TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling

Abstract

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 in vivo. 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.

DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury

“…In addition, the enrichment of the pain response terms among DLK-dependent DEGs is consistent with the recent finding that DLK regulates pain sensitivity following peripheral nerve injury (Wlaschin et al, 2018). Additionally, the DLK-dependent activation of the pain response-pathway might be another route for regulating the axon regeneration program, as stimulating a nociceptive TRPV1 channel with an agonist, capsaicin, can induce the regenerative potential of DRG neurons (Frey et al, 2018).…”

The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling

“…The WT DRG neurons were able to shift their physiological condition from a resting state to a regenerative state following the replating injury, which resulted in a 2.6-fold increase in the average axon length compared with the control neurons with no replating injury ( Fig. 3 A and B ), as reported previously ( 57 , 58 ). In contrast, Prom1 KO neurons displayed significant defects in axonal growth, as shown by the shorter axon lengths ( Fig.…”

HSP90 is a chaperone for DLK and is required for axon injury signaling

“…Indeed, our capsazepine hit suggested that TRPV1 is necessary to induce the regeneration program; however, we found that capsazepine still inhibited preconditioned neurite regrowth in TRPV1 knockout neurons, showing that this is an off-target effect. Interestingly, using a similar screening approach, our group recently showed that TRPV1 activation is sufficient to induce the regeneration program in small diameter sensory neurons (55). Lastly, several hits, such as curcumin or resveratrol, target dozens of proteins and thus provide little mechanistic information.…”