Department of Neurology, University Medicine Göttingen, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Mol Cell Neurosci. 2009 Dec;42(4):427-37. doi: 10.1016/j.mcn.2009.09.005. Epub 2009 Sep 25.
CNS regeneration is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. Inhibition of ROCK has been previously shown to promote regeneration in retinal ganglion cells (RGC) whereas Cdk5 inhibition mainly promoted survival. Therefore, we have evaluated the effects of combined treatment with inhibitors of ROCK and Cdk5. We show that in vitro, the co-application of the Cdk5 inhibitor, Indolinone A, and the ROCK inhibitor, Y-27632, potentiated the survival-promoting effect of either substance alone. However, neurite outgrowth in vitro was promoted only by the presence of Y-27632, not by Indolinone A alone. In the ex vivo explant and the in vivo optic nerve crush model the combination of both inhibitors significantly increased neurite outgrowth at small distances, but this effect leveled off for longer neurites. In summary, the combined treatment with the Cdk5 inhibitor Indolinone A and the ROCK inhibitor Y-27632 results in a strong additive effect on neuronal survival, but is not able to increase the regenerative response beyond the effect of the ROCK inhibitor.
中枢神经系统的再生受到损伤诱导的神经元凋亡和抑制轴突伸长的环境的限制。先前的研究表明，抑制 ROCK 可以促进视网膜神经节细胞（RGC）的再生，而抑制 Cdk5 主要促进存活。因此，我们评估了联合使用 ROCK 和 Cdk5 抑制剂的效果。我们发现，在体外，Cdk5 抑制剂 Indolinone A 和 ROCK 抑制剂 Y-27632 的共同应用增强了单独使用任何一种物质的存活促进作用。然而，体外的神经突生长仅由 Y-27632 的存在促进，而不是由 Indolinone A 单独促进。在离体外植体和体内视神经挤压模型中，两种抑制剂的联合使用显著增加了短距离的神经突生长，但对于较长的神经突，这种效果趋于平稳。总之，Cdk5 抑制剂 Indolinone A 和 ROCK 抑制剂 Y-27632 的联合治疗对神经元存活产生了强烈的附加效应，但不能使再生反应超过 ROCK 抑制剂的效果。
