Combined inhibition of Cdk5 and ROCK additively increase cell survival, but not the regenerative response in regenerating retinal ganglion cells
Combined inhibition of Cdk5 and ROCK additively increase cell survival, but not the regenerative response in regenerating retinal ganglion cells
复制标题
DOI：
10.1016/j.mcn.2009.09.005
复制
发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Lingor, Paul
中科院分区：
文献类型：
--
作者：
Bermel, Christina;Toenges, Lars;Lingor, Paul
CNS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。ROCK的抑制先前已显示促进视网膜神经节细胞（RGC）的再生，而Cdk 5抑制主要促进存活。因此，我们评估了ROCK和Cdk 5抑制剂联合治疗的效果。我们表明，在体外，Cdk 5抑制剂，吲哚酮A，和ROCK抑制剂，Y-27632的共同应用，增强了单独的任一物质的生存促进作用。然而，在体外的神经突生长促进只有Y-27632的存在下，而不是单独的吲哚酮A。在离体外植体和体内视神经挤压模型中，两种抑制剂的组合显著增加了小距离处的神经突生长，但这种作用在较长的神经突上趋于平稳。总之，用Cdk 5抑制剂吲哚酮A和ROCK抑制剂Y-27632的组合治疗导致对神经元存活的强加和效应，但不能增加超过ROCK抑制剂的效应的再生响应。(C)2009 Elsevier Inc. All rights reserved.
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. (C) 2009 Elsevier Inc. All rights reserved.