Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK-ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats.

Chengmei Sun,Keren Zhou,Qiquan Zhu,Budbazar Enkhjargal,Lingyun Wu,Zhiyi Xie,Cesar Reis,Tongyu Zhang,Jiping Tang,John H Zhang,Xiaodan Jiang

doi:10.3390/cells8090980

Chengmei Sun, Keren Zhou + Show 9 more

Open Access

https://doi.org/10.3390/cells8090980

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Abstract

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.

Highlights

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating subtype of hemorrhagic stroke with high mortality and disability [1,2]
Early administration of recombinant OPN (rOPN) in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that focal adhesion kinase (FAK)–ERK signaling may be involved in OPN-enhanced autophagy in the early brain injury (EBI) phase after
Brain injury (EBI), which occurs within 72 h after SAH is the primary cause of the poor outcomes for the high mortality and delayed neurological deficits in patients who suffer from subarachnoid hemorrhage (SAH) [3,4]

Summary

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating subtype of hemorrhagic stroke with high mortality and disability [1,2]. The rupture of intracranial aneurysms initially lead to emergency illness such as elevated intracranial pressure, decreased cerebral blood flow, and decreased cerebral perfusion pressure. These events consecutively initiate various cascades of pathophysiological processes such as inflammation, oxidative stress, blood–brain barrier dysfunction, and apoptosis [5,6]. Among all these processes, neuronal apoptosis is an important pathologic event in the pathogenesis of SAH-induced EBI [7]

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Discussion

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