Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype.
Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype.
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DOI：
10.1038/cddis.2014.286
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发表时间：
2014-07-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是小胶质细胞释放的肿瘤坏死因子超家族成员，参与了局灶性脑缺血后细胞凋亡的诱导。事实上，脑缺血与受损区域的进行性扩大和明显的炎症有关。为减轻脑缺血引起的炎症反应，改善脑损伤，本研究旨在探讨TRAIL及其受体在卒中及脑缺血预适应中的作用，并通过调节TRAIL通路，为卒中的治疗提供新的策略。为达到这一目的，采用大脑中动脉短暂性阻断100 ，再灌流24 h建立大鼠伤害性局灶性脑缺血模型和大鼠缺血预适应模型，脑缺血前给予30 m in的tMCAO作为预适应保护性刺激。结果表明，缺血预适应通过上调TRAIL诱骗受体和下调TRAIL本身及其死亡受体而发挥神经保护作用。作为一种反保护措施，TRAIL在tMCAO动物中的免疫中和作用显著地抑制了组织损伤，并显著地恢复了功能。我们的数据揭示了成年哺乳动物脑缺血后持续神经元损伤的机制，并为治疗干预提供了新的分子靶点。旨在抑制死亡诱导配体TRAIL、拮抗死亡受体或激活诱骗受体的策略为中风的治疗开辟了新的视角。
TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved in the induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia and ameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke and ischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achieve this aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middle cerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia was preceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors and downregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on the mechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new molecular targets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the death receptors, or to activate the decoy receptors open new perspectives for the treatment of stroke.
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影响因子：
3
作者：
Cantarella, Giuseppina;Di Benedetto, Giulia;Bernardini, Renato
通讯作者：
Bernardini, Renato
影响因子：
3.3
作者：
Cantarella, Giuseppina;Lempereur, Laurence;Bernardini, Renato
通讯作者：
Bernardini, Renato
DOI：
10.1038/nrd3930
发表时间：
2013-02
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
1.2
作者：
Nakajima, T;Iwabuchi, S;Kawahara, K
通讯作者：
Kawahara, K
缺氧缺血上调未成熟大鼠大脑中的 TRAIL 和 TRAIL 受体
影响因子：
2.9
作者：
Huang, Zhiheng;Song, Lili;Chen, Chao
通讯作者：
Chen, Chao