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Research ArticleArticle

Pharmacological Inhibition of Histone Deacetylases by Suberoylanilide Hydroxamic Acid Specifically Alters Gene Expression and Reduces Ischemic Injury in the Mouse Brain

Giuseppe Faraco, Tristano Pancani, Laura Formentini, Paolo Mascagni, Gianluca Fossati, Flavio Leoni, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 2006, 70 (6) 1876-1884; DOI: https://doi.org/10.1124/mol.106.027912
Giuseppe Faraco
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Tristano Pancani
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Laura Formentini
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Paolo Mascagni
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Gianluca Fossati
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Flavio Leoni
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Flavio Moroni
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Alberto Chiarugi
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Abstract

Pharmacological manipulation of gene expression is considered a promising avenue to reduce postischemic 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. It is noteworthy that in the ischemic brain tissue subjected to6hof 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 approximately 8-fold after 6 h) and prevented histone deacetylation in the ischemic brain. 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. It is noteworthy that at the same time point, mice injected with SAHA at 25 and 50 mg/kg had smaller infarct volumes compared with vehicle-receiving animals (28.5% and 29.8% reduction, p < 0.05 versus 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 underscores the therapeutic potential of molecules inhibiting HDACs for stroke therapy.

Footnotes

  • This study was supported by grants from the University of Florence, the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (Programma Cofinanziato 2002), and Ente Cassa di Risparmio di Firenze.

  • ABBREVIATIONS: HAT, histone acetyl transferase; HDAC, histone deacetylase; SAHA, suberoylanilide hydroxamic acid; PaO2, arterial oxygen pressure; PaCO2, partial pressure of carbon dioxide; MCAO, middle cerebral artery occlusion; PBS, phosphate-buffered saline; TBST, phosphate-buffered saline containing 0.1% Tween 20; iNOS, inducible nitric-oxide synthase; COX-2, cyclooxygenase-2; 3D, three-dimensional; Hsp70, 70-kDa heat shock protein; ANOVA, analysis of variance; GFAP, glial fibrillary acidic protein.

    • Received June 14, 2006.
    • Accepted August 30, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (6)
Molecular Pharmacology
Vol. 70, Issue 6
1 Dec 2006
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Research ArticleArticle

Pharmacological Inhibition of Histone Deacetylases by Suberoylanilide Hydroxamic Acid Specifically Alters Gene Expression and Reduces Ischemic Injury in the Mouse Brain

Giuseppe Faraco, Tristano Pancani, Laura Formentini, Paolo Mascagni, Gianluca Fossati, Flavio Leoni, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 1, 2006, 70 (6) 1876-1884; DOI: https://doi.org/10.1124/mol.106.027912

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Research ArticleArticle

Pharmacological Inhibition of Histone Deacetylases by Suberoylanilide Hydroxamic Acid Specifically Alters Gene Expression and Reduces Ischemic Injury in the Mouse Brain

Giuseppe Faraco, Tristano Pancani, Laura Formentini, Paolo Mascagni, Gianluca Fossati, Flavio Leoni, Flavio Moroni and Alberto Chiarugi
Molecular Pharmacology December 1, 2006, 70 (6) 1876-1884; DOI: https://doi.org/10.1124/mol.106.027912
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