ABSTRACT
Title
Targeting epigenetic regulation of NF-KappaB and histones in the therapy of post-ischemic brain injury
Authors
C. Branca (1), A. Lanzillotta (1), I. Sarnico (1), M. Benarese (1), G. Pignataro (2), O. Cuomo (2), L. Annunziato (2), G. Faraco (3), F.Blasi (3), A. Chiarugi (3), PF. Spano (1), M. Pizzi (1).
(1) Department of Biomedical Sciences & Biotechnologies, School of Medicine, University of Brescia, 25123 Brescia, Italy; (2) Department of Neuroscience, School of Medicine, Federico II University of Naples, Italy; (3) Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
(1) Department of Biomedical Sciences & Biotechnologies, School of Medicine, University of Brescia, 25123 Brescia, Italy; (2) Department of Neuroscience, School of Medicine, Federico II University of Naples, Italy; (3) Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Abstract
The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury. We tested whether epigenetic mechanisms affecting the acetylation state of RelA and histones might be involved in neurotoxic events secondary to brain ischemia and may be promising druggable targets.
RelA and histones acetylation is modulated by a family of histone acetyl transferase (HAT) and histone deacetylase (HDAC). HDAC belonging to class I and class II, inhibited by newly identified molecules including MS-275, are mainly involved. A Class III HDAC, sirtuin 1 (SIRT1), activated by resveratrol, also selectively deacetylates RelA at Lys310 residue.
Both in animal and cellular models of lethal ischemia, the activation of p50/RelA is associated with increased Lys310 versus total RelA Lysine acetylation. Furthermore, in neurons exposed to oxygen glucose deprivation (OGD) H3 acetylation decreased suggesting a different gene expression. We found that treatment with resveratrol, by restoring the normal RelA acetylation, produced neuroprotection, likewise treatment with MS-275 which, conversely, restored the H3 acetylation. The combined admnistration of subthreshold doses of MS-275 and resveratrol elicited a synergistic neuroprotection in cortical neurons as well as in mice subjected to middle cerebral artery occlusion (MCAO). The drug combination reduced infarct volume and neurological deficits even when administrated 5 hours after the transient ischemia.
The neuroprotective effect of the drug combination correlated with significant decrease in acetylation at Lys310 together with recovering general RelA.Also, neurons coexposed to the drugs totally recovered the optimal H3 histone acetylation.
The results of our study reveal new molecular targets to selectively inhibit the pathological activation of NF-kB and limit both inflammation and neuronal loss associated with cerebral ischemia.
RelA and histones acetylation is modulated by a family of histone acetyl transferase (HAT) and histone deacetylase (HDAC). HDAC belonging to class I and class II, inhibited by newly identified molecules including MS-275, are mainly involved. A Class III HDAC, sirtuin 1 (SIRT1), activated by resveratrol, also selectively deacetylates RelA at Lys310 residue.
Both in animal and cellular models of lethal ischemia, the activation of p50/RelA is associated with increased Lys310 versus total RelA Lysine acetylation. Furthermore, in neurons exposed to oxygen glucose deprivation (OGD) H3 acetylation decreased suggesting a different gene expression. We found that treatment with resveratrol, by restoring the normal RelA acetylation, produced neuroprotection, likewise treatment with MS-275 which, conversely, restored the H3 acetylation. The combined admnistration of subthreshold doses of MS-275 and resveratrol elicited a synergistic neuroprotection in cortical neurons as well as in mice subjected to middle cerebral artery occlusion (MCAO). The drug combination reduced infarct volume and neurological deficits even when administrated 5 hours after the transient ischemia.
The neuroprotective effect of the drug combination correlated with significant decrease in acetylation at Lys310 together with recovering general RelA.Also, neurons coexposed to the drugs totally recovered the optimal H3 histone acetylation.
The results of our study reveal new molecular targets to selectively inhibit the pathological activation of NF-kB and limit both inflammation and neuronal loss associated with cerebral ischemia.