Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, China.
J Neurosci Res. 2017 Dec;95(12):2409-2419. doi: 10.1002/jnr.24068. Epub 2017 May 17.
New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.
必须开发新策略来解决中风治疗的问题。近年来，基于干细胞的中风后治疗已成为公众和学术界关注的焦点。此前，我们已经表明，小分子化合物 ZL006 可使神经元型一氧化氮合酶 (nNOS) 与突触后密度蛋白-95 (PSD-95) 解偶联，从而改善雄性局灶性脑缺血大鼠的缺血性损伤并促进内源性神经干细胞 (NSC) 的神经元分化。在这项研究中，我们将外源性 NSCs 移植到雄性大鼠的对侧半球，并在缺血性中风后用 ZL006 进行治疗。我们发现 ZL006 处理促进了移植的 NSCs 向缺血损伤区域的迁移，并促进了这些细胞的神经元分化，这不是由于 ZL006 对外源性 NSCs 的直接作用，而是与神经元中 cAMP 反应元件结合蛋白 (CREB) 的磷酸化增加和有利的微环境有关。此外，还发现 ZL006 治疗组的功能结果得到了改善。总之，我们的数据表明，ZL006 可使神经元中的 nNOS-PSD-95 解偶联，正向调节移植 NSCs 的命运，并有益于雄性大鼠中风后的功能结果。
