title: Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation.
abstract: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizure-induced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. SAHA is a histone deacetylase inhibitor that regulates gene expression by increasing chromatin histone acetylation. In this study, we investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model.
  
  
  
  Sprague-Dawley rats with kainic acid (KA)-induced seizures were treated with SAHA. The expression of TLR4, MYD88, NF-κB P65 and IL-1β in hippocampus was detected at hour 2 and 6 and day 1, 2, and 3 post seizure. SAHA pretreatment increased seizure latency and decreased seizure scores. The expression levels of TLR4, MYD88, NF-κB and IL-1β increased significantly in both activated microglia and apoptotic neurons after KA treatment. The effects were attenuated by SAHA. Chromatin immunoprecipitation assays indicated that the H3 histone acetylation levels significantly decreased while H3K9 levels significantly increased in the KA treatment group. The H3 and H3K9 acetylation levels returned to control levels after SAHA (50 mg/kg) pretreatment. There was a positive correlation between the expression of TLR4 and the acetylation levels of H3K9.
  
  
  
  Histone deacetylase inhibitor SAHA can suppress seizure-induced TLR4/MYD88 signaling and inhibit TLR4 gene expression through histone acetylation regulation. This suggests that SAHA may protect against seizure-induced brain damage.
authors.affiliation: Department of Pediatrics, The Second Xiang-Ya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
authors.forename: Qing-Peng
authors.initials: QP
authors.lastname: Hu
authors.affiliation: Department of Pediatrics, The Second Xiang-Ya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China. ma_jinan@yahoo.com.
authors.forename: Ding-An
authors.initials: DA
authors.lastname: Mao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007608:Kainic Acid; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D000927:Anticonvulsants; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000077337:Vorinostat; D007608:Kainic Acid
keywords: Histone acetylation; Histone deacetylase; MYD88; Microglia; SAHA; Seizures; Toll-like-receptor 4 (TLR4)