Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK–ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats
Chengmei Sun,
Budbazar Enkhjargal,
Cesar Reis,
Tongyu Zhang,
Qiquan Zhu,
Keren Zhou,
Zhiyi Xie,
Lingyun Wu,
Jiping Tang,
Xiaodan Jiang,
John H. Zhang
Affiliations
Chengmei Sun
The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, China
Budbazar Enkhjargal
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Cesar Reis
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Tongyu Zhang
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Qiquan Zhu
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Keren Zhou
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Zhiyi Xie
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Lingyun Wu
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Jiping Tang
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Xiaodan Jiang
The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, China
John H. Zhang
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, CA 92354, USA
Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague−Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and the potential effect of recombinant OPN (rOPN) administration to improve long-term outcomes after SAH. Rats were randomly divided into five groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), SAH + rOPN (5 μg/rat recombinant OPN), SAH + rOPN + Fib-14 (30 mg/kg of focal adhesion kinase (FAK) inhibitor-14), and SAH + rOPN + DMSO (dimethyl sulfoxide). Short-term and long-term neurobehavior tests were performed, followed by a collection of brain samples for assessment of autophagy markers in neurons, pathway proteins expression, and delayed hippocampal injury. Western blot, double immunofluorescence staining, Nissl staining, and Fluoro-Jade C staining assay were used. Results showed that rOPN administration increased autophagy in neurons and improved neurobehavior in a rat model of SAH. With the administration of FAK inhibitor-14 (Fib-14), neurobehavioral improvement and autophagy enhancement induced by rOPN were abolished, and there were consistent changes in the phosphorylation level of ERK1/2. In addition, early administration of rOPN in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that FAK−ERK signaling may be involved in OPN-enhanced autophagy in the EBI phase after SAH. Early administration of rOPN may be a preventive and therapeutic strategy against delayed brain injury after SAH.
