Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury

Fleiss, B, Nilsson, M, Blomgren, K and Mallard, C 2012, 'Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury', Journal of Neuroinflammation, vol. 9, pp. 1-16.


Document type: Journal Article
Collection: Journal Articles

Title Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury
Author(s) Fleiss, B
Nilsson, M
Blomgren, K
Mallard, C
Year 2012
Journal name Journal of Neuroinflammation
Volume number 9
Start page 1
End page 16
Total pages 16
Publisher BioMed Central Ltd.
Abstract Background: Perinatal brain injury is complex and associated with both inflammation and hypoxia-ischaemia (HI). In adult inflammatory brain injury models, therapies to increase acetylation are efficacious in reducing inflammation and cerebral injury. Our aim in the present study was to examine the neuropathological and functional effects of the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) in a model of neonatal lipopolysaccharide (LPS)-sensitised HI. We hypothesised that, by decreasing inflammation, TSA would improve injury and behavioural outcome. Furthermore, TSAs effects on oligodendrocyte development, which is acetylation-dependent, were investigated. Methods: On postnatal day 8 (P8), male and female mice were exposed to LPS together with or without TSA. On P9 (14 hours after LPS), mice were exposed to HI (50 minutes at 10% O2). Neuropathology was assessed at 24 hours, 5 days and 27 days post-LPS/HI via immunohistochemistry and/or Western blot analysis for markers of grey matter (microtubule-associated protein 2), white matter (myelin basic protein) and cell death (activated caspase-3). Effects of TSA on LPS or LPS/HI-induced inflammation (cytokines and microglia number) were assessed by Luminex assay and immunohistochemistry. Expression of acetylation-dependent oligodendrocyte maturational corepressors was assessed with quantitative PCR 6 hours after LPS and at 24 hours and 27 days post-LPS/HI. Animal behaviour was monitored with the open-field and trace fear-conditioning paradigms at 25 days post-LPS/HI to identify functional implications of changes in neuropathology associated with TSA treatment. Results: TSA induced increased Ac-H4 in females only after LPS exposure. Also only in females, TSA reduced grey matter and white matter injury at 5 days post-LPS/HI. Treatment altered animal behaviour in the open field and improved learning in the fear-conditioning test in females compared with LPS/HI-only females at 25 days post-HI. None of the infl
Subject Innate Immunity
Neurology and Neuromuscular Diseases
Paediatrics
Keyword(s) Histone deacetylase
Hypoxia-ischaemia
Lipopolysaccharide
Neonatal
Trichostatin a
DOI - identifier 10.1186/1742-2094-9-70
Copyright notice © 2012 Fleiss et al.
ISSN 1742-2094
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