Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition.
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is known to protect against cerebral ischemia. The effects of VPA on blood-brain barrier (BBB) disruption were investigated in rats subjected to transient middle cerebral artery occlusion (MCAO). Postischemic VPA treatment remarkably attenuated MCAO-induced BBB disruption and brain edema. Meanwhile, VPA significantly reduced MCAO-induced elevation of matrix metalloproteinase-9 (MMP-9), degradation of tight junction proteins, and nuclear translocation of nuclear factor-κB (NF-κB). Sodium butyrate, another HDAC inhibitor, mimicked these effects of VPA. Our findings suggest that BBB protection by VPA involves HDAC inhibition-mediated suppression of NF-κB activation, MMP-9 induction, and tight junction degradation.
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
Zhifei
Z
Wang
Yan
Y
Leng
Li-Kai
LK
Tsai
Peter
P
Leeds
De-Maw
DM
Chuang
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002087:Butyrates / Q000494:pharmacology; D004396:Coloring Agents; D005070:Evans Blue; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
D002087:Butyrates; D004396:Coloring Agents; D056572:Histone Deacetylase Inhibitors; D007074:Immunoglobulin G; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D005070:Evans Blue; D014635:Valproic Acid; D006655:Histone Deacetylases