TY - JOUR
T1 - Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway
AU - Huang, Yi
AU - Guo, Yong
AU - Huang, Lei
AU - Fang, Yuanjian
AU - Li, Dujuan
AU - Liu, Rui
AU - Lu, Qin
AU - Ren, Reng
AU - Tang, Lihui
AU - Lian, Lifei
AU - Hu, Yongmei
AU - Tang, Jiping
AU - Chen, Gao
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - GPR 54
KW - Kisspeptin 54
KW - Neuronal apoptosis
KW - Oxidative stress
KW - Rat
KW - Subarachnoid hemorrhage
KW - Oxidative Stress
KW - Signal Transduction
KW - Humans
KW - Rats
KW - Male
KW - beta-Arrestin 2/pharmacology
KW - Neuroprotective Agents/pharmacology
KW - Proto-Oncogene Proteins c-akt/genetics
KW - Rats, Sprague-Dawley
KW - Animals
KW - Brain Injuries
KW - Neurons/metabolism
KW - Glycogen Synthase Kinase 3 beta/genetics
KW - Kisspeptins/genetics
KW - Apoptosis
KW - Receptors, Kisspeptin-1/genetics
KW - Subarachnoid Hemorrhage/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85106286270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106286270&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/83d159d8-39e8-341f-a520-c909f2532517/
U2 - 10.1016/j.freeradbiomed.2021.05.012
DO - 10.1016/j.freeradbiomed.2021.05.012
M3 - Article
C2 - 33989759
SN - 0891-5849
VL - 171
SP - 99
EP - 111
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -