Neuronal TRPV1-CGRP axis regulates peripheral nerve regeneration through ERK/HIF-1 signaling pathway

Area of Science:

• Neuroscience
• Regenerative Medicine
• Molecular Biology

Background:

• Peripheral nerve injury is a significant clinical challenge.
• Calcitonin gene-related peptide (CGRP) plays a role in nerve repair.
• Neuronal transient receptor potential vanilloid type 1 (TRPV1) is a potential regulator of CGRP.

Purpose of the Study:

• To investigate the role of the neuronal TRPV1-CGRP axis in sciatic nerve (SN) repair.
• To explore the effects of TRPV1-CGRP activation on Schwann cell (SC) function.
• To elucidate the underlying molecular mechanisms involving ERK/HIF-1 signaling.

Main Methods:

• Established a mouse model of SN crush injury.
• Administered capsaicin (Cap) to activate and capsazepine (Cpz) to inhibit the TRPV1-CGRP axis.
• Utilized an in vitro indirect co-culture model of neurons and rat SC line (RSC96).
• Assessed SC proliferation, migration, myelination protein expression, and neurotrophic secretion.
• Measured extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation and hypoxia-inducible factor 1α (HIF-1α) accumulation.

Main Results:

• Intrathecal capsaicin activated the TRPV1-CGRP axis and promoted SN repair.
• Capsazepine inhibited the TRPV1-CGRP axis and delayed SN repair.
• Activation of neuronal TRPV1 positively correlated with enhanced SC proliferation, migration, and function.
• The TRPV1-CGRP axis upregulated ERK1/2 phosphorylation and HIF-1α accumulation in SCs, promoting their proliferation and migration.
• Local CGRP restoration at the injury site improved nerve repair.

Conclusions:

• The neuronal TRPV1-CGRP axis is a key regulator of Schwann cell biological behavior and axon regeneration after peripheral nerve injury.
• Activation of the TRPV1-CGRP axis promotes nerve repair via the ERK/HIF-1 signaling pathway.
• This axis represents a novel therapeutic target for treating nerve damage and developing regenerative biomaterials.