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Int. J. Mol. Sci. 2018, 19(1), 172; https://doi.org/10.3390/ijms19010172

Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke

1
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
2
Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy
3
IRCCS, S. Camillo Hospital, 30126 Venice, Italy
4
IRCCS, SDN, Via Gianturco, 113, 80142 Naples, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 10 November 2017 / Revised: 15 December 2017 / Accepted: 2 January 2018 / Published: 6 January 2018
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Abstract

Histone deacetylation, together with altered acetylation of NF-κB/RelA, encompassing the K310 residue acetylation, occur during brain ischemia. By restoring the normal acetylation condition, we previously reported that sub-threshold doses of resveratrol and entinostat (MS-275), respectively, an activator of the AMP-activated kinase (AMPK)-sirtuin 1 pathway and an inhibitor of class I histone deacetylases (HDACs), synergistically elicited neuroprotection in a mouse model of ischemic stroke. To improve the translational power of this approach, we investigated the efficacy of MS-275 replacement with valproate, the antiepileptic drug also reported to be a class I HDAC blocker. In cortical neurons previously exposed to oxygen glucose deprivation (OGD), valproate elicited neuroprotection at 100 nmol/mL concentration when used alone and at 1 nmol/mL concentration when associated with resveratrol (3 nmol/mL). Resveratrol and valproate restored the acetylation of histone H3 (K9/18), and they reduced the RelA(K310) acetylation and the Bim level in neurons exposed to OGD. Chromatin immunoprecipitation analysis showed that the synergistic drug association impaired the RelA binding to the Bim promoter, as well as the promoter-specific H3 (K9/18) acetylation. In mice subjected to 60 min of middle cerebral artery occlusion (MCAO), the association of resveratrol 680 µg/kg and valproate 200 µg/kg significantly reduced the infarct volume as well as the neurological deficits. The present study suggests that valproate and resveratrol may represent a promising ready-to-use strategy to treat post-ischemic brain damage. View Full-Text
Keywords: valproate; resveratrol; oxygen glucose deprivation (OGD); middle cerebral artery occlusion (MCAO); RelA valproate; resveratrol; oxygen glucose deprivation (OGD); middle cerebral artery occlusion (MCAO); RelA
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Faggi, L.; Pignataro, G.; Parrella, E.; Porrini, V.; Vinciguerra, A.; Cepparulo, P.; Cuomo, O.; Lanzillotta, A.; Mota, M.; Benarese, M.; Tonin, P.; Annunziato, L.; Spano, P.; Pizzi, M. Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. Int. J. Mol. Sci. 2018, 19, 172.

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