Cellular Signaling and Anti-Apoptotic Effects of Prolactin-Releasing Peptide and Its Analog on SH-SY5Y Cells.

Anna Zmeškalová,Blanka Železná,Jaroslav Kuneš,Lenka Maletínská,Andrea Popelová,Aneta Exnerová

doi:10.3390/ijms21176343

Abstract

Prolactin-releasing peptide (PrRP), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). Recently, the neuroprotective effects of lipidized PrRP analogs have been proven. In this study, we focused on the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11-PrRP31 in the human neuroblastoma cell line SH-SY5Y to describe their cellular signaling and possible anti-apoptotic properties. PrRP31 significantly upregulated the phosphoinositide-3 kinase-protein kinase B/Akt (PI3K-PKB/Akt) and extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) signaling pathways that promote metabolic cell survival and growth. In addition, we proved via protein kinase inhibitors that activation of signaling pathways is mediated specifically by PrRP31 and its palmitoylated analog. Furthermore, the potential neuroprotective properties were studied through activation of anti-apoptotic pathways of PrRP31 and palm11-PrRP31 using the SH-SY5Y cell line and rat primary neuronal culture stressed with toxic methylglyoxal (MG). The results indicate increased viability of the cells treated with PrRP and palm11-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders.

Highlights

Neuropeptide with the misleading name prolactin-releasing peptide (PrRP) belongs to the family of RF-amide peptides
PrRP immunoreactive fibers, as well as its receptor GPR10, can be found in the brain in nuclei implicated in food intake and energy balance regulation [1], such as in the nucleus of the solitary tract (NTS) of the brainstem, and in several hypothalamic nuclei, where it acts as an anorexigenic compound [2,3]
We aimed to identify the signaling pathways activated by PrRP with an emphasis on pathways implicated in anti-apoptotic actions using the human neuroblastoma cell line SH-SY5Y, which is widely used for the study of neurodegeneration, as well as rat primary cortical neurons

Summary

Introduction

Neuropeptide with the misleading name prolactin-releasing peptide (PrRP) belongs to the family of RF-amide peptides. PrRP immunoreactive fibers, as well as its receptor GPR10, can be found in the brain in nuclei implicated in food intake and energy balance regulation [1], such as in the nucleus of the solitary tract (NTS) of the brainstem, and in several hypothalamic nuclei, where it acts as an anorexigenic compound [2,3]. None of the isoforms can decrease food intake after acute peripheral administration [5]. Our group designed and synthesized a series of lipidized PrRP31 and PrRP20 analogs that are able to act centrally after peripheral administration, as shown by decreased acute food intake and c-Fos activation, namely, in the paraventricular nucleus of the hypothalamus (PVN) and NTS, in fasted. Palm11-PrRP31 significantly improved glucose tolerance in Zucker diabetic rats or in spontaneously hypertensive obese rats [7,8]

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