Neuroprotective Effects of Valproic Acid on Blood-Brain Barrier Disruption and Apoptosis-Related Early Brain Injury in Rats Subjected to Subarachnoid Hemorrhage Are Modulated by Heat Shock Protein 70/Matrix Metalloproteinases and Heat Shock Protein 70/AKT Pathways
| Autor: | Guangyu Ying, Gao Chen, Brandon Dixon, Feng Yan, Chao-hui Jing, Lin Wang, Jianru Li, Jingyin Chen, Cheng Wu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Perforation (oil well) Apoptosis Pharmacology Occludin Neuroprotection Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Subarachnoid Hemorrhage Traumatic 0302 clinical medicine In Situ Nick-End Labeling Animals Medicine HSP70 Heat-Shock Proteins cardiovascular diseases Protein kinase B Evans Blue business.industry Valproic Acid Matrix Metalloproteinases Extravasation Rats nervous system diseases Hsp70 Disease Models Animal Neuroprotective Agents 030104 developmental biology Biochemistry chemistry Blood-Brain Barrier lipids (amino acids peptides and proteins) Surgery Neurology (clinical) business 030217 neurology & neurosurgery |
| Zdroj: | Neurosurgery. 79:286-295 |
| ISSN: | 0148-396X |
| Popis: | Background Blood-brain barrier (BBB) disruption and neural apoptosis are thought to promote early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that valproic acid (VPA) decreased brain injury in a prechiasmatic injection model of SAH in mice. It should be noted that the beneficial effects of VPA and the underlying mechanisms have not been fully elucidated. Objective To characterize the effects of VPA on BBB disruption and neural apoptosis and to determine mechanisms involved in EBI after SAH. Methods An endovascular perforation model was used to induce SAH in rats. VPA (300 mg/kg) was promptly administered after SAH induction, and the same dose was given 12 hours later. Quercetin (100 mg/kg), an inhibitor of heat shock protein 70 (HSP70), was injected into the peritoneum 2 hours before SAH induction. Mortality, SAH grades, neurological function, Evans Blue extravasation, brain edema, transmission electron microscopy, Western blot, double fluorescence labeling, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining also were used. Results VPA treatment decreased BBB disruption and brain edema, attenuated neural apoptosis, and improved neurobehavioral functions in EBI after SAH. Double fluorescence labeling indicated that matrix metallopeptidase 9 (MMP-9) was located predominately in neurons and endothelial cells. VPA upregulated the expression of HSP70, effectively decreased the expression and activity of MMP-9, and reduced claudin-5 and occludin degradation. Meanwhile, VPA also upregulated the expression of phosphorylated Akt and bcl-2. Both the anti-BBB disruption and antiapoptotic effects of VPA were abolished by quercetin. Conclusion VPA prevented BBB disruption and alleviated neural apoptosis after SAH. The action of VPA appeared to be mediated though the HSP70/MMPs and HSP70/Akt pathways. Abbreviations BBB, blood-brain barrierEBI, early brain injuryHSP, heat shock proteinMMP, matrix metalloproteinasePBS, phosphate-buffered salineSAH, subarachnoid hemorrhageTUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelingVPA, valproic acid. |
| Databáze: | OpenAIRE |
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