Fasudil, a Rho-Associated Coiled Coil-Forming Protein Kinase Inhibitor, Recovers Methylmercury-Induced Axonal Degeneration by Changing Microglial Phenotype in Rats
Fasudil, a Rho-Associated Coiled Coil-Forming Protein Kinase Inhibitor, Recovers Methylmercury-Induced Axonal Degeneration by Changing Microglial Phenotype in Rats
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DOI：
10.1093/toxsci/kfy281
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发表时间：
2019-03-01
影响因子：
3.8
通讯作者：
Nakamura, Atsushi
中科院分区：
文献类型：
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作者：
Fujimura, Masatake;Usuki, Fusako;Nakamura, Atsushi
甲基汞 (MeHg) 是一种环境神经毒物，可引起神经病理变化。在这项研究中，我们建立了慢性甲基汞中毒大鼠。这些大鼠存活下来，并持续发生甲基汞诱导的轴突变性，包括背根神经和脊髓背柱；这些变化在甲基汞戒断后持续了 12 周。我们首次证明了 Fasudil（一种 Rho 相关卷曲线圈形成蛋白激酶的特异性抑制剂）对已建立的慢性甲基汞中毒大鼠的轴突变性和相应的神经功能障碍的恢复作用。为了研究这种恢复作用的机制，我们重点关注 Rho 蛋白家族的表达。我们之前的研究证实了这一点，该研究表明，在体外和亚急性甲基汞中毒大鼠中，与法舒地尔联合治疗可通过减轻甲基汞诱导的 Rac1 抑制引起的神经突伸展/收缩不协调来预防轴突变性。然而，法舒地尔对慢性甲基汞中毒大鼠轴突变性的恢复作用机制不同于甲基汞介导的神经炎伸展/收缩不协调。我们发现法舒地尔的恢复作用是由法舒地尔诱导的小胶质细胞表型从促炎到抗炎的变化引起的；此外，Fasudil 抑制 Rho 相关卷曲线圈形成蛋白激酶活性。 Fasudil 治疗降低了促炎因子的表达，包括肿瘤坏死因子、诱导型一氧化氮合酶、白细胞介素 1 和白细胞介素 6；此外，它还使活化 B 细胞途径的核因子 kappa-轻链增强子失活。此外，Fasudil 治疗与抗炎因子精氨酸酶 1 和白细胞介素 10 水平升高相关。这些结果表明，Rho 相关的卷曲线圈形成蛋白激酶抑制可能会恢复慢性甲基汞中毒中甲基汞介导的轴突变性和神经功能障碍。
Methylmercury (MeHg) is an environmental neurotoxicant that induces neuropathological changes. In this study, we established chronic MeHg-intoxicated rats. These rats survived, and sustained MeHg-induced axonal degeneration, including the dorsal root nerve and the dorsal column of the spinal cord; these changes persisted 12weeks after MeHg withdrawal. We demonstrated for the first time the restorative effect of Fasudil, a specific inhibitor of Rho-associated coiled coil-forming protein kinase, on axonal degeneration and corresponding neural dysfunction in the established chronic MeHg-intoxicated rats. To investigate the mechanism of this restorative effect, we focused on the expression of Rho protein families. This was supported by our previous study, which demonstrated that cotreatment with Fasudil prevented axonal degeneration by mitigating neurite extension/retraction incoordination caused by MeHg-induced suppression of Rac1 in vitro and in subacute MeHg-intoxicated rats. However, the mechanism of the restorative effect of Fasudil on axonal degeneration in chronic MeHg-intoxicated rats differed from MeHg-mediated neuritic extension/retraction incoordination. We found that the restorative effect of Fasudil was caused by the Fasudil-induced change of microglial phenotype, from proinflammatory to anti-inflammatory; moreover, Fasudil suppressed Rho-associated coiled coil-forming protein kinase activity. Treatment with Fasudil decreased the expression of proinflammatory factors, including tumor necrosis factor-, inducible nitric oxide synthase, interleukin-1, and interleukin-6; furthermore, it inactivated the nuclear factor kappa-light-chain-enhancer of activated B cells pathway. Additionally, Fasudil treatment was associated with increased levels of anti-inflammatory factors arginase-1 and interleukin-10. These results suggest that Rho-associated coiled coil-forming protein kinase inhibition may recover MeHg-mediated axonal degeneration and neural dysfunction in chronic MeHg intoxication.