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Translational Stroke Research
Published in: Translational Stroke Research 5/2020

01-10-2020 | Stroke | Original Article

Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke

Authors: Rudy Matheson, Kohei Chida, Hui Lu, Victoria Clendaniel, Marc Fisher, Ajith Thomas, Eng H. Lo, Magdy Selim, Amjad Shehadah

Published in: Translational Stroke Research | Issue 5/2020

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Abstract

Histone deacetylase 3 (HDAC3) has been implicated as neurotoxic in several neurodegenerative conditions. However, the role of HDAC3 in ischemic stroke has not been thoroughly explored. We tested the hypothesis that selective inhibition of HDAC3 after stroke affords neuroprotection. Adult male Wistar rats (n = 8/group) were subjected to 2 h of middle cerebral artery occlusion (MCAO), and randomly selected animals were treated intraperitoneally twice with either vehicle (1% Tween 80) or a selective HDAC3 inhibitor (RGFP966, 10 mg/kg) at 2 and 24 h after MCAO. Long-term behavioral tests were performed up to 28 days after MCAO. Another set of rats (n = 7/group) were sacrificed at 3 days for histological analysis. Immunostaining for HDAC3, acetyl-Histone 3 (AcH3), NeuN, TNF-alpha, toll-like receptor 4 (TLR4), cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), Akt, and TUNEL were performed. Selective HDAC3 inhibition improved long-term functional outcome (p < 0.05) and reduced infarct volume (p < 0.0001). HDAC3 inhibition increased levels of AcH3 in the ischemic brain (p = 0.016). Higher levels of AcH3 were significantly correlated with better neurological scores and smaller infarct volumes (r = 0.74, p = 0.002; r = 0.6, p = 0.02, respectively). The RGFP966 treatment reduced apoptosis—TUNEL+, cleaved caspase-3+, and cleaved PARP+ cells—and neuroinflammation—TNF-alpha+ and TLR4+ cells—in the ischemic border compared to vehicle control (p < 0.05). The RGFP966 treatment also increased Akt expression in the ipsilateral cortex (p < 0.001). Selective HDAC3 inhibition after stroke improves long-term neurological outcome and decreases infarct volume. The neuroprotective effects of HDAC3 inhibition are associated with a reduction in apoptosis and inflammation and upregulation of the Akt pathway.
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Metadata
Title
Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke
Authors
Rudy Matheson
Kohei Chida
Hui Lu
Victoria Clendaniel
Marc Fisher
Ajith Thomas
Eng H. Lo
Magdy Selim
Amjad Shehadah
Publication date
01-10-2020
Publisher
Springer US
Keyword
Stroke
Published in
Translational Stroke Research / Issue 5/2020
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-020-00783-3

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