New strategy for drug development of cerebral ischemia; zinc signal is a potential target

越来越多的证据表明，脑缺血后突触前末梢锌的过度释放可导致神经元细胞死亡。据报道，锌螯合剂对游离锌的阻断可消除脑缺血引起的神经变性。这些结果支持了锌是缺血性神经细胞死亡介质之一的观点。然而，该机制尚未完全理解。在这项研究中，我们解决了锌诱导的神经毒性的分子机制。我们在这里表明，锌诱导的细胞凋亡可能受到调节，至少部分，通过改变剪接模式的促凋亡因子Bim。据我们所知，这是首次报道锌作为剪接调节剂的新功能。此外，我们提供的证据表明，阿扑吗啡，多巴胺受体激动剂，防止锌诱导的神经毒性独立的多巴胺受体。

There is increasing evidence that excessive zinc release from presynaptic terminals following cerebral ischemia induces neuronal cell death. It was reported that the blockade of free zinc by zinc chelators abolishes the neurodegeneration induced by cerebral ischemia. These findings support the concept that zinc is one of mediators of ischemic neuronal cell death. However, the mechanism is not fully understood. In this study, we addressed molecular mechanisms of zinc-induced neurotoxicity. We demonstrated here that zinc-induced apoptosis might be regulated, at least in part, through alterations in splicing pattern of pro-apoptotic factor Bim. To our knowledge, this is first report showing a novel function of zinc as a splicing regulator. In addition, we provided evidence that apomorphine, a dopamine receptor agonist, protects against zinc-induced neurotoxicity independently of dopamine receptors.