Abstract
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.