Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush
Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush
复制标题
DOI：
10.1007/s12035-015-9676-2
复制
发表时间：
2017-01-01
影响因子：
5.1
通讯作者：
Lingor, Paul
中科院分区：
文献类型：
--
作者：
Ribas, Vinicius T.;Koch, Jan C.;Lingor, Paul
轴突变性是许多创伤性和神经退行性中枢神经系统 (CNS) 疾病的初始步骤之一，因此是一个有前途的治疗靶点。局灶性轴突病变之后，两个相邻轴突部分发生急性轴突变性（AAD），之后近端和远端部分在稍后的时间点遵循不同的退变命运。先前研究表明，通过钙通道抑制剂阻断钙流入可减轻视神经挤压 (ONC) 后的 AAD。然而，目前尚不清楚 AAD 的减弱是否也会促进连续的轴突再生。在这里，我们使用大鼠ONC模型来研究钙通道抑制剂对轴突变性、视网膜神经节细胞（RGC）存活和轴突再生的影响以及所涉及的分子机制。钙通道抑制剂的应用减弱了 ONC 后的 AAD，并通过视神经轴突的实时成像观察到保留了轴突的完整性。 ONC 后 28 天，这连续提高了 RGC 的存活率并改善了轴突再生。我们进一步表明，钙通道抑制减弱了损伤附近损伤诱导的钙蛋白酶激活，并抑制了 c-Jun N 端激酶途径的激活。视网膜中通过 Akt 发出的促生存信号也增加了。因此，我们的数据表明，AAD 的减弱可改善连续神经元存活和轴突再生，并且钙通道抑制剂可能是治疗创伤性和退行性中枢神经系统疾病的有价值的工具。
Axonal degeneration is one of the initial steps in many traumatic and neurodegenerative central nervous system (CNS) disorders and thus a promising therapeutic target. A focal axonal lesion is followed by acute axonal degeneration (AAD) of both adjacent axon parts, before proximal and distal parts follow different degenerative fates at later time points. Blocking calcium influx by calcium channel inhibitors was previously shown to attenuate AAD after optic nerve crush (ONC). However, it remains unclear whether the attenuation of AAD also promotes consecutive axonal regeneration. Here, we used a rat ONC model to study the effects of calcium channel inhibitors on axonal degeneration, retinal ganglion cell (RGC) survival, and axonal regeneration, as well as the molecular mechanisms involved. Application of calcium channel inhibitors attenuated AAD after ONC and preserved axonal integrity as visualized by live imaging of optic nerve axons. Consecutively, this resulted in improved survival of RGCs and improved axonal regeneration at 28 days after ONC. We show further that calcium channel inhibition attenuated lesion-induced calpain activation in the proximity of the crush and inhibited the activation of the c-Jun N-terminal kinase pathway. Pro-survival signaling via Akt in the retina was also increased. Our data thus show that attenuation of AAD improves consecutive neuronal survival and axonal regeneration and that calcium channel inhibitors could be valuable tools for therapeutic interventions in traumatic and degenerative CNS disorders.