Neuroprotective role of apelin receptor (APLNR) in GT1-7 neurons

Neurotoxicity is known as the detrimental effect on the structure or function of the nervous system and a consequence of oxidative stress induction in the body due to being exposed to biological or synthetic substances. The most important brain region in regulating homeostasis known as hypothalamus is implicated in the pathogenesis of various neurotoxic disorders including Parkinson's Disease, Alzheimer's Disease, Cerebral Ischemia, Multiple Sclerosis, ALS and epilepsy. For this reason, targeting potential protective signaling pathways in hypothalamic neurons are crucial for promoting neuronal cell survival and treating neurotoxic disorders. In the current study the potential protective action of Aplnr signaling was evaluated in an oxidative stress induced neurotoxicity in vitro model conducted by H202 and hypoxia induced cell stress using GT1-7 hypothalamic neuronal cell line. The effect of Aplnr activation via Apelin and ML-233, inhibition with ML-221 and downregulation via siAplnr against neurotoxicity was assessed by performing cell proliferation analysis, gene expression analysis on apoptotic and inflammatory markers, oxidative stress enzyme activity analysis and immunostaining assays. Overall, the activation of Aplnr signaling with Apelin and ML-233 was shown to protect GnRH neurons against H202 and hypoxia induced cell stress by increasing anti-apoptotic and cell proliferation markers, and the activity of antioxidant enzymes. Transient overexpression of Aplnr showed a protective role in viability of GT1-7 cells under H2O2 and hypoxia induced cell stress. However, inhibition with ML-221 and knocking down of Aplnr caused a significant decrease in aforementioned parameters, and reversed its protective action against neurotoxicity. Furthermore, Aplnr signaling showed a regulatory role in the release of GnRH for the first time in literature. As a result, Aplnr signaling was shown to be essential for GnRH neuronal cell survival against oxidative stress induced neurotoxicity.