Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia

Wen Hsin Lu, Chih Yen Wang, Po See Chen, Jing Wen Wang, De Maw Chuang, Chung Shi Yang, Shun Fen Tzeng

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 (P2X4R), 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 P2X4R 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 P2X4R 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 P2X4R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues.

Original languageEnglish
Pages (from-to)694-705
Number of pages12
JournalJournal of Neuroscience Research
Volume91
Issue number5
DOIs
Publication statusPublished - 2013 May 1

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Purinergic P2X4 Receptors
Valproic Acid
Microglia
Spinal Cord
Spinal Cord Injuries
Histone Deacetylase Inhibitors
Hindlimb
trichostatin A
Purinergic P1 Receptors
Gliosis
Butyric Acid
p38 Mitogen-Activated Protein Kinases
Locomotion
Astrocytes
Lipopolysaccharides
Down-Regulation
Adenosine Triphosphate
Macrophages
Gene Expression

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

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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 (P2X4R), 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 P2X4R 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 P2X4R 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 P2X4R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues.",
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Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia. / Lu, Wen Hsin; Wang, Chih Yen; Chen, Po See; Wang, Jing Wen; Chuang, De Maw; Yang, Chung Shi; Tzeng, Shun Fen.

In: Journal of Neuroscience Research, Vol. 91, No. 5, 01.05.2013, p. 694-705.

Research output: Contribution to journalArticle

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