Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy.
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.
Department of Anesthesiology, Zhejiang Cancer Hospital, Guangji Road 38, Hangzhou, China, anesth668@hotmail.com.
Jun
J
Fang
Yanhong
Y
Lian
Kangjie
K
Xie
Shunv
S
Cai
Penglu
P
Wen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001927:Brain Diseases / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D013028:Space Perception / Q000187:drug effects; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C012589:trichostatin A; D000077337:Vorinostat; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases