Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
Stroke. 2013 Jul;44(7):1965-72. doi: 10.1161/STROKEAHA.111.000831. Epub 2013 May 21.
Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis and improves neurological outcome in experimental neurodegenerative diseases and stroke. The Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. The present study tests whether the Shh pathway mediates cerebrolysin-induced neurogenesis and improves neurological outcome after stroke.
Rats subjected to embolic stroke were treated with cerebrolysin with or without cyclopamine.
Using neural progenitor cells derived from the subventricular zone of the lateral ventricle of adult rats, we found that cerebrolysin significantly increased neural progenitor cells proliferation and their differentiation into neurons and myelinating oligodendrocytes, which were associated with upregulation of Shh and its receptors patched and smoothened. Blockage of the Shh signaling pathway with a pharmacological smoothened inhibitor, cyclopamine, abolished cerebrolysin-induced in vitro neurogenesis and oligodendrogenesis. In the ischemic rats, treatment with cerebrolysin starting 24 hours after stroke significantly increased neural progenitor cell proliferation in the subventricular zone and enhanced neurogenesis, oligodendrogenesis, and axonal remodeling in the peri-infarct area. Moreover, profound neurological function improvements were observed in rats treated with cerebrolysin from week 3 to week 5 after stroke onset compared with vehicle-treated rats. However, in vivo inhibition of the Shh pathway with cyclopamine completely reversed the effects of cerebrolysin on neurorestoration and functional recovery.
These results demonstrate that the Shh pathway mediates cerebrolysin-enhanced neurogenesis and white matter remodeling and improves functional recovery in rats after stroke.
脑活素是一种神经营养肽混合物，可增强神经发生并改善实验性神经退行性疾病和中风后的神经功能预后。Sonic hedgehog（Shh）信号通路可刺激中风后神经发生。本研究旨在探讨 Shh 通路是否介导脑活素诱导的神经发生，并改善中风后的神经功能预后。
对栓塞性中风大鼠进行脑活素治疗，并用环巴胺进行处理。
使用源自成年大鼠侧脑室室下区的神经祖细胞，我们发现脑活素可显著增加神经祖细胞的增殖，并促进其分化为神经元和髓鞘形成少突胶质细胞，这与 Shh 及其受体 patched 和 smoothened 的上调有关。用药物 smoothened 抑制剂环巴胺阻断 Shh 信号通路，可消除脑活素诱导的体外神经发生和少突胶质细胞发生。在缺血性大鼠中，中风后 24 小时开始用脑活素治疗可显著增加侧脑室室下区的神经祖细胞增殖，并增强梗死周围区域的神经发生、少突胶质细胞发生和轴突重塑。此外，与对照组相比，中风后第 3 周到第 5 周用脑活素治疗的大鼠神经功能显著改善。然而，用环巴胺体内抑制 Shh 通路完全逆转了脑活素对神经修复和功能恢复的作用。
这些结果表明，Shh 通路介导脑活素增强的神经发生和白质重塑，并改善中风后大鼠的功能恢复。
