title: Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia.
abstract: Peripheral injection with a high dose of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, into animals with mild or moderate spinal cord injury (SCI) for 1 week can reduce spinal cord tissue loss and promote hindlimb locomotor recovery. A purinergic adenosine triphosphate (ATP) receptor subtype, P2X4 receptor (P2X4 R), has been considered as a potential target to diminish SCI-associated inflammatory responses. In this study, using a minipump-based infusion system, we found that intraspinal infusion with VPA for 3 days into injured spinal cord significantly improved hindlimb locomotion of rats with severe SCI induced by a 10-g NYU impactor dropping from the height of 50 mm onto the spinal T9/10 segment. The neuronal fibers in the injured spinal cord tissues were significantly preserved in VPA-treated rats compared with those observed in vehicle-treated animals. Moreover, the accumulation of microglia/macrophages and astrocytes in the injured spinal cord was attenuated in the animal group receiving VPA infusion. VPA also significantly reduced P2X4 R expression post-SCI. Furthermore, in vitro study indicated that VPA, but not the other HDAC inhibitors, sodium butyrate and trichostatin A (TSA), caused downregulation of P2X4 R in microglia activated with lipopolysaccharide (LPS). Moreover, p38 mitogen-activated protein kinase (MAPK)-triggered signaling was involved in the effect of VPA on the inhibition of P2X4 R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4 R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues. © 2013 Wiley Periodicals, Inc.
authors: Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan.
authors: Wen-Hsin
authors: WH
authors: Lu
authors: Chih-Yen
authors: CY
authors: Wang
authors: Po-See
authors: PS
authors: Chen
authors: Jing-Wen
authors: JW
authors: Wang
authors: De-Maw
authors: DM
authors: Chuang
authors: Chung-Shi
authors: CS
authors: Yang
authors: Shun-Fen
authors: SF
authors: Tzeng
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006614:Hindlimb / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D017628:Microglia / Q000187:drug effects*; D009412:Nerve Fibers / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D058848:Receptors, Purinergic P2X4; C051774:neurofilament protein H; D014635:Valproic Acid; D002374:Catalase; D013482:Superoxide Dismutase
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