Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.
Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.
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DOI：
10.4103/1673-5374.382258
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发表时间：
2024-04
影响因子：
6.1
通讯作者：
Lopez PHH
中科院分区：
文献类型：
--
作者：
Berardo A;Bacaglio CR;Báez BB;Sambuelli R;Sheikh KA;Lopez PHH
抗神经节苷脂抗体与吉兰-巴雷综合征的延迟/不良临床恢复相关，主要与轴突再生停止相关。细胞表面神经节苷脂通过抗神经节苷脂抗体的交联在轴突再生的体外和体内范例中触发神经修复的抑制。这些作用涉及小GTdR RhoA/ROCK信号通路的激活，其负调节生长锥细胞骨架，类似于迄今为止描述的已确立的轴突再生抑制剂。这项工作的目的是进行一项概念验证研究，以证明Y-27632（ROCK的选择性药理学抑制剂）在外周神经轴突再生小鼠模型中的有效性，其中先前报告了用靶向神经节苷脂GD 1a和GT 1b的单克隆抗体进行被动免疫，对有髓和无髓纤维的再生产生有效的抑制作用。我们的研究结果表明，有髓和无髓轴突的差异敏感性的促再生作用的Y-27632。总剂量为9 mg/kg的Y-27632治疗可完全预防抗GD 1a/GT 1b单克隆抗体介导的对皮肤无髓鞘纤维轴突再生的抑制，并可恢复机械皮肤敏感性的功能。相反，相同剂量对有髓纤维的再生显示出毒性作用。有趣的是，在仅暴露于Y-27632的动物中，将Y-27632的剂量按比例缩小至5 mg/kg导致暴露于抗GD 1a/GT 1b单克隆抗体的再生有髓鞘轴突显著但不完全恢复，而不存在毒性。总之，这些发现证实了RhoA/ROCK信号通路在体内参与了与抗GD 1a/GT 1b单克隆抗体诱导的轴突再生抑制相关的分子机制。我们的研究结果开辟了针对RhoA/Rock途径进行治疗性药理干预的可能性，这些干预与抗神经节苷脂抗体的存在以及周围神经系统损伤后临床恢复延迟或不完全相关。
Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrè syndrome, mostly related to halted axon regeneration. Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration. These effects involve the activation of the small GTPase RhoA/ROCK signaling pathways, which negatively modulate growth cone cytoskeleton, similarly to well stablished inhibitors of axon regeneration described so far. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in a mouse model of axon regeneration of peripheral nerves, where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the in vivo participation of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.
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