Abstract 127: Class IIa Histone Deacetylases Are Essential for Neuronal Remodeling and Functional Recovery After Stroke

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Abstract

Background: Histone deacetylases (HDACs) have recently emerged as a potential therapeutic target for stroke. We have previously demonstrated that stroke induces nuclear shuttling of class IIa HDAC isoform 4 (but not 5) in neurons. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested whether class IIa HDACs are essential to endogenous neuronal remodeling and functional recovery after stroke.

Methods: Adult male Wistar rats (n=13/group) were subjected to MCAO. At 1 day after MCAO, rats were gavaged with: SAHA (non-selective HDAC inhibitor, 25 mg/kg/d), MC1568 (selective inhibitor of class IIa HDAC, 25 mg/kg/2d) or vehicle for 7 days. A battery of behavioral tests was performed. Lesion volume was measured at 28 days after MCAO and immunohistochemistry was performed using antibodies against microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination). Nuclear HDAC activity was measured using a colorimetric assay.

Results: Stroke significantly increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere (2 fold; p<0.05). Stroke-increased HDAC activity was significantly decreased by the administration of SAHA, as well as by MC1568. However, SAHA, but not MC1568, significantly improved functional outcome compared to vehicle-control. Selective class IIa inhibition with MC1568 increased mortality and lesion volume (43% vs. 35% in vehicle-control, p<0.05). In addition, MC1568 significantly decreased MAP2, pNFH and MBP immunoreactivity in the peri-infarct cortex compared to vehicle-control. Quantitative RT-PCR analysis of neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-FOS expression (p<0.05). Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons compared to vehicle-control.

Conclusions: Selective inhibition of class IIa HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-FOS by MC1568 likely contributes to this detrimental effect. Thus, class IIa HDACs play a crucial role in regulating brain remodeling and functional recovery after stroke.

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