Exendin-4 attenuates neuronal death via GLP-1R/PI3K/Akt pathway in early brain injury after subarachnoid hemorrhage in rats

• Published in: Neuropharmacology Vol. 128; pp. 142 - 151
• Main Authors: Xie, Zhiyi, Enkhjargal, Budbazar, Wu, Lingyun, Zhou, Keren, Sun, Chengmei, Hu, Xin, Gospodarev, Vadim, Tang, Jiping, You, Chao, Zhang, John H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2018
• Subjects: Animals; Apoptosis - drug effects; Brain Injuries - drug therapy; Brain Injuries - etiology; Brain Injuries - pathology; Calcium-Binding Proteins - metabolism; Chromones - pharmacology; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Exenatide; Exendin-4; GLP-1R; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; Injections, Intraventricular; Male; Microfilament Proteins - metabolism; Morpholines - pharmacology; Nerve Tissue Proteins - metabolism; Neuronal apoptosis; Neuroprotective Agents - therapeutic use; Oncogene Protein v-akt - metabolism; Peptides - pharmacology; Peptides - therapeutic use; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt signaling; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - complications; Venoms - pharmacology; Venoms - therapeutic use; Neuronal apoptosis; PI3K/Akt signaling; Subarachnoid hemorrhage; Exendin-4; GLP-1R
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.09.040

Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.
•Ex-4 significantly improved neurological function after SAH.•GLP-1R mainly expressed in neurons after SAH.•Ex-4 did not increased risk of hypoglycemia after SAH in SD rats.•Ex-4 improved spatial learning capacity and reference memory after SAH.•The anti-apoptotic effect of Ex-4 was mediated via GLP-1R/PI3K/Akt pathway.