trichostatin-a and Hypoxia-Ischemia--Brain

Hypoxia-ischemia (HI) in the neonatal brain frequently results in neurologic impairments, including cognitive disability. Unfortunately, there are currently no known treatment options to minimize ischemia-induced neural damage. We previously showed the neuroprotective/neurogenic potential of a histone deacetylase inhibitor (HDACi), sodium butyrate (SB), in a neonatal HI rat pup model. The aim of the present study was to examine the capacity of another HDACi-Trichostatin A (TSA)-to stimulate neurogenesis in the subgranular zone of the hippocampus. We also assessed some of the cellular/molecular processes that could be involved in the action of TSA, including the expression of neurotrophic factors (glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF)) as well as the TrkB receptor and its downstream signalling substrate- cAMP response element-binding protein (CREB). Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 1 h. TSA was administered directly after the insult (0.2 mg/kg body weight). The study demonstrated that treatment with TSA restored the reduced by hypoxia-ischemia number of immature neurons (neuroblasts, BrdU/DCX-positive) as well as the number of oligodendrocyte progenitors (BrdU/NG2+) in the dentate gyrus of the ipsilateral damaged hemisphere. However, new generated cells did not develop the more mature phenotypes. Moreover, the administration of TSA stimulated the expression of BDNF and increased the activation of the TrkB receptor. These results suggest that BDNF-TrkB signalling pathways may contribute to the effects of TSA after neonatal hypoxic-ischemic injury.

Topics: Animals; Animals, Newborn; Brain; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Doublecortin Protein; Female; Glial Cell Line-Derived Neurotrophic Factor; Histone Deacetylase Inhibitors; Hydroxamic Acids; Hypoxia-Ischemia, Brain; Male; Nerve Growth Factor; Neurogenesis; Rats; Rats, Wistar; Receptor, trkB

Perinatal brain injury is complex and often 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.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Female; Histone Deacetylase Inhibitors; Hydroxamic Acids; Hypoxia-Ischemia, Brain; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents