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The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice

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Abstract

Spontaneous intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Though ICH is known to induce severe neurological damage, the molecular mechanisms of neurological injury after ICH remain largely unclear. Given the emerging role of epigenetic mechanisms in neurodegeneration, the present study evaluated whether suberoylanilide hydroxamic acid (SAHA: vorinostat), a clinically well-tolerated pan-histone deacetylase inhibitor (HDACi), would attenuate neurological injury and improve functional outcomes in a preclinical model of ICH. Mice were administered with SAHA or vehicle after an induction of ICH and acute neuronal death, glial activation, and neurological outcomes were assessed. SAHA-treated mice exhibited less neurodegeneration with concomitant improvement in neurological outcomes than vehicle-treated mice. Furthermore, SAHA downregulated glial activation and the expression of heme oxygenase-1, a stress-inducible enzyme that plays critical roles in neurological damage after ICH. Altogether, the data strongly suggest the role of epigenetic mechanisms in inducing neurological injury after ICH and raise the possible clinical utility of SAHA for therapeutic intervention after ICH.

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Acknowledgments

This work was supported by grants from the American Heart Association (14SDG18730034 to SSR) and National Institute of Health (R01NS065172, R21NS075774 to KMD).

Conflict of Interest

The authors declare that they have no competing interests.

Compliance with Ethical Standards

All institutional and national guidelines for the care and use of animals were followed.

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Authors and Affiliations

  1. Department of Neurosurgery, Georgia Regents University, 1120 15th Street CA1010, Augusta, GA, 30912, USA

    Sangeetha Sukumari-Ramesh, Cargill H. Alleyne Jr. & Krishnan M. Dhandapani

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  1. Sangeetha Sukumari-Ramesh
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  2. Cargill H. Alleyne Jr.
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  3. Krishnan M. Dhandapani
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Corresponding author

Correspondence to Sangeetha Sukumari-Ramesh.

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Supplementary Figure 1

HO-1 expression is co localized in Iba1 positive microglia. Brain sections from vehicle/SAHA-treated ICH mice were immunolabeled for HO-1 (green), and Iba1 (red), 3 days post-surgery. HO-1 expression was mostly observed in Iba1 positive microglia and SAHA treatment attenuated both HO-1 expression and number of amoeboid microglia after ICH. n = 4–6/group. (GIF 340 kb)

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Sukumari-Ramesh, S., Alleyne, C.H. & Dhandapani, K.M. The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice. Transl. Stroke Res. 7, 141–148 (2016). https://doi.org/10.1007/s12975-015-0421-y

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  • DOI: https://doi.org/10.1007/s12975-015-0421-y

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