title: 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.
abstract: 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.
  
  
  
  To characterize the effects of VPA on BBB disruption and neural apoptosis and to determine mechanisms involved in EBI after SAH.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: ‡Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; §Department of Neurosurgery, XinHua Hospital, Affiliated With Shanghai Jiao Tong University School of Medicine, Shanghai, China; ¶Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated With Zhejiang University School of Medicine, Hangzhou, China; ‖Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Ying
authors.forename: Chao-Hui
authors.initials: CH
authors.lastname: Jing
authors.forename: Jian-Ru
authors.initials: JR
authors.lastname: Li
authors.forename: Cheng
authors.initials: C
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Jing-Yin
authors.initials: JY
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Dixon
authors.forename: Gao
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020206:Subarachnoid Hemorrhage, Traumatic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D014635:Valproic Acid; D020782:Matrix Metalloproteinases