Investigation of PACAP38 and PAC1 Receptor Expression in Human Retinoblastoma and the Effect of PACAP38 Administration on Human Y-79 Retinoblastoma Cells.

Retinoblastoma represents the most prevalent malignant neoplasm affecting the eyes in childhood. The clear-cut origin of retinoblastoma has not yet been determined; however, based on experiments, it has been suggested that RB1 loss in cone photoreceptors causes retinoblastoma. Pituitary adenylate-cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide which has been shown to be affected in certain tumorous transformations, such as breast, lung, kidney, pancreatic, colon, and endocrine cancers. This study aimed to investigate potential changes in both PACAP38 and PAC1 receptor (PAC1R) expression in human retinoblastoma and the effect of PACAP38 administration on the survival of a human retinoblastoma cell line (Y-79). We analyzed human enucleation specimens removed because of retinoblastoma for PACAP38 and PAC1R immunostaining and the effect of PACAP38 on the survival of the Y-79 cell line. We described for the first time that human retinoblastoma cells from patients showed only perinuclear, dot-like immunopositivity for both PACAP38 and PAC1R, irrespective of laterality, genetic background, or histopathological features. Nanomolar (100 nM and 500 nM) PACAP38 concentrations had no effect on the viability of Y-79 cells, while micromolar (2 µM and 6 µM) PACAP38 significantly decreased tumor cell viability. These findings, along with general observations from animal studies showing that PACAP38 has strong anti-apoptotic, anti-inflammatory, and antioxidant effects on ocular tissues, together suggest that PACAP38 and its analogs are promising candidates in retinoblastoma therapy.

Protective Effects of PACAP in Peripheral Organs.

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.

PACAP and PAC1 receptor expression in pancreatic ductal carcinoma.

Pancreatic carcinoma is one of the most malignant diseases and is associated with a poor survival rate. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide that acts on three different G protein-coupled receptors: the specific PAC1 and the VPAC1/2 that also bind vasoactive intestinal peptide. PACAP is widely distributed in the body and has diverse physiological effects. Among other things, it acts as a trophic factor and influences proliferation and differentiation of several different cells both under normal circumstances and tumourous transformation. Changes of PACAP and its receptors have been shown in various tumour types. However, it is not known whether PACAP and its specific receptor are altered in pancreatic cancer. Perioperative data of patients with pancreas carcinoma was investigated over a five-year period. Histological results showed Grade 2 or Grade 3 adenocarcinoma in most cases. PACAP and PAC1 receptor expression were investigated by immunohistochemistry. Staining intensity of PAC1 receptor was strong in normal tissues both in the exocrine and endocrine parts of the pancreas, the receptor staining was markedly weaker in the adenocarcinoma. PACAP immunostaining was weak in the exocrine part and very strong in the islets and nerve elements in non-tumourous tissues. The PACAP immunostaining almost disappeared in the adenocarcinoma samples. Based on these findings a decrease or lack of the PAC1 receptor/PACAP signalling might have an influence on tumour growth and/or differentiation.

Therapeutic potential of PACAP in alcohol toxicity.

Alcohol addiction is a worldwide concern as its detrimental effects go far beyond the addicted individual and can affect the entire family as well as the community. Considerable effort is being expended in understanding the neurobiological basis of such addiction in hope of developing effective prevention and/or intervention strategies. In addition, organ damage and neurotoxicological effects of alcohol are intensely investigated. Pharmacological approaches, so far, have only provided partial success in prevention or treatment of alcohol use disorder (AUD) including the neurotoxicological consequences of heavy drinking. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino-acid neuropeptide with demonstrated protection against neuronal injury, trauma as well as various endogenous and exogenous toxic agents including alcohol. In this mini-review, following a brief presentation of alcohol addiction and its neurotoxicity, the potential of PACAP as a therapeutic intervention in toxicological consequences of this devastating disorder is discussed.

Intestinal Microbiota Changes in Mice Lacking Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) - Bifidobacteria Make the Difference.

Pituitary adenylate cyclase activating polypetide (PACAP) constitutes a neuropeptide that is widely distributed in the host exerting essential cytoprotective properties, whereas PACAP-/- mice display increased susceptibility to distinct immunopathological conditions. The orchestrated interplay between the gut microbiota and the host is pivotal in immune homeostasis and resistance to disease. Potential pertubations of the intestinal microbiota in PACAP-/- mice, however, have not been addressed so far. For the first time, we performed a comprehensive survey of the intestinal microbiota composition in PACAP-/- and wildtype (WT) mice starting 2 weeks postpartum until 18 months of age applying quantitative culture-independent techniques. Fecal enterobacteria and enterococci were lower in PACAP-/- than WT mice aged 1 month and ≥6 months, respectively. Whereas Mouse Intestinal Bacteroides were slightly higher in PACAP-/- versus WT mice aged 1 and 6 months, this later in life held true for Bacteroides/Prevotella spp. (≥12 months) and lactobacilli (>15 months of age). Strikingly, health-beneficial bifidobacteria were virtually absent in the intestines of PACAP-/- mice, even when still breastfed. In conclusion, PACAP deficiency is accompanied by distinct changes in fecal microbiota composition with virtually absent bifidobacteria as a major hallmark that might be linked to increased susceptibility to disease.