Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure
Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure
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DOI：
10.1016/j.taap.2010.09.011
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发表时间：
2011-01-01
影响因子：
3.8
通讯作者：
Izumo, Shuji
中科院分区：
文献类型：
--
作者：
Fujimura, Masatake;Usuki, Fusako;Izumo, Shuji
甲基汞（MeHg）是一种环境神经毒物，可引起中枢神经系统和外周感觉神经系统的病理改变。我们最近的研究表明，下调Ras相关的C3肉毒杆菌毒素底物1（Rac 1），这是已知的，以促进神经炎的扩展，在培养的皮质神经元中的甲基汞诱导的损伤之前，这表明甲基汞介导的轴突变性是由于神经炎的扩展的干扰。因此，我们推测，甲基汞诱导的轴突变性可能是由于神经炎性伸展/收缩不协调。这一想法引起了我们对Ras同源基因（Rho）/Rho相关卷曲螺旋形成蛋白激酶（ROCK）途径的注意，因为已知它与轴突的发育和凋亡性神经元细胞死亡相关。在这里，我们表明，抑制Rho/ROCK途径防止甲基汞中毒在体外和体内。Rho抑制剂，C3毒素，和2 ROCK抑制剂，法舒地尔和Y-27632，显着保护对甲基汞诱导的轴突变性和神经元细胞凋亡在培养的皮质神经元细胞暴露于100 nM甲基汞3天。此外，法舒地尔可部分预防甲基汞中毒模型大鼠（20 ppm甲基汞饮水28天）背根神经节中大苍白神经元的丢失、背脊根神经轴突变性和脊髓背柱空泡变性。在此模型中，后肢交叉征（一种特征性的甲基汞中毒征）被显著抑制。结果表明，抑制Rho/ROCK通路挽救了甲基汞介导的神经炎性伸展/收缩不协调，并有效地预防甲基汞诱导的轴突变性和凋亡神经元细胞死亡。(C)2010年爱思唯尔公司All rights reserved.
Methylmercury (MeHg) is an environmental neurotoxicant which induces neuropathological changes in both the central nervous and peripheral sensory nervous systems. Our recent study demonstrated that down-regulation of Ras-related C3 botulinum toxin substrate 1 (Rac1), which is known to promote neuritic extension, preceded MeHg-induced damage in cultured cortical neurons, suggesting that MeHg-mediated axonal degeneration is due to the disturbance of neuritic extension. Therefore we hypothesized that MeHg-induced axonal degeneration might be caused by neuritic extension/retraction incoordination. This idea brought our attention to the Ras homolog gene (Rho)/Rho-associated coiled coil-forming protein kinase (ROCK) pathway because it has been known to be associated with the development of axon and apoptotic neuronal cell death. Here we show that inhibition of the Rho/ROCK pathway prevents MeHg-intoxication both in vitro and in vivo. A Rho inhibitor, C3 toxin, and 2 ROCK inhibitors, Fasudil and Y-27632, significantly protected against MeHg-induced axonal degeneration and apoptotic neuronal cell death in cultured cortical neuronal cells exposed to 100 nM MeHg for 3 days. Furthermore, Fasudil partially prevented the loss of large pale neurons in dorsal root ganglia, axonal degeneration in dorsal spinal root nerves, and vacuolar degeneration in the dorsal columns of the spinal cord in MeHg-intoxicated model rats (20 ppm MeHg in drinking water for 28 days). Hind limb crossing sign, a characteristic MeHg-intoxicated sign, was significantly suppressed in this model. The results suggest that inhibition of the Rho/ROCK pathway rescues MeHg-mediated neuritic extension/retraction incoordination and is effective for the prevention of MeHg-induced axonal degeneration and apoptotic neuronal cell death. (C) 2010 Elsevier Inc. All rights reserved.