Capsaicin Induces a Pro-regenerative Response and Axon Outgrowth in a Subset of Adult Dorsal Root Ganglion Neurons

After injury, neurons typically fail to regenerate axons and reinnervate target cells adequately to restore function. Injury to a peripheral nerve results in a retrograde signal that induces cytoskeletal reorganization and speeds axon growth. This pro-regenerative transcriptional program must be initiated before efficient axon regeneration can occur but is often not sufficient to establish long-distance regeneration. In a preconditioning response, prior injury accelerates a more robust axonal regenerative response to a second injury. Using an assay that they previously validated, Frey and colleagues performed a drug screen to search for agents that mimic the preconditioning response to induce a regenerative state in the absence of injury. As isolation of adult dorsal root ganglion (DRG) neurons is an injury in itself, isolated DRG neurons were first cultured for 4 – 6 ­days before exposure to >480 drugs individually during an activation phase of 24 hours. The drugs were subsequently washed out before the neurons were replated for a growth phase of 18 hours. The application of drugs in the activation phase represents a restricted time point during which agents that can induce a regenerative state prior to axon growth can be identified. The timing of the activation phase in vitro also excludes endogenous injury signaling factors that could hamper efficacious axon growth. Frey and colleagues found that a brief 10-minute pulse of capsaicin during the activation phase induced the pro-regenerative program and promoted axon outgrowth in a small subset of DRG neurons (Figure 1). Capsaicin is an agonist for the nociceptive ion channel TRPV1; these pain fibers are normally refractory to regeneration. The involvement of TRVP1 in capsaicin-induced axon outgrowth was confirmed by in vitro experiments using both the TRPV1 inhibitor capsazepine and TRVP1 knockout mice. This study represents an important advance in the field because it highlights the potential to find cell-type specific ligands to induce regeneration in subsets of neurons. Importantly, such ligands can be identified in the absence of potentially confounding injury signaling factors. More widespread drug screening would hopefully uncover more ligands that could promote axon regeneration in individuals with neurodegenerative diseases of the peripheral or central nervous system.

Figure 1. A brief capsaicin pulse during the activation phase induces axon outgrowth. (A) Since TRPV1 channels open transiently in response to stimulation, DRG neurons were treated with a 10-min pulse of capsaicin (blue bar) during the activation phase. After 10 min, capsaicin was removed, and the neurons were replated 24 hours later and grown for a further 18 hours before axon regeneration (AxR) was assessed. (B) Capsaicin (CAPS) exposure resulted in robust axon outgrowth compared to control DMSO treatment (Adapted from Figure 2A,B in Frey et al., 2018).

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TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling
Erin Frey, Scott Karney-Grobe, Trevor Krolak, Jeff Milbrandt and Aaron DiAntonio