ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells
ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells
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DOI：
10.1093/brain/awm284
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发表时间：
2008-01-01
期刊：
影响因子：
14.5
通讯作者：
Baehr, Mathias
中科院分区：
文献类型：
--
作者：
Lingor, Paul;Tonges, Lars;Baehr, Mathias
中枢神经系统的功能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。一个尚未解决的主要问题是这两个主要因素之间的相互作用。因此，我们评估了rho激酶（ROCK），髓鞘衍生的轴突生长抑制的关键介质和CNTF，视网膜神经节细胞（RGC）的一种有效的神经营养因子，在体外和体内的视网膜神经节细胞凋亡和神经突生长/再生模型的药理学抑制的作用。在这里，我们首次表明ROCK抑制剂Y-27632在体外和体内显著增强了RGC的存活。在体外，CNTF和Y-27632的共同应用加强了单独的物质的作用。ROCK抑制导致内源性MAPK通路的激活，CNTF和Y-27632的组合导致甚至更明显的MAPK激活。虽然CNTF也诱导STAT 3磷酸化，但额外应用ROCK抑制剂令人惊讶地减弱了CNTF对STAT 3磷酸化的影响。ROCK活性也以加性方式被两种物质降低。在体内，CNTF和Y-27632都促进RGC再生到非允许性视神经损伤模型中，并且在联合治疗后观察到累加效应。使用特异性抑制剂的进一步评估将STAT 3描述为神经突生长的负调节剂和细胞存活的正调节剂，而MAPK和Akt支持神经突生长。这些结果表明，Y-27632对神经营养因子ROCK的抑制作用强有力地支持受损的成年CNS神经元的存活。CNTF和Y-27632的共同施用导致对神经突生长和再生的累加效应。然而，细胞内信号传导途径的相互作用可能会减弱更明显的协同作用，并且必须考虑到未来的治疗策略。
Functional regeneration in the CNS is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. A principal, yet unresolved question is the interaction between these two major factors. We thus evaluated the role of pharmacological inhibition of rho kinase (ROCK), a key mediator of myelin-derived axonal growth inhibition and CNTF, a potent neurotrophic factor for retinal ganglion cells (RGC), in models of retinal ganglion cell apoptosis and neurite outgrowth/regeneration in vitro and in vivo. Here, we show for the first time that the ROCK inhibitor Y-27632 significantly enhanced survival of RGC in vitro and in vivo. In vitro, the co-application of CNTF and Y-27632 potentiated the effect of either substance alone. ROCK inhibition resulted in the activation of the intrinsic MAPK pathway, and the combination of CNTF and Y-27632 resulted in even more pronounced MAPK activation. While CNTF also induced STAT3 phosphorylation, the additional application of ROCK inhibitor surprisingly diminished the effects of CNTF on STAT3 phosphorylation. ROCK activity was also decreased in an additive manner by both substances. In vivo, both CNTF and Y-27632 enhanced regeneration of RGC into the non-permissive optic nerve crush model and additive effects were observed after combination treatment. Further evaluation using specific inhibitors delineate STAT3 as a negative regulator of neurite growth and positive regulator of cell survival, while MAPK and Akt support neurite growth. These results show that next to neurotrophic factors ROCK inhibition by Y-27632 potently supports survival of lesioned adult CNS neurons. Co-administration of CNTF and Y-27632 results in additive effects on neurite outgrowth and regeneration. The interaction of intracellular signalling pathways may, however, attenuate more pronounced synergy and has to be taken into account for future treatment strategies.