Received for publication June 14, 2006.
Revised August 4, 2006.
Accepted for publication August 30, 2006.

Pharmacological inhibition of Histone Deacetylases (HDACs) by Suberoylanilide Hydroxamic Acid (SAHA) Specifically Alters Gene Expression and Reduces Ischemic Injury in the Mouse Brain

Abstract

Pharmacological manipulation of gene expression is considered a promising avenue to reduce post-ischemic brain damage. Histone deacetylases (HDACs) play a central role in epigenetic regulation of transcription, and inhibitors of HDACs are emerging as neuroprotective agents. In this study, we investigated the effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on histone acetylation in control and ischemic mouse brain. We report that brain histone H3 acetylation was constitutively present at specific lysine residues in neurons and astrocytes. Of note, in the ischemic brain tissue subjected to 6 h middle cerebral artery occlusion histone H3 acetylation levels drastically decreased, without evidence for a concomitant change of histone acetyl-transferase or deacetylase activities. Treatment with SAHA (50 mg/kg i.p.) increased histone H3 acetylation within the normal brain (of about 8-fold after 6 hrs), and prevented histone deacetylation in the ischemic one. These effects were accompanied by increased expression of the neuroprotective proteins Hsp70 and Bcl-2 in both control and ischemic brain tissue 24 h after the insult. Importantly, at the same time point mice injected with SAHA at 25 and 50 mg/kg had smaller infarct volumes compared to vehicle-receiving animals (28,5 % and 29,8 % reduction, p<0,05 vs vehicle, Student's t-test). At higher doses, SAHA was less efficient in increasing Bcl-2 and HSP70 expression and did not afford significant ischemic neuroprotection (13,9 % infarct reduction). Data demonstrate that pharmacological inhibition of HDACs promotes expression of neuroprotective proteins within the ischemic brain, and underscore the therapeutic potential of molecules inhibiting HDACs for stroke therapy.

Key words: Transcriptional coactivators, Mechanisms of cell killing/apoptosis, Transcription targets, Excitotoxicity, neurodegeneration, Ischemia/Reperfusion

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