Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan Province, China.
Neuropharmacology. 2024 Dec 15;261:110169. doi: 10.1016/j.neuropharm.2024.110169. Epub 2024 Sep 25.
Peripheral nerve injury (PNI), typically caused by traumatic accidents or medical events, is currently one of the most common diseases that leads to limb disability. After PNI, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated at the lesion site. Our earlier study suggested that ropivacaine promotes axon regrowth by regulating Nav1.8-mediated macrophage signaling. Nevertheless, the mechanism of ropivacaine in regulation of Nav1.8 expression remains incompletely understood. Kinesin family 5b (KIF5b) was reported to mediate the Nav1.8 axonal transport from dorsal root ganglia (DRGs) to lesion site. Herein, we investigated whether ropivacaine promotes axon regeneration through inhibition of KIF5b-mediated Nav1.8 transport. Reduced levels of KIF5b and Nav1.8 in DRGs coincide with their increase at the lesion site. Nav1.8 mRNA was significantly increased at the lesion site but not in DRGs. Surprisingly, ropivacaine reversed the alterations of Nav1.8 and KIF5b protein expression without affecting Nav1.8 mRNA level. Due to KIF5b overexpression in DRGs, Nav1.8 protein level was significantly decreased in DRGs and increased at the lesion site. We also found KIF5b overexpression significantly impaired behavioral functions, reduced the recovery index of compound muscle action potential (CMAP) amplitude, inhibited axonal regrowth, slowed M1 macrophage infiltration and shift to M2 phenotype, and delayed myelin debris clearance. Notably, all aforementioned results caused by KIF5b overexpression were alleviated by ropivacaine. Furthermore, we demonstrated that inhibition of Nav1.8 transport by A-803467 produced mitigating effects on the impairment of regenerative capacity induced by KIF5b overexpression similar to ropivacaine. These results suggest that ropivacaine promotes axonal regeneration at least partially by inhibiting KIF5b-mediated Nav1.8 forward transport.
周围神经损伤（PNI）通常由创伤事故或医疗事件引起，是导致肢体残疾的最常见疾病之一。在 PNI 后，毒素不敏感电压门控钠通道 Nav1.8 在损伤部位上调。我们之前的研究表明，罗哌卡因通过调节 Nav1.8 介导的巨噬细胞信号来促进轴突再生。然而，罗哌卡因调节 Nav1.8 表达的机制尚不完全清楚。驱动蛋白家族 5b（KIF5b）被报道介导 Nav1.8 从背根神经节（DRG）到损伤部位的轴突运输。在此，我们研究了罗哌卡因是否通过抑制 KIF5b 介导的 Nav1.8 运输来促进轴突再生。DRG 中 KIF5b 和 Nav1.8 水平降低与损伤部位的增加相吻合。Nav1.8 mRNA 在损伤部位显著增加，但在 DRG 中没有增加。令人惊讶的是，罗哌卡因逆转了 Nav1.8 和 KIF5b 蛋白表达的改变，而不影响 Nav1.8 mRNA 水平。由于 DRG 中 KIF5b 的过表达，Nav1.8 蛋白水平在 DRG 中显著降低，而在损伤部位增加。我们还发现 KIF5b 的过表达显著损害了行为功能，降低了复合肌肉动作电位（CMAP）幅度的恢复指数，抑制了轴突再生，减缓了 M1 巨噬细胞浸润和向 M2 表型的转变，并延迟了髓鞘碎片的清除。值得注意的是，KIF5b 过表达引起的所有上述结果都被罗哌卡因减轻。此外，我们证明，A-803467 抑制 Nav1.8 运输对 KIF5b 过表达引起的再生能力损害产生了类似于罗哌卡因的缓解作用。这些结果表明，罗哌卡因通过抑制 KIF5b 介导的 Nav1.8 正向运输至少部分促进了轴突再生。
