2月9日，《神经科学杂志》刊登了中科院上海生科院神经所突触生理学研究组的论文，此工作是由博士后段波和博士研究生王宜之在徐天乐研究员的指导下共同完成的。
缺血性脑损伤是中风病人当中存在的一个主要问题。目前研究结果表明，酸敏感离子通道（ASICs）在缺血性神经元死亡中具有重要的作用，但其具体机制一直不清楚。该论文研究证实，内源性的精胺可以敏化ASIC1a，从而加剧缺血性神经元死亡。运用药物阻断ASIC1a或者敲除ASIC1基因，均可以显著的降低精胺所加剧的那部分损伤。机制方面，精胺存在的情况下，可大大降低质子与ASIC1的表观亲和力，从而显著的减缓ASIC1开放后的脱敏速度，同时极大的加速其再次开放的速度，而且可以使原本处在稳态脱敏状态中的通道恢复至可以激活的状态。因此，精胺存在时，在脑缺血时酸碱震荡的重复刺激之下，ASIC1会多次开放，造成大量钙离子流入，导致神经元死亡。在体缺血实验结果进一步表明，抑制内源性精胺的合成会明显抑制ASIC1介导的缺血性神经元死亡，说明内源性精胺在ASIC1介导的缺血性神经元死亡中具有关键作用。因此，这篇文章为临床治疗缺血性中风提供了新的药物设计靶标，具有广泛的应用前景。
TTC染色表明，ASIC1的抑制剂PcTX1和内源性精胺合成抑制剂DFMO都可以降低小鼠缺血脑损伤。ASIC1基因敲除对缺血性脑损伤有明显的抵抗作用，此时DFMO也不再起效。
该工作得到了国家自然科学基金，科技部973项目，中科院王宽诚博士后基金以及上海市科委优秀学科带头人计划等项目的支持。（生物谷Bioon.com）
生-物-谷推荐原文出处：
The Journal of Neuroscience doi:10.1523/JNEUROSCI.4351-10.2011
Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis
Bo Duan,1 * Yi-Zhi Wang,1 * Tao Yang,2 Xiang-Ping Chu,2 Ye Yu,1 Yu Huang,1 Hui Cao,1 Jillian Hansen,2 Roger P. Simon,2,3 Michael X. Zhu,4 Zhi-Gang Xiong,2,3 and Tian-Le Xu1
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, 2Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, 3Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia 30310, and 4Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas 77030
Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca2+ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.
