Valproic Acid Attenuates Microgliosis in Injured Spinal Cord and Purinergic P2X4 Receptor Expression in Activated Microglia

J Neurosci Res. 2013 May;91(5):694-705. doi: 10.1002/jnr.23200. Epub 2013 Feb 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalase / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gene Expression Regulation / drug effects*
  • Glial Fibrillary Acidic Protein / metabolism
  • Hindlimb / physiopathology
  • Locomotion / drug effects
  • Macrophages / drug effects
  • Macrophages / pathology
  • Microglia / drug effects*
  • Nerve Fibers / metabolism
  • Neurofilament Proteins / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X4 / genetics
  • Receptors, Purinergic P2X4 / metabolism*
  • Spinal Cord Injuries / drug therapy
  • Spinal Cord Injuries / pathology*
  • Superoxide Dismutase / metabolism
  • Valproic Acid / pharmacology*
  • Valproic Acid / therapeutic use

Substances

  • Enzyme Inhibitors
  • Glial Fibrillary Acidic Protein
  • Neurofilament Proteins
  • RNA, Messenger
  • Receptors, Purinergic P2X4
  • neurofilament protein H
  • Valproic Acid
  • Catalase
  • Superoxide Dismutase