Effects of PACAP on Schwann Cells: Focus on Nerve Injury

Abstract

Schwann cells, the most abundant glial cells of the peripheral nervous system, represent the key players able to supply extracellular microenvironment for axonal regrowth and restoration of myelin sheaths on regenerating axons. Following nerve injury, Schwann cells respond adaptively to damage by acquiring a new phenotype. In particular, some of them localize in the distal stump to form the Bungner band, a regeneration track in the distal site of the injured nerve, whereas others produce cytokines involved in recruitment of macrophages infiltrating into the nerve damaged area for axonal and myelin debris clearance. Several neurotrophic factors, including pituitary adenylyl cyclase-activating peptide (PACAP), promote survival and axonal elongation of injured neurons. The present review summarizes the evidence existing in the literature demonstrating the autocrine and/or paracrine action exerted by PACAP to promote remyelination and ameliorate the peripheral nerve inflammatory response following nerve injury.

Doxycycline and Minocycline act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells

“…This theory has been partly confirmed by recent evidence in vivo, where PACAP was found to promote myelin regeneration following sciatic nerve injury [6]. PACAP is significantly increased in peripheral neurons post-injury, and it is detectable at higher levels one month after nerve damage, suggesting it plays a key role in both axon regeneration and the late remyelination process [35]. Moreover, axon regeneration following injury is severely disrupted in PACAP knockout mice [20].…”

Pituitary Adenylate Cyclase-Activating Polypeptide: A Potent Therapeutic Agent in Oxidative Stress

“…Understanding the hormesis of PAC1 receptor activity under oxidative stress conditions may elucidate a therapeutic strategy in stroke, as preconditioning with low levels of H2O2 may further bolster PAC1 receptor activity [81]. Through the promotion of the endoplasmic reticulum(ER) oxidoreductase and selenoprotein T (SELENOT), PACAP generates anti-oxidative mechanisms [82][83][84]. In sympathoadrenal (SA) precursors, PACAP triggered the cAMP pathway and subsequently activated canonical signaling, which mediated the functionality of mitochondria, leading to transcription of the SELENOT gene [82].…”

The Protective Effects of Endogenous PACAP in Oxygen-Induced Retinopathy

“…The strong neuro-and general cytoprotective role of PACAP are mainly due to its anti-apoptotic, antioxidant, and anti-inflammatory effects (Soles-Tarres et al 2020;Toth et al 2020). Due to the lack of these protective actions in PACAP-deficient animals, increased vulnerability and pathological responses have been observed in different peripheral injuries, such as kidney ischemia, callus formation, and cardiomyopathy (Jozsa et al 2019;Mori et al 2010;Reglodi et al 2012) and also in injuries of the nervous system, such as spinal cord injury, ischemia, and nerve degeneration (Armstrong et al 2008;Maugeri et al 2020;Ohtaki et al 2006;Tsuchikawa et al 2012). This endogenous protective effect of the peptide has also been confirmed in carotid artery occlusion-induced retinal injury (Szabadfi et al 2012).…”