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Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke.
Int J Mol Sci. 2018 Jan 06; 19(1)IJ

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.

Authors+Show Affiliations

Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. l.faggi@unibs.it.Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy. giuseppe.pignataro@unina.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. edoardo.parrella@unibs.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. v.porrini@unibs.it.Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy. antonio.vinciguerra@unina.it.Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy. lino.cepparulo@gmail.com.Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy. orcuomo@yahoo.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. annamaria.lanzillotta@unibs.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. m.coelhodamota@unibs.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. marina.benarese@unibs.it.IRCCS, S. Camillo Hospital, 30126 Venice, Italy. paolo.tonin@ospedalesancamillo.net.Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy. lucio.annunziato@unina.it. IRCCS, SDN, Via Gianturco, 113, 80142 Naples, Italy. lucio.annunziato@unina.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. pierfranco.spano@unibs.it. IRCCS, S. Camillo Hospital, 30126 Venice, Italy. pierfranco.spano@unibs.it.Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. marina.pizzi@unibs.it. IRCCS, S. Camillo Hospital, 30126 Venice, Italy. marina.pizzi@unibs.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29316653

Citation

Faggi, Lara, et al. "Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke." International Journal of Molecular Sciences, vol. 19, no. 1, 2018.
Faggi L, Pignataro G, Parrella E, et al. Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. Int J Mol Sci. 2018;19(1).
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. (2018). Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. International Journal of Molecular Sciences, 19(1). https://doi.org/10.3390/ijms19010172
Faggi L, et al. Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. Int J Mol Sci. 2018 Jan 6;19(1) PubMed PMID: 29316653.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. AU - Faggi,Lara, AU - Pignataro,Giuseppe, AU - Parrella,Edoardo, AU - Porrini,Vanessa, AU - Vinciguerra,Antonio, AU - Cepparulo,Pasquale, AU - Cuomo,Ornella, AU - Lanzillotta,Annamaria, AU - Mota,Mariana, AU - Benarese,Marina, AU - Tonin,Paolo, AU - Annunziato,Lucio, AU - Spano,PierFranco, AU - Pizzi,Marina, Y1 - 2018/01/06/ PY - 2017/11/10/received PY - 2017/12/15/revised PY - 2018/01/02/accepted PY - 2018/1/11/entrez PY - 2018/1/11/pubmed PY - 2018/7/27/medline KW - RelA KW - middle cerebral artery occlusion (MCAO) KW - oxygen glucose deprivation (OGD) KW - resveratrol KW - valproate JF - International journal of molecular sciences JO - Int J Mol Sci VL - 19 IS - 1 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/29316653/Synergistic_Association_of_Valproate_and_Resveratrol_Reduces_Brain_Injury_in_Ischemic_Stroke_ L2 - https://www.mdpi.com/resolver?pii=ijms19010172 DB - PRIME DP - Unbound Medicine ER -