近日，復(fù)旦大學(xué)醫(yī)學(xué)神經(jīng)生物學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室,、腦科學(xué)研究院教授趙冰樵帶領(lǐng)研究團(tuán)隊(duì)首次發(fā)現(xiàn),，腦內(nèi)一種名叫“caspase-3”的分子，一旦被激活,，不僅在人的腦卒中發(fā)生初期起“細(xì)胞殺手”作用,，而且在腦卒中的恢復(fù)期繼續(xù)起破壞作用；研究團(tuán)隊(duì)還發(fā)現(xiàn),，藥物可以抑制caspase-3的破壞作用,，從而促進(jìn)腦卒中后神經(jīng)干細(xì)胞的再生。目前該成果已刊登在最新一期著名學(xué)術(shù)期刊《干細(xì)胞》上,。
腦卒中造成的神經(jīng)功能障礙,，臨床上至今尚無(wú)有效治療手段。腦損傷后,，新生神經(jīng)干細(xì)胞的存活能力和形成成熟神經(jīng)細(xì)胞的能力都非常有限,。因此,，腦卒中后神經(jīng)干細(xì)胞再生和分化機(jī)制研究，以及如何促進(jìn)神經(jīng)元的有效新生,，如何重塑腦中風(fēng)后受損的神經(jīng)功能,，一直是困擾腦中風(fēng)研究領(lǐng)域的重大瓶頸。
趙冰樵團(tuán)隊(duì)研究發(fā)現(xiàn),，caspase-3是腦內(nèi)神經(jīng)干細(xì)胞再生的重要抑制分子,，也是一種關(guān)鍵的導(dǎo)致正常細(xì)胞死亡的執(zhí)行因子。團(tuán)隊(duì)還研究發(fā)現(xiàn),，腦卒中雖然引起caspase-3在小鼠腦內(nèi)神經(jīng)干細(xì)胞中大量聚集,，即便采用多種實(shí)驗(yàn)手段，這些caspase-3也并不執(zhí)行讓細(xì)胞凋亡的功能,。他們進(jìn)一步研究證實(shí),，使用藥物可以抑制caspase-3的活性，從而促進(jìn)腦卒中后神經(jīng)干細(xì)胞的再生,，并可加快新生神經(jīng)干細(xì)胞向成熟神經(jīng)細(xì)胞即神經(jīng)元轉(zhuǎn)化,，協(xié)助腦損傷后的功能修復(fù)。
以往的研究?jī)H證明抑制caspase-3的活性后,，對(duì)急性腦卒中具有保護(hù)作用,，但趙冰樵團(tuán)隊(duì)的研究結(jié)果進(jìn)一步證明caspase-3在腦卒中后繼續(xù)有破壞作用。該成果不但對(duì)臨床上如何促進(jìn)腦卒中后的神經(jīng)再生,，而且對(duì)開(kāi)發(fā)既保護(hù)腦損傷又促進(jìn)腦損傷后功能重塑,、找到新型治療藥物新靶點(diǎn)具有重要意義。（生物谷 Bioon.com）
生物谷推薦的英文摘要
Stem Cell DOI: 10.1002/stem.1503
Caspase-3 Modulates Regenerative Response after Stroke
Wenying Fan1,*, Yiqin Dai1, Haochen Xu1, Ximin Zhu1, Ping Cai1, Lixiang Wang1, Chungang Sun1, Changlong Hu1,2, Ping Zheng1, Bing-Qiao Zhao1,*
Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently however, accumulating data indicate that caspase-3 also participate in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus (DG) during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its self-renewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs, and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke.
