2月9日,，《神經(jīng)科學(xué)雜志》刊登了中科院上海生科院神經(jīng)所突觸生理學(xué)研究組的論文，此工作是由博士后段波和博士研究生王宜之在徐天樂(lè)研究員的指導(dǎo)下共同完成的,。
缺血性腦損傷是中風(fēng)病人當(dāng)中存在的一個(gè)主要問(wèn)題,。目前研究結(jié)果表明,，酸敏感離子通道（ASICs）在缺血性神經(jīng)元死亡中具有重要的作用，但其具體機(jī)制一直不清楚,。該論文研究證實(shí),，內(nèi)源性的精胺可以敏化ASIC1a，從而加劇缺血性神經(jīng)元死亡,。運(yùn)用藥物阻斷ASIC1a或者敲除ASIC1基因,，均可以顯著的降低精胺所加劇的那部分損傷。機(jī)制方面,，精胺存在的情況下,，可大大降低質(zhì)子與ASIC1的表觀親和力，從而顯著的減緩ASIC1開放后的脫敏速度,，同時(shí)極大的加速其再次開放的速度,，而且可以使原本處在穩(wěn)態(tài)脫敏狀態(tài)中的通道恢復(fù)至可以激活的狀態(tài)。因此,，精胺存在時(shí),，在腦缺血時(shí)酸堿震蕩的重復(fù)刺激之下，ASIC1會(huì)多次開放,，造成大量鈣離子流入,，導(dǎo)致神經(jīng)元死亡,。在體缺血實(shí)驗(yàn)結(jié)果進(jìn)一步表明,，抑制內(nèi)源性精胺的合成會(huì)明顯抑制ASIC1介導(dǎo)的缺血性神經(jīng)元死亡，說(shuō)明內(nèi)源性精胺在ASIC1介導(dǎo)的缺血性神經(jīng)元死亡中具有關(guān)鍵作用,。因此,，這篇文章為臨床治療缺血性中風(fēng)提供了新的藥物設(shè)計(jì)靶標(biāo)，具有廣泛的應(yīng)用前景,。
TTC染色表明,，ASIC1的抑制劑PcTX1和內(nèi)源性精胺合成抑制劑DFMO都可以降低小鼠缺血腦損傷。ASIC1基因敲除對(duì)缺血性腦損傷有明顯的抵抗作用,，此時(shí)DFMO也不再起效,。
該工作得到了國(guó)家自然科學(xué)基金，科技部973項(xiàng)目,，中科院王寬誠(chéng)博士后基金以及上海市科委優(yōu)秀學(xué)科帶頭人計(jì)劃等項(xiàng)目的支持,。（生物谷Bioon.com）
生-物-谷推薦原文出處：
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.
