Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke
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ORIGINAL ARTICLE
Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke Rudy Matheson 1 & Kohei Chida 2 & Hui Lu 1,3 & Victoria Clendaniel 1 & Marc Fisher 4 & Ajith Thomas 5 & Eng H. Lo 6 & Magdy Selim 4 & Amjad Shehadah 4
Received: 7 August 2019 / Revised: 21 January 2020 / Accepted: 22 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Histone deacetylase 3 (HDAC3) . RGFP966 . Acetyl-histone 3 (AcH3) . Apoptosis . Inflammation Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-020-00783-3) contains supplementary material, which is available to authorized users. * Amjad Shehadah [email protected] 1
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
2
Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
3
Xuan Wu Hospital/Capital Medical University, Xicheng district, Beijing 100053, People’s Republic of China
4
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
5
Department of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical
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