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

Abstract

Pre-conditioning 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 pre-conditioning response, and identified a nociceptive ligand that activates a pre-conditioning-like response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured DRG sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration only occurs 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 PKA activation to induce a pre-conditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar pre-conditioning-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.

Significance Statement After injury or neurodegenerative disease, axons need to regenerate to restore function. Unfortunately, no current therapies achieve this goal. We performed a drug screen in adult sensory neurons to identify agents that effectively re-program neurons into a pro-growth state. We demonstrate that capsaicin, a TRPV1 agonist, activates a pro-axon growth program. This mechanism requires calcium influx and PKA activity, and leads to the activation of the pro-regenerative transcription factor CREB. Hence, activation of ion channels can promote axon regeneration, an exciting finding since many ion channels are druggable targets. Moreover, these findings suggest an approach for enhancing axon regeneration in selective populations of neurons.