴奋性毒性应激和能量缺乏的影响。电生理记录显示TRPM 4依赖的神经元离子内流和兴奋性毒性刺激后的神经细胞肿胀。因此，干扰TRPM 4可以转化为一种新的神经保护治疗策略。
In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.