Department of Anesthesiology, Zhejiang Cancer Hospital, Guangji Road 38, Hangzhou, China,
Neurol Sci. 2014 Feb;35(2):283-8. doi: 10.1007/s10072-013-1508-4. Epub 2013 Aug 8.
Sepsis-associated encephalopathy (SAE), which associates with neuronal apoptosis and cognitive disorders, is a common complication of systemic sepsis. However, the mechanism involving its modulation remains to be elucidated. Recent studies showed that histone deacetylases (HDACs) were implicated in neurodegeneration and cognitive functions. The current study was designed to investigate whether septic brain is epigenetically modulated by HDACs, using cecal ligation and peroration (CLP) rats and primary hippocampal neuronal cultures. We found that hippocampal acetylated histone 3 (AcH3), acetylated histone 4 (AcH4), cytoplasmic HDAC4 and Bcl-XL were inhibited in septic brain. Hippocampal Bax and nuclear HDAC4 expressions were enhanced in CLP rats. Administration of HDACs inhibitor, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) rescued the changes of Bcl-XL and Bax in vivo, and decreased apoptotic cells in vitro. In addition, HDAC4 shRNA transfection significantly enhanced AcH3, AcH4 and Bcl-XL, but suppressed Bax. Neuronal apoptosis was also reduced by transfection of HDAC4 shRNA. Furthermore, CLP rats exhibited significant spatial learning and memory deficits, which could be ameliorated by application of TSA or SAHA without influence on locomotive activity. These results reveal that epigenetic modulation is involved in septic brain, and the inhibition of HDACs may serve as a potential therapeutic approach for SAE treatment.
脓毒症相关性脑病（SAE）与神经元凋亡和认知障碍有关，是全身脓毒症的常见并发症。然而，其调节机制仍有待阐明。最近的研究表明，组蛋白去乙酰化酶（HDACs）参与神经退行性变和认知功能。本研究旨在通过盲肠结扎穿孔（CLP）大鼠和原代海马神经元培养物来研究脓毒症大脑是否通过 HDACs 进行表观遗传调节。我们发现脓毒症大脑中海马乙酰化组蛋白 3（AcH3）、乙酰化组蛋白 4（AcH4）、细胞质 HDAC4 和 Bcl-XL 受到抑制。CLP 大鼠海马 Bax 和核 HDAC4 表达增强。给予 HDACs 抑制剂曲古抑菌素 A（TSA）或丁酸钠（SAHA）可挽救体内 Bcl-XL 和 Bax 的变化，并减少体外凋亡细胞。此外，HDAC4 shRNA 转染可显著增强 AcH3、AcH4 和 Bcl-XL，但抑制 Bax。HDAC4 shRNA 的转染也减少了神经元凋亡。此外，CLP 大鼠表现出明显的空间学习和记忆缺陷，应用 TSA 或 SAHA 可改善这些缺陷，而不影响运动活动。这些结果表明表观遗传调节参与了脓毒症大脑，抑制 HDACs 可能是治疗 SAE 的一种潜在治疗方法。
