Distinct VIP and PACAP Functions in the Distal Nerve Stump During Peripheral Nerve Regeneration

Patricia K Woodley,Nina F Mulvey,Xin-Peng Dun,Qing Min,Yankun Li,David B Parkinson

doi:10.3389/fnins.2019.01326

Abstract

Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylyl Cyclase Activating Peptide (PACAP) are regeneration-associated neuropeptides, which are up-regulated by neurons following peripheral nerve injury. So far, they have only been studied for their roles as autocrine signals for both neuronal survival and axon outgrowth during peripheral nerve regeneration. In this report, we examined VIP and PACAP’s paracrine effects on Schwann cells and macrophages in the distal nerve stump during peripheral nerve regeneration. We show that VPAC1, VPAC2, and PAC1 are all up-regulated in the mouse distal nerve following peripheral nerve injury and are highly expressed in Schwann cells and macrophages within the distal sciatic nerve. We further investigated the effect of VIP and PACAP on cultured rat Schwann cells, and found that VIP and PACAP can not only promote myelin gene expression in Schwann cells but can also inhibit the release of pro-inflammatory cytokines by Schwann cells. Furthermore, we show that VIP and PACAP inhibit the release of pro-inflammatory cytokines and enhance anti-inflammatory cytokine expression in sciatic nerve explants. Our results provide evidence that VIP and PACAP could have important functions in the distal nerve stump following injury to promote remyelination and regulate the inflammatory response. Thus, VIP and PACAP receptors appear as important targets to promote peripheral nerve repair following injury.

Highlights

The peripheral nervous system has a remarkable ability to regenerate following injury and the up-regulation of regeneration-associated genes in neurons contributes significantly to the success of repair following injury (Navarro et al, 2007; Ma and Willis, 2015)
RT-PCR result showed that VPAC1, VPAC2, and PAC1 mRNAs are all present in the intact mouse sciatic nerve and are all seemingly increased in the distal nerve stump following injury (Figure 1A)
Previous studies have been focused upon studying the autocrine effect of Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylyl Cyclase Activating Peptide (PACAP) on neuronal survival and axon outgrowth during peripheral nerve regeneration, these studies have revealed that the increase of VIP and PACAP expression in neurons was accompanied by a decrease in expression of their receptors (Zhou et al, 1999)

Summary

Introduction

The peripheral nervous system has a remarkable ability to regenerate following injury and the up-regulation of regeneration-associated genes in neurons contributes significantly to the success of repair following injury (Navarro et al, 2007; Ma and Willis, 2015). Neuropeptides such as galanin, neuropeptide Y, Vasoactive Intestinal Peptide (VIP), and Pituitary Adenylyl Cyclase Activating Peptide (PACAP) are important regeneration-associated neuropeptides for peripheral nerve regeneration (Navarro et al, 2007; Waschek, 2013). Three receptors, named as VPAC1, VPAC2, and PAC1, have been identified for the VIP and PACAP ligands. These receptors are G-protein coupled receptors with seven transmembrane domains and the binding of VIP and PACAP to these receptors typically activates Gs and Gq/11 proteins and increases both intracellular cyclic AMP (cAMP) and inositol1,4,5-trisphosphate/diacylglycerol levels in target cells (Harmar et al, 1998; Castorina et al, 2014)

Methods

Results

Conclusion