The activity of antiepileptic drugs as histone deacetylase inhibitors

Sara Eyal, Boris Yagen, Eyal Sobol, Yoram Altschuler, Miriam Shmuel, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

Purpose: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. Methods: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. Results: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 ± 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinone-n-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 ± 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. Conclusions: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.

Original languageAmerican English
Pages (from-to)737-744
Number of pages8
JournalEpilepsia
Volume45
Issue number7
DOIs
StatePublished - Jul 2004

Keywords

  • Antiepileptic drugs
  • Histone deacetylase
  • Levetiracetam
  • Topiramate
  • Valproic acid

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