Rho kinase inhibition enhances axonal regeneration in the injured CNS
Rho kinase inhibition enhances axonal regeneration in the injured CNS
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DOI：
10.1523/jneurosci.23-04-01416.2003
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发表时间：
2003-02-15
影响因子：
5.3
通讯作者：
Strittmatter, SM
中科院分区：
文献类型：
--
作者：
Fournier, AE;Takizawa, BT;Strittmatter, SM
髓磷脂相关抑制剂限制损伤脑和脊髓的轴突再生。许多神经突生长抑制剂的共同目标是小gtpase的Rho家族。激活Rho及其下游效应物p160ROCK可抑制神经突生长。在这里，我们证明Rho被髓磷脂相关抑制剂Nogo-66直接激活。通过结合实验测量Rho活性，我们检测到Nogo-66刺激后PC12和背根神经节（DRG）细胞裂解物中GTP Rho水平升高。Rho活性水平不受氨基nogo刺激的影响。体外用C3转移酶灭活Rho能促进鸡DRG神经元的神经突生长，但在本研究中使用的给药方法，不能促进成年大鼠皮质脊髓束（CST）病变后的神经突生长。Y-27632抑制p160ROCK也促进髓鞘相关抑制剂的神经突生长。此外，Y-27632还能促进体内CST纤维的发芽，加速成年大鼠CST病变后的运动恢复。
Myelin-associated inhibitors limit axonal regeneration in the injured brain and spinal cord. A common target of many neurite outgrowth inhibitors is the Rho family of small GTPases. Activation of Rho and a downstream effector of Rho, p160ROCK, inhibits neurite outgrowth. Here, we demonstrate that Rho is directly activated by the myelin-associated inhibitor Nogo-66. Using a binding assay to measure Rho activity, we detected increased levels of GTP Rho in PC12 and dorsal root ganglion (DRG) cell lysates after Nogo-66 stimulation. Rho activity levels were not affected by Amino-Nogo stimulation. Rho inactivation with C3 transferase promotes neurite outgrowth of chick DRG neurons in vitro, but with the delivery method used here, it fails to promote neurite outgrowth after corticospinal tract (CST) lesions in the adult rat. Inhibition of p160ROCK with Y-27632 also promotes neurite outgrowth on myelin-associated inhibitors in vitro. Furthermore, Y-27632 enhances sprouting of CST fibers in vivo and accelerates locomotor recovery after CST lesions in adult rats.