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Title: [Protective effect of the histone deacetylase inhibitor ACY1215 against brain edema in mice with acute liver failure].
Author: Jiao FZ, Zhang HY, Yang F, Wang LW, Gong ZJ.
Journal: Zhonghua Gan Zang Bing Za Zhi; 2017 Sep 20; 25(9):695-700. PubMed ID: 29108192.
Abstract:
Objective: To investigate the protective effect of ACY1215 (Rocilinostat), a histone deacetylase inhibitor, against brain edema in mice with acute liver failure. Methods: Lipopolysaccharide combined with D-galactosamine was used to establish a mouse model of acute liver failure, and ACY1215 was used for intervention. The effect of ACY1215 on histopathological changes of the liver was observed after 24 hours, as well as the changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood ammonia, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), brain water content, blood-brain barrier structure, NF-κB-p65, histone, acetylated histone, and TNF-α mRNA in brain tissue. Results: The mice with acute liver failure had marked pathological damage in liver tissue, as well as significant increases in the levels of ALT, AST, blood ammonia, TNF-α, and IFN-γ (t≥5.367, all P < 0.05). ACY1215 significantly improved the pathological damage in liver tissue and reduced the serum levels of ALT, AST, blood ammonia, TNF-α, and IFN-γ (t≤-3.515, all P < 0.05). ACY1215 also significantly reduced the expression of NF-κB-p65 (t = -5.871, P = 0.004) and the mRNA expression of TNF-α (t = -11.913, P < 0.01) in brain tissue and brain water content (t = -2.355, P < 0.01). According to the results of electron microscopy, the model group had an abnormal blood-brain barrier structure, and the ACY1215 group had slighter damage than the model group. Compared with the normal group, the model group had significant increases in the acetylation level of histone H3 and H4 in brain tissue (t≥3.009, both P < 0.05), while ACY1215 further upregulated the acetylation levels of histone H3 and H4 (t≥6.682, both P < 0.05). Conclusion: ACY1215 exerts a protective effect against brain edema in mice with acute liver failure, possibly by regulating histone acetylation and inhibiting inflammation. 目的： 观察组蛋白去乙酰化酶抑制剂ACY1215（Rocilinostat）对急性肝衰竭小鼠脑水肿的保护作用。 方法： 采用脂多糖及D-氨基半乳糖联合诱导小鼠急性肝衰竭模型，并用ACY1215对其干预，24 h后观察ACY1215对小鼠肝组织病理变化的影响，及其对血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、血氨、肿瘤坏死因子（TNF）α、干扰素（IFN）γ水平与脑组织含水量、血脑屏障结构以及脑组织核因子（NF）-κB-p65蛋白、组蛋白、乙酰化组蛋白变化和脑组织TNFα mRNA改变的影响。对多组间数据比较采用方差分析，两组间数据采用t检验分析。 结果： 急性肝衰竭模型组小鼠肝组织出现明显病理性损害，伴ALT、AST、血氨、TNFα、IFNγ水平升高（t≥5.367，P值均< 0.05）。ACY1215改善了肝组织病理损害，降低了血清ALT、AST、血氨、TNFα、IFNγ水平（F≥16.355，P值均< 0.05）；ACY1215降低了模型组小鼠脑组织NF-κB-p65蛋白（0.43±0.22与0.54±0.03，t = -5.871，P < 0.01）和TNFα mRNA（1.4±0.1与3.4±0.3，t = -11.913，P < 0.01）的相对表达水平及脑组织含水量（78.010%±0.006%与79.550%±0.004%，t = -2.355，P < 0.01）。电镜观察模型组小鼠脑组织血脑屏障结构异常，ACY1215组相比模型组损伤较轻；模型组小鼠脑组织组蛋白H3、H4乙酰化水平较正常组升高（t≥3.009，P值均< 0.05），而ACY1215进一步上调组蛋白H3、H4乙酰化水平（t≥6.682，P值均< 0.05）。 结论： ACY1215对急性肝衰竭小鼠脑水肿具有保护作用，可能与其调控组蛋白乙酰化抑制炎症相关。.

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