Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

H. Kanai, Akira Sawa, R. W. Chen, P. Leeds, D. M. Chuang

Research output: Contribution to journalArticle

Abstract

Valproic acid (VPA), used to treat bipolar mood disorder and seizures, also inhibits histone deacetylase (HDAC). Here, we found that VPA and other HDAC inhibitors, butyrate and trichostatin A, robustly protected mature cerebellar granule cell cultures from excitotoxicity induced by SYM 2081 ((2S, 4R)-4-methylglutamate), an inhibitor of excitatory amino-acid transporters and an agonist of low-affinity kainate receptors. These neuroprotective effects required protracted treatment and were correlated with enhanced acetylated histone levels, indicating HDAC inhibition. SYM-induced excitotoxicity was blocked by MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine hydrogen maleate), supporting that the toxicity was largely N-methyl-D-aspartate receptor dependent. SYM excitotoxicity had apoptotic characteristics and was prevented by a caspase inhibitor. SYM-induced apoptosis was associated with a rapid and robust nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene previously shown to be proapoptotic. VPA pretreatment suppressed SYM 2081-induced GAPDH nuclear accumulation, concurrent with its neuroprotective effects. Chromatin immunoprecipitation (ChIP) revealed that GAPDH is copresent with acetylated histone H3, including Lys9-acetylated histone, and that VPA treatment caused a time-dependent decrease in the levels of nuclear GAPDH with a concomitant increase in acetylated histones in the ChIP complex. Our results strongly suggest that VPA protects neurons from excitotoxicity through inhibition of HDAC activity and that this protective effect may involve suppression of excitotoxicity-induced accumulation of GAPDH protein in the nucleus).

Original languageEnglish (US)
Pages (from-to)336-344
Number of pages9
JournalPharmacogenomics Journal
Volume4
Issue number5
DOIs
StatePublished - 2004

Fingerprint

Glyceraldehyde-3-Phosphate Dehydrogenases
Histone Deacetylases
Valproic Acid
Histones
Neurons
Chromatin Immunoprecipitation
Neuroprotective Agents
trichostatin A
Excitatory Amino Acid Agonists
Amino Acid Transport Systems
Kainic Acid Receptors
Histone Deacetylase Inhibitors
Caspase Inhibitors
Imines
Dizocilpine Maleate
Butyrates
Essential Genes
N-Methyl-D-Aspartate Receptors
Mood Disorders
Bipolar Disorder

Keywords

  • Cerrebellar granule cells
  • Excitotoxicity
  • GAPDH
  • Histone deacetylase
  • Neuroprotection
  • Valproate

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Genetics

Cite this

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. / Kanai, H.; Sawa, Akira; Chen, R. W.; Leeds, P.; Chuang, D. M.

In: Pharmacogenomics Journal, Vol. 4, No. 5, 2004, p. 336-344.

Research output: Contribution to journalArticle

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