Li Qin, Huang Xian-Ju, He Wei, Ding Jie, Jia Jun-Ting, Fu Gang, Wang Hong-Xing, Guo Lian-Jun
Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Cell Mol Neurobiol. 2009 Mar;29(2):169-80. doi: 10.1007/s10571-008-9308-8. Epub 2008 Sep 11.
We previously reported that inhibition of Rho-kinase (ROCK) by hydroxyl fasudil improves cognitive deficit and neuronal damage in rats with chronic cerebral ischemia (Huang et al., Cell Mol Neurobiol 28:757-768, 2008). In this study, fasudil mesylate (FM) was investigated for its neuroprotective potential in rats with ischemia following middle cerebral artery occlusion (MCAO) and reperfusion. The effect of fasudil mesylate was also studied in rat brain cortical and hippocampal slices treated with oxygen-glucose deprivation (OGD) injury. Gross anatomy showed that cerebral infarct size, measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in the FM-treated than in the non-FM-treated ischemic rats. In the brain regions vulnerable to ischemia of ischemic rats, fasudil mesylate was also found to significantly restore the enzyme protein expression level of endothelial nitric oxide synthase (eNOS), which was decreased in ischemia. However, it remarkably reduced the protein synthesis of inducible nitric oxide synthase (iNOS) that was induced by ischemia and reperfusion. In rat brain slices treated with OGD injury, fasudil mesylate increased the neuronal cell viability by 40% for cortex and by 61% for hippocampus, respectively. Finally, in the presence of OGD and fasudil mesylate, superoxide dismutase (SOD) activity was increased by 50% for cortex and by 58% for hippocampus, compared to OGD only group. In conclusion, our in vivo study showed that fasudil mesylate not only decreased neurological deficit but also reduced cerebral infarct size, possibly and at least partially by augmenting eNOS protein expression and inhibiting iNOS protein expression after ischemia-reperfusion.
我们之前报道过，羟基法舒地尔抑制Rho激酶（ROCK）可改善慢性脑缺血大鼠的认知缺陷和神经元损伤（Huang等人，《细胞与分子神经生物学》28:757 - 768，2008年）。在本研究中，对甲磺酸法舒地尔（FM）在大脑中动脉闭塞（MCAO）和再灌注后的缺血大鼠中的神经保护潜力进行了研究。还在氧 - 葡萄糖剥夺（OGD）损伤处理的大鼠脑皮质和海马切片中研究了甲磺酸法舒地尔的作用。大体解剖显示，用2,3,5 - 三苯基四氮唑氯化物（TTC）染色测量，FM治疗的缺血大鼠的脑梗死面积明显小于未用FM治疗的缺血大鼠。在缺血大鼠易缺血的脑区，还发现甲磺酸法舒地尔能显著恢复缺血时降低的内皮型一氧化氮合酶（eNOS）的酶蛋白表达水平。然而，它显著降低了缺血和再灌注诱导的诱导型一氧化氮合酶（iNOS）的蛋白质合成。在用OGD损伤处理的大鼠脑切片中，甲磺酸法舒地尔使皮质神经元细胞活力分别提高了40%，海马神经元细胞活力提高了61%。最后，与仅OGD组相比，在存在OGD和甲磺酸法舒地尔的情况下，皮质超氧化物歧化酶（SOD）活性提高了50%，海马提高了58%。总之，我们的体内研究表明，甲磺酸法舒地尔不仅减少了神经功能缺损，还减小了脑梗死面积，这可能至少部分是通过在缺血再灌注后增强eNOS蛋白表达和抑制iNOS蛋白表达来实现的。
