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Exp Neurol. 2019 Oct;320:113008. doi: 10.1016/j.expneurol.2019.113008. Epub 2019 Jul 8.

Activation of GPR30 with G1 attenuates neuronal apoptosis via src/EGFR/stat3 signaling pathway after subarachnoid hemorrhage in male rats.

Author information

1
Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570000, China; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA.
2
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
3
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92354, USA.
4
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, Mie University, Tsu, Mie 514-8507, Japan.
5
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, Taicang People's Hospital, Taicang 215400, Jiangsu, China.
6
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA.
7
Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570000, China. Electronic address: xiaying008@163.com.
8
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92354, USA; Department of Anesthesiology, Loma Linda University, Loma Linda, CA 92354, USA. Electronic address: johnzhang3910@yahoo.com.

Abstract

BACKGROUND:

Neuron apoptosis plays a vital role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies showed that the activation of G protein-coupled receptor 30 (GPR30) with GPR30 agonist G1 was anti-apoptotic after experimental trauma brain injury and global cerebral ischemia in male rats or mice. However, the role of GPR30 activation with G1 has not been clarified in SAH. The aim of this study was to investigate the anti-apoptotic effect of GPR30 activation and the underlying mechanism of src/EGFR/stat3 signaling pathway in a male rat model of SAH.

METHODS:

A total of 215 male rats and 18 female rats were used. SAH was induced by intravascular perforation. G1 was administrated intravenously 1 h after SAH. For mechanism study, the GPR30 antagonist G15 or epidermal growth factor receptor (EGFR) antagonist AG1478 was administrated intravenously 1 h before SAH, small interfering ribonucleic acid (siRNA) for GPR30 and EGFR were administered intracerebroventricularly 48 h before SAH. Post-SAH assessments included SAH Grade, neurological deficits, western blot, terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling (TUNEL) staining, Fluoro-Jade C (FJC) staining, Nissl staining and immunofluorescence.

RESULTS:

The expression of endogenous GPR30 in male rats was increased at 3 h and peaked at 24 h after SAH, which mainly co-localized with neurons, but there was no significant increase in intact female rats at 24 h after SAH. The G1 post-treatment significantly reduced the short-term and long-term neurological deficit as well as neuronal apoptosis in male rats, but it did not significantly improve the short-term outcome of intact female rats. Mechanistic studies indicated that G15 or GPR30 siRNA and AG1478 or EGFR siRNA reversed the anti-neuronal apoptosis effects of G1 and its effects on protein expressions of src/EGFR/stat3 signaling pathway.

CONCLUSION:

G1 reduced EBI through attenuating neuronal apoptosis after SAH in male rats, partly via activating src/EGFR/stat3/signaling pathway. G1 may provide a promising therapeutic strategy for SAH patients.

KEYWORDS:

Apoptosis; Bcl-2; Early brain injury; Estrogen receptor; G1; GPER1; GPR30; Rat; Subarachnoid hemorrhage

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