Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury.
Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury.
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DOI：
10.1186/1742-2094-9-70
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发表时间：
2012-04-18
影响因子：
9.3
通讯作者：
Mallard C
中科院分区：
文献类型：
--
作者：
Fleiss B;Nilsson MK;Blomgren K;Mallard C
围产期脑损伤是复杂的，往往与炎症和缺氧缺血（HI）。在成人炎性脑损伤模型中，增加乙酰化的疗法在减少炎症和脑损伤方面是有效的。本研究的目的是在新生儿脂多糖（LPS）致敏HI模型中研究组蛋白去乙酰化酶抑制剂（HDACi）阿司他丁A（TSA）的神经病理学和功能作用。我们假设，通过减少炎症，TSA将改善损伤和行为结果。此外，TSA对乙酰化依赖的少突胶质细胞发育的影响也进行了研究。在出生后第8天（P8），雄性和雌性小鼠暴露于LPS与或不与TSA。在P9（LPS后14小时），将小鼠暴露于HI（在10%O2下50分钟）。在LPS/HI后24小时、5天和27天通过免疫组织化学和/或Western印迹分析灰质（微管相关蛋白2）、白色物质（髓鞘碱性蛋白）和细胞死亡（活化的半胱天冬酶-3）的标记物来评估神经病理学。通过Luminex测定和免疫组织化学评估TSA对LPS或LPS/HI诱导的炎症（细胞因子和小胶质细胞数目）的影响。在LPS后6小时以及LPS/HI后24小时和27天，用定量PCR评估乙酰化依赖性少突胶质细胞成熟辅抑制因子的表达。在LPS/HI后25天，用旷场和微量恐惧调节范式监测动物行为，以确定与TSA治疗相关的神经病理学变化的功能意义。TSA只在LPS暴露后诱导雌性Ac-H4增加。同样仅在雌性中，TSA在LPS/HI后5天减少灰质和白色物质损伤。治疗改变了动物的行为，在开放领域和改善学习的恐惧条件反射测试中的女性相比，LPS/HI只有女性在HI后25天。在成人中，已知通过HDACi介导神经保护作用的炎症机制评估均与TSA治疗的新生儿女性的结局改善无关。少突胶质细胞的成熟是没有不同的LPS，只有和LPS + TSA治疗的小鼠之前或之后暴露于HI。TSA的超乙酰化在LPS/HI后的雌性新生小鼠中具有神经保护作用，并与长期学习改善相关。TSA似乎通过新生儿特有的机制发挥神经保护作用。解读年龄，性别和炎症致敏作用对HDACi脑反应的影响是进一步促进超乙酰化作为可行的神经保护剂的潜力的关键。TSA没有损害少突胶质细胞的成熟，这增加了这种策略可能的临床意义。
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.
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影响因子：
4.7
作者：
Gibson CL;Murphy SP
通讯作者：
Murphy SP
DOI：
10.1179/096805100101532108
发表时间：
2000-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
影响因子：
--
作者：
Chakravortty, D;Koide, N;Yokochi, T
通讯作者：
Yokochi, T
影响因子：
3.4
作者：
Eklind, S;Mallard, C;Hagberg, H
通讯作者：
Hagberg, H
DOI：
10.1124/jpet.107.120188
发表时间：
2007-06-01
影响因子：
3.5
作者：
Kim, Hyeon Ju;Rowe, Michael;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
影响因子：
5.3
作者：
Dou, HY;Ellison, B;Gendelman, HE
通讯作者：
Gendelman, HE