Role of endocrine PACAP in age-related diseases

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a conserved neuropeptide, which confers diverse anti-aging endocrine and paracrine/autocrine effects, including anti-apoptotic, anti-inflammatory and antioxidant action. The results of the in vivo and in vitro experiments show that increasing emphasis is being placed on the diagnostic/prognostic biomarker potential of this neuropeptide in a wide array of age-related diseases. After the initial findings regarding the presence and alteration of PACAP in different body fluids in physiological processes, an increasing number of studies have focused on the changes of its levels in various pathological conditions associated with advanced aging. Until 2016 – when the results of previous human studies were reviewed – a vast majority of the studies had dealt with age-related neurological diseases, like cerebrovascular and neurodegenerative diseases, multiple sclerosis, as well as some other common diseases in elderly such as migraine, traumatic brain injury and post-traumatic stress disorder, chronic hepatitis and nephrotic syndrome. The aim of this review is to summarize the old and the new results and highlight those ‘classical’ and emerging clinical fields in which PACAP may become subject to further investigation as a diagnostic and/or prognostic biomarker in age-related diseases.

Diagnostic and Prognostic Value of PACAP in Multiple Myeloma

“…We hypothesize that the lower PACAP levels result in reduced tumor control as the anti-inflammatory, antioxidant, and immunomodulatory properties of PACAP may play a protective role against tumor proliferation. Aging processes and many harmful environmental variables may presumably cause a pathological reduction in PACAP with age [ 62 , 63 ]. However, the evolution of manifest MM from asymptomatic forms (MGUS, SMM) is an extremely slow process, and prolonged progression leads to clonal heterogeneity of tumor cells, which also significantly compromises the efficacy of therapy and limits clinical options [ 4 ].…”

“…However, we do not yet know what exactly causes the decline in PACAP levels. Presumably, aging processes and various deleterious environmental factors may lead to a pathological decline in PACAP with age [ 62 , 63 ]. It is also possible that the decreased PACAP level in this disease is directly due to the altered tumor cell microenvironment [ 24 , 29 ].…”

Anorexigenic neuropeptides as anti-obesity and neuroprotective agents

“…This finding highlights the possible neuroprotective effects of PACAP in the treatment of dementia. Postmortem analysis of brains from patients with AD revealed a negative correlation between the level of Aβ plaques and PACAP, and between the level of PACAP and tau pathology (according to Braak stages of AD severity) [ 157 ]. As summarized in Table 2 , 3-month-long intranasal application of PACAP to APP(V717I) mice harboring the London mutation improved short-term memory in the novel object recognition test, decreased the level of soluble Aβ, and increased the levels of neurotrophin BDNF [ 158 ].…”

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

“…Interestingly, a specific staining pattern was observed in the ganglion cell layer, where some ganglion cells showed very strong, and others showed negative, immunosignals [30]. PACAP takes part in a wide range of physiological [31][32][33] and pathological processes [34,35]. In vitro studies with human corneal endothelial cells and pigment epithelial cells proved that PACAP stimulates adenylate cyclase and various intracellular signaling pathways to protect the cells against various noxas, including hyperglycemia, oxidative stress, and growth factor deprivation [36][37][38][39][40][41].…”

“…These effects depend on numerous factors, like the origin and type of the tumor, the stage of differentiation, and the tumoral environment [52,54]. As PACAP is shown to be involved in certain tumorous transformations [55] and changes in PACAP and PAC1R can be detected under pathological conditions [34,35], this study aimed to investigate potential alterations in the expression of PACAP38 and PAC1R within tumor tissue samples obtained from enucleation specimens of retinoblastoma patients and the effect of PACAP38 treatment on the survival of human Y-79 retinoblastoma cells.…”