Institute of Organic Chemistry and Biochemistry, AS CR, Prague 16000, Czech Republic.
First Faculty of Medicine, Charles University, Prague 12108, Czech Republic.
Int J Mol Sci. 2020 Sep 1;21(17):6343. doi: 10.3390/ijms21176343.
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 palm-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 palm-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 palm-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders.
促泌乳素释放肽（PrRP）是 GPR10 受体的天然配体，是一种具有厌食和抗糖尿病特性的神经肽。由于其在调节食物摄入中的作用，PrRP 是肥胖症治疗和相关 2 型糖尿病（T2DM）的潜在药物。最近，已经证明了脂质化 PrRP 类似物的神经保护作用。在这项研究中，我们专注于天然 PrRP31 及其棕榈酸化类似物 palm-PrRP31 在人神经母细胞瘤细胞系 SH-SY5Y 中的作用机制，以描述其细胞信号转导和可能的抗凋亡特性。PrRP31 显著上调了磷酸肌醇-3 激酶-蛋白激酶 B/Akt（PI3K-PKB/Akt）和细胞外信号调节激酶/cAMP 反应元件结合蛋白（ERK-CREB）信号通路，促进代谢细胞存活和生长。此外，我们通过蛋白激酶抑制剂证明，信号通路的激活是由 PrRP31 及其棕榈酸化类似物特异性介导的。此外，通过使用 SH-SY5Y 细胞系和用毒性甲基乙二醛（MG）处理的大鼠原代神经元培养物激活 PrRP31 和 palm-PrRP31 的抗凋亡途径，研究了其潜在的神经保护特性。结果表明，用 PrRP 和 palm-PrRP31 处理的细胞活力增加，MG 诱导的细胞凋亡程度降低，表明它们在治疗神经紊乱方面具有潜在用途。
