Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Genetics, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
eNeuro. 2018 May 30;5(3). doi: 10.1523/ENEURO.0095-18.2018. eCollection 2018 May-Jun.
Preconditioning nerve injuries activate a pro-regenerative program that enhances axon regeneration for most classes of sensory neurons. However, nociceptive sensory neurons and central nervous system neurons regenerate poorly. In hopes of identifying novel mechanisms that promote regeneration, we screened for drugs that mimicked the preconditioning response and identified a nociceptive ligand that activates a preconditioning-like response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured dorsal root ganglion (DRG) sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration occurs only in NF200-negative nociceptive neurons, consistent with a cell-autonomous mechanism. Moreover, we identify a signaling pathway in which TRPV1 activation leads to calcium influx and protein kinase A (PKA) activation to induce a preconditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar preconditioning-like response and induces enhanced axonal outgrowth, indicating that this pathway can be induced . These findings highlight the use of local ligands to induce regeneration and suggest that it may be possible to target selective neuronal populations for repair, including cell types that often fail to regenerate.
预处理神经损伤会激活一个促再生程序，从而增强大多数感觉神经元的轴突再生。然而，伤害感受性感觉神经元和中枢神经系统神经元的再生能力很差。为了寻找促进再生的新机制，我们筛选了模拟预处理反应的药物，并鉴定出一种伤害感受性配体，它能激活类似于预处理的反应，从而促进轴突生长。我们发现用辣椒素来激活离子通道 TRPV1 会诱导培养的背根神经节 (DRG) 感觉神经元的轴突生长，而这种效应在 TRPV1 敲除神经元中被阻断。只有 NF200 阴性伤害感受神经元发生再生，这与细胞自主机制一致。此外，我们还确定了一个信号通路，其中 TRPV1 的激活导致钙内流和蛋白激酶 A（PKA）的激活，从而诱导类似于预处理的反应。最后，辣椒素给药于小鼠坐骨神经会激活类似的预处理反应，并诱导增强的轴突生长，表明该途径可以被诱导。这些发现强调了使用局部配体来诱导再生，并表明有可能针对特定的神经元群体进行修复，包括那些经常无法再生的细胞类型。
