Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway

Yi Huang  ¹ , Yong Guo  ² , Lei Huang  ³ , Yuanjian Fang  ⁴ , Dujuan Li  ⁵ , Rui Liu  ⁵ , Qin Lu  ⁵ , Reng Ren  ⁴ , Lihui Tang  ⁵ , Lifei Lian  ⁵ , Yongmei Hu  ⁵ , Jiping Tang  ⁵ , Gao Chen  ⁶ , John H Zhang  ⁷ Affiliations

• PMID: 33989759
• PMCID: PMC8388553 (available on 2022-08-01)
• DOI: 10.1016/j.freeradbiomed.2021.05.012

Abstract

Oxidative stress-induced neuron apoptosis plays a crucial role in the early brain injury (EBI) after subarachnoid hemorrhage (SAH). Kisspeptin has been reported as antioxidant to reduce oxidative stress-induced neuronal cell death through G protein-coupled receptor 54 (GPR54). The goal of this study was to determine the neuroprotection of the Kisspeptin/GRP54 signaling pathway against EBI after SAH. Two hundred and ninety-two Sprague Dawley male rats were used and SAH was induced by the endovascular perforation. Exogenous Kisspeptin 54 (KP54) was delivered intranasally. Small interfering ribonucleic acid (siRNA) for endogenous KISS1, a selective GPR54 antagonist kisspeptin 234, or β-arrestin 2 siRNA for ARRB2 (a functional adaptor of GPR54) were administered intracerebroventricularly. Post-SAH evaluations included neurobehavioral tests, SAH grade, Western blot, immunofluorescence, Fluoro-Jade C, TUNEL, and Nissl staining. The results showed that endogenous KISS1 knockdown aggravated but exogenous KP54 (1.0 nmol/kg) treatment attenuated neurological deficits, brain oxidative stress, and neuronal apoptosis at 24 h after SAH. The benefits of KP54 persisted to 28 days after SAH, which significantly improved cognitive function in SAH rats. The GPR54 blockade or the ARRB2 knockout offset the neuroprotective effects of KP54 in SAH rats. In conclusion, our results suggested that administration of KP54 attenuated oxidative stress, neuronal apoptosis and neurobehavioral impairments through GPR54/ARRB2/AKT/GSK3β signaling pathway after SAH in rat. Thus, KP54 may provide an effective treatment strategy for SAH patients.

Keywords: GPR 54; Kisspeptin 54; Neuronal apoptosis; Oxidative stress; Rat; Subarachnoid hemorrhage.