Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke.
We have previously demonstrated that stroke induces nuclear shuttling of class IIa histone deacetylase 4 (HDAC4). Stroke-induced nuclear shuttling of HDAC4 is positively and significantly correlated with improved indices of neuronal remodeling in the peri-infarct cortex. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested the effects of selective inhibition of class IIa HDACs on functional recovery and neuronal remodeling when administered 24hr after stroke. Adult male Wistar rats (n = 15-17/group) were subjected to 2 h MCAO and orally gavaged with MC1568 (a selective class IIa HDAC inhibitor), SAHA (a non-selective HDAC inhibitor), or vehicle-control for 7 days starting 24 h after MCAO. A battery of behavioral tests was performed. Lesion volume measurement and immunohistochemistry were performed 28 days after MCAO. We found that stroke increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere. Stroke-increased HDAC activity was significantly decreased by the administration of SAHA as well as by MC1568. However, SAHA significantly improved functional outcome compared to vehicle control, whereas selective class IIa inhibition with MC1568 increased mortality and lesion volume and did not improve functional outcome. In addition, MC1568 decreased microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination) immunoreactivity in the peri-infarct cortex. Quantitative RT-PCR of cortical neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-fos expression. Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons. Taken together, these findings demonstrate that 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.
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Haifa
H
Kassis
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Amjad
A
Shehadah
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Chao
C
Li
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Yi
Y
Zhang
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Yisheng
Y
Cui
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Cynthia
C
Roberts
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Neema
N
Sadry
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Xianshuang
X
Liu
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; Department of Physics, Oakland University, Rochester, MI 48309, USA.
Michael
M
Chopp
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA. Electronic address: zhazh@neuro.hfh.edu.
Zheng Gang
ZG
Zhang
D000818:Animals; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000201:enzymology* / Q000473:pathology
D056572:Histone Deacetylase Inhibitors; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2
Epigenetics; Neuronal repair; Stroke