Abstract Details

Title Histone Deacetylase 3 as a Novel Therapeutic Target for Ischemic Stroke

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S22 - Stroke Genetics, Cellular Responses, and Animal Models (4:03 PM-4:14 PM)

Poster/Presentation
Number 004

Background HDAC3 has been implicated as neurotoxic in several neurodegenerative conditions. However, the role of HDAC3 in ischemic stroke has not been thoroughly explored.

Objective In this study, we tested the hypothesis that selective inhibition of histone deacetylase 3 (HDAC3) after stroke affords neuroprotection.

Design/Methods Adult male Wistar rats (n=7/group) were subjected to middle cerebral artery occlusion (MCAO), and randomly selected animals were treated with either vehicle (1% Tween 80) or a selective HDAC3 inhibitor (RGFP966, 10 mg/kg) at 2 and 24 h after MCAO. Behavioral tests were performed at 3 h, 1 d, and 3 d after MCAO. Rats were sacrificed 3 d after MCAO. Infarct volumes were measured with H&E. Immunostaining for HDAC3, acetyl-Histone 3 (AcH3), NeuN, tumor necrosis factor alpha (TNF-alpha), toll-like receptor 4 (TLR4), cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), Akt, and TUNEL assays were performed by blinded investigators.

Results Selective HDAC3 inhibition improved neurologic functional outcome (p<0.05) and reduced infarct volume (p<0.001) after stroke. HDAC3 inhibition increased levels of acetylated histone 3 (p=0.016) in the ischemic brain, and AcH3 levels were significantly and negatively correlated with neurological severity scores and infarct volumes (r=0.74, p=0.002; r=0.6, p=0.02; respectively). RGFP966 treatment reduced apoptosis—as measured by the numbers of TUNEL+, cleaved caspase-3+, and cleaved PARP+ cells—in the ischemic brain (p<0.05). Selective HDAC3 inhibition also reduced total and neuronal TNF-alpha and TLR4 in the ischemic border compared to vehicle control (p<0.05). In addition, RGFP966 treatment increased Akt expression in the ipsilateral cortex (p<0.001).

Conclusions

Selective HDAC3 inhibition after stroke improves functional outcome, decreases infarct volume, and increases histone acetylation levels in the ischemic brain. The neuroprotective effects of HDAC3 inhibition are associated with a reduction in apoptosis and attenuation of inflammation. Akt pathway may contribute to the neuroprotective effects of HDAC3 inhibition after ischemia.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
Eng Lo, MD (Massachusetts General Hospital)	Eng Lo, MD has nothing to disclose.
Magdy H. Selim, MD, PhD (Beth Israel Deaconess Med. Ctr.)	Dr. Selim has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MedRhythms Inc..
Amjad Shehadah, MD (U.S. Food and Drug Administration)	Dr. Shehadah has nothing to disclose.

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