Expression of Histone Deacetylases in Cellular Compartments of the Mouse Brain and the Effects of Ischemia
- PDF / 1,867,249 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 44 Downloads / 172 Views
ORIGINAL ARTICLE
Expression of Histone Deacetylases in Cellular Compartments of the Mouse Brain and the Effects of Ischemia Selva Baltan & Amelia Bachleda & Richard S. Morrison & Sean P. Murphy
Received: 26 April 2011 / Revised: 19 May 2011 / Accepted: 23 May 2011 / Published online: 4 June 2011 # Springer Science+Business Media, LLC 2011
Abstract Drugs that inhibit specific histone deacetylase (HDAC) activities have enormous potential in preventing the consequences of acute injury to the nervous system and in allaying neurodegeneration. However, very little is known about the expression pattern of the HDACs in the central nervous system (CNS). Identifying the cell types that express HDACs in the CNS is important for determining therapeutic targets for HDAC inhibitors and evaluating potential side effects. We characterized the cellular expression of HDACs 1–3, and HDACs 4 and 6, in the adult mouse brain in the cingulate cortex, parietal cortex, dentate gyrus, and CA1 regions of the hippocampus and subcortical white matter. Expression of class I HDACs showed a celland region-specific pattern. Transient focal ischemia induced by temporary middle cerebral artery occlusion, or global ischemia induced by in vitro oxygen–glucose deprivation, altered the extent of HDAC expression in a region- and cell-specific manner. The pan-HDAC inhibitor, SAHA, reduced ischemia-induced alterations in HDACs. The results suggest that in addition to promoting epigenetic S. Baltan : A. Bachleda Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA R. S. Morrison : S. P. Murphy Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA Present Address: S. Baltan (*) Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, NC30, Cleveland, OH 44195, USA e-mail: [email protected]
changes in transcriptional activity in the nucleus of neurons and glia, HDACs may also have non-transcriptional actions in axons and the distant processes of glial cells and may significantly modulate the response to injury in a cell- and region-specific manner. Keywords Axon . Dentate gyrus . Astrocytes . Neurogenesis . Neurovascular unit
Introduction Histone deacetylases (HDACs) are categorized as either “zinc-dependent” or “NAD-dependent” (sirtuins). The former are class I (HDAC 1–3 and 8), class II (HDAC 4– 7, 9, and 10), or class IV (HDAC 11) based upon sequence similarity. Roles for specific HDACs in brain maturation and function, and in the CNS response to injury, are slowly being elucidated [1–5]. Inhibitors of the zinc-dependent HDACs promote “neuronal” differentiation of neural progenitor cells [3, 6] and also protect existing neurons from insult [7–9]. These inhibitors are structurally diverse, suggesting different mechanisms of action, and all exhibit some HDAC isoform selectivity [10]. The hydroxamate compounds (such as SAHA and TSA) and the small carboxylates inhibit class I and class II HDACs. The benzamide MS-275 and also valproic
Data Loading...
