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In this study, we examined the effects of HDAC3 inhibition on cerebral edema and blood\u2013brain barrier (BBB) leakage and explored its underlying mechanisms. Adult male Wistar rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and randomly treated i.p. with either vehicle or a selective HDAC3 inhibitor (RGFP966) at 2 and 24\u00a0h after stroke. Modified neurological severity scores (mNSS) were calculated at 2\u00a0h, 1\u00a0day, and 3\u00a0days. H&amp;E, Evans blue dye (EBD) assay, and fluorescein isothiocyanate (FITC)-dextran were employed to assess cerebral edema and BBB leakage. Western blot for matrix metalloproteinase-9 (MMP9), MMP-9 zymography, and immunostaining for HDAC3, GFAP, Iba-1, albumin, aquaporin-4, claudin-5, ZO-1, and NF-kB were performed. Early RGFP966 administration decreased cerebral edema (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002) and BBB leakage, as measured by EBD assay, FITC-dextran, and albumin extravasation (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). RGFP966 significantly increased tight junction proteins (claudin-5 and ZO-1) in the peri-infarct area. RGFP966 also significantly decreased HDAC3 in GFAP\u2009+\u2009astrocytes, which correlated with better mNSS (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.67,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.03) and decreased cerebral edema (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.64,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04). RGFP966 decreased aquaporin-4 in GFAP\u2009+\u2009astrocytes (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002), as well as, the inflammatory markers Iba-1, NF-kB, and MMP9 in the ischemic brain (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Early HDAC3 inhibition decreases cerebral edema and BBB leakage. BBB protection by RGFP966 is mediated in part by the upregulation of tight junction proteins, downregulation of aquaporin-4 and HDAC3 in astrocytes, and decreased neuroinflammation.\n                  <\/jats:p>","DOI":"10.1007\/s12035-022-03083-z","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T15:02:46Z","timestamp":1666105366000},"page":"235-246","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Histone Deacetylase 3 Inhibition Decreases Cerebral Edema and Protects the Blood\u2013Brain Barrier After Stroke"],"prefix":"10.1007","volume":"60","author":[{"given":"Hui","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Ashiqueali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin I","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aashlesha","family":"Walchale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Clendaniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Matheson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng H.","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdy","family":"Selim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-3774","authenticated-orcid":false,"given":"Amjad","family":"Shehadah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"issue":"9","key":"3083_CR1","doi-asserted-by":"publisher","first-page":"e139","DOI":"10.1161\/CIR.0000000000000757","volume":"141","author":"SS Virani","year":"2020","unstructured":"Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN et al (2020) Heart disease and stroke statistics-2020 update: a report from the American Heart Association. 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