Che Huiling, Du Yu, Jiang Yixuan, Zhu Zhanfeng, Bai Mingxuan, Zheng Jianan, Yang Mao, Xiang Lin, Gong Ping
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Neurochem. 2025 Jan;169(1):e16281. doi: 10.1111/jnc.16281.
Severe trauma frequently leads to nerve damage. Peripheral nerves possess a degree of regenerative ability, and actively promoting their recovery can help restore the sensory and functional capacities of tissues. The neuropeptide calcitonin gene-related peptide (CGRP) is believed to regulate the repair of injured peripheral nerves, with neuronal transient receptor potential vanilloid type 1 (TRPV1) potentially serving as a crucial upstream factor. In this study, we established a mouse model of sciatic nerve (SN) crush injury and found that intrathecal injection of capsaicin (Cap) activated the neuronal TRPV1-CGRP axis, thereby promoting SN repair. Conversely, the application of capsazepine (Cpz), which inhibits the neuronal TRPV1-CGRP axis, delayed SN repair. Local restoration of CGRP expression at the injury site enhanced the repair process. In vitro experiments, we employed the rat Schwann cell (SC) line RSC96 to establish an indirect co-culture model of neurons and SCs. We observed that the proliferation, migration, expression of myelination-associated proteins, and neurotrophic secretion functions of RSC96 cells are positively correlated with the degree of activation of neuronal TRPV1. Inhibition of neuronal TRPV1, followed by the restoration of CGRP levels, improved these functions in RSC96 cells. Furthermore, activation of the neuronal TRPV1-CGRP axis resulted in an upregulation of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation levels and an increase in hypoxia-inducible factor 1α (HIF-1α) accumulation in RSC96 cells, thereby promoting their proliferation and migration. In summary, this study demonstrates that neuronal TRPV1-CGRP axis can regulate biological behavior of SCs and axon regeneration by activating the ERK/HIF-1 signaling pathway following peripheral nerve injury. This finding clarifies the role of CGRP in neuroregulatory networks and provides a novel reference point for the development of drugs and biomaterials for treating nerve damage.
严重创伤常导致神经损伤。周围神经具有一定程度的再生能力，积极促进其恢复有助于恢复组织的感觉和功能能力。神经肽降钙素基因相关肽（CGRP）被认为可调节受损周围神经的修复，神经元瞬时受体电位香草酸亚型1（TRPV1）可能是关键的上游因子。在本研究中，我们建立了小鼠坐骨神经挤压伤模型，发现鞘内注射辣椒素（Cap）可激活神经元TRPV1-CGRP轴，从而促进坐骨神经修复。相反，应用抑制神经元TRPV1-CGRP轴的辣椒素拮抗剂（Cpz）会延迟坐骨神经修复。损伤部位CGRP表达的局部恢复可增强修复过程。在体外实验中，我们使用大鼠雪旺细胞（SC）系RSC96建立了神经元与雪旺细胞的间接共培养模型。我们观察到，RSC96细胞的增殖、迁移、髓鞘相关蛋白的表达以及神经营养分泌功能与神经元TRPV1的激活程度呈正相关。抑制神经元TRPV1，随后恢复CGRP水平，可改善RSC96细胞的这些功能。此外，激活神经元TRPV1-CGRP轴导致RSC96细胞中细胞外信号调节激酶（ERK1/2）磷酸化水平上调以及缺氧诱导因子1α（HIF-1α）积累增加，从而促进其增殖和迁移。总之，本研究表明，神经元TRPV1-CGRP轴可通过激活外周神经损伤后的ERK/HIF-1信号通路来调节雪旺细胞的生物学行为和轴突再生。这一发现阐明了CGRP在神经调节网络中的作用，并为开发治疗神经损伤的药物和生物材料提供了新的参考依据。
