Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal
peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs),
perform a wide variety of effects in human cancers, including glioblastoma multiforme
(GBM). This tumor is characterized by extensive areas of hypoxia, which triggers the
expression of hypoxia-inducible factors (HIFs). HIFs not only mediate angiogenesis
but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to
epidermal growth factor receptor (EGFR) overexpression. Previous studies have shown
that VIP interferes with the invasive nature of gliomas by regulating cell migration.
However, the role of VIP family members in GBM infiltration under low oxygen tension
has not been clarified yet. Therefore, in the present study we have investigated, for
the first time, the molecular mechanisms involved in the anti-invasive effect of
PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with
desferrioxamine (DFX). The results suggest that either PACAP or VIP exert an
anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR
expression, key elements involved in cell migration and angiogenesis. These peptides
act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are
known to have a crucial role in HIFs regulation.
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.
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