Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury
1 Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, Gothenburg, 405 30, Sweden
2 Institute of Neuroscience and Physiology, University of Gothenburg, Box 432, Gothenburg, 405 30, Sweden
3 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Box 432, Gothenburg, 405 30, Sweden
4 Karolinska Institutet, Department of Women’s and Children’s Health, Karolinska University Hospital Q2:07, Stockholm, SE 171 76, Sweden
5 Inserm U676, Hôpital Robert Debré, 48 blvd Serurier, Paris, F-75019, France
Journal of Neuroinflammation 2012, 9:70 doi:10.1186/1742-2094-9-70Published: 18 April 2012
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, TSA’s effects on oligodendrocyte development, which is acetylation-dependent, were investigated.
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.
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 inflammatory mechanisms assessed that are known to mediate neuroprotection by HDACi in adults correlated with improved outcome in TSA-treated neonatal females. Oligodendrocyte maturation was not different between the LPS-only and LPS + TSA-treated mice before or after exposure to HI.
Hyperacetylation with TSA is neuroprotective in the female neonatal mouse following LPS/HI and correlates with improved learning long-term. TSA appears to exert neuroprotection via mechanisms unique to the neonate. Deciphering the effects of age, sex and inflammatory sensitisation in the cerebral response to HDACi is key to furthering the potential of hyperacetylation as a viable neuroprotectant. TSA did not impair oligodendrocyte maturation, which increases the possible clinical relevance of this strategy.