Neuroprotective epi-drugs quench the inflammatory response and microglial/macrophage activation in a mouse model of perm
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RESEARCH
Open Access
Neuroprotective epi-drugs quench the inflammatory response and microglial/ macrophage activation in a mouse model of permanent brain ischemia Mariana Mota1†, Vanessa Porrini1†, Edoardo Parrella1* , Marina Benarese1, Arianna Bellucci1, Sina Rhein2, Markus Schwaninger2 and Marina Pizzi1
Abstract Background: Activation of NF-kappaB RelA deacetylated at the lysine residues, except the lysine 310, drives proapoptotic transcription in noxious brain ischemia. We showed that the sinergistic combination of the histone deacetilase inhibitor MS-275 with the sirtuin 1 activator resveratrol, at very low doses, restores normal RelA acetylation and elicit neuroprotection in mice subjected to transient middle cerebral artery occlusion (tMCAO) and primary cortical neurons exposed to oxygen-glucose-deprivation (OGD). The present study aims at corroborating the neuroprotective potential of the epigenetic treatment in a model of permanent brain ischemia and investigate its effect on post-ischemic inflammation and microglia activation. Methods: Male mice subjected to permanent occlusion of the distal MCAO (pMCAO) were treated with vehicle or MS-275 (20 μg/kg) and resveratrol (680 μg/kg) i.p. immediately after the ischemia. Microglia-containing mixed glial cultures were prepared from the brain of 1–3-day-old mice. Primary cortical neurons were prepared from 15-dayold embryonic mice. Results: MS-275 and resveratrol in combination, but not individually, reduced infarct volume and neurological deficits evaluated 48 h after the pMCAO. At 24 h, the treatment inhibited the RelA binding to Nos2 promoter, reduced the elevated expression of Nos2, Il6, Il1b, Mrc1 and Ym1 and the leukocytes infiltration in the ischemic area. The effect was nonpermanent. The treatment did not limit the sustained leukocyte infiltration or Nos2 and Il1b transcription observed at 7 days. Though, it induced alternative activation markers of microglia/macrophages, Arg1, Ym1 and Fcgr2b that could be added to Mrc1, Tgfb1 and Trem2 spontaneously increased at 7 days after ischemia. At 24 hours the drug treatment quenched the microglia/macrophages activation in the ischemic cortical sections, as shown by the recovered ramified morphology and lowered iNOS or CD68 immunoreactivity in Iba1-positive cells. Both microglia and astrocytes in mixed glial cultures, but not pure astrocytes, displayed signs of activation and iNOS-immunoreactivity when treated with a conditioned medium (NCM) from OGD-exposed cortical neurons. The (Continued on next page)
* Correspondence: [email protected] † Mariana Mota and Vanessa Porrini contributed equally to this work. 1 Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in an
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