title: Reduced AKT phosphorylation contributes to endoplasmic reticulum stress-mediated hippocampal neuronal apoptosis in rat recurrent febrile seizure.
abstract: OBJECTIVE
  Febrile seizure (FS) is one of the most common types of seizures in childhood. Recurrent FS can result in hippocampus injury and thus impair learning capacity and memory, while the underlying molecular mechanisms are still elusive. Studies indicated that endoplasmic reticulum stress (ERS), involved in many diseases including some neurodegenerative diseases, can increase the expression of tribbles-related protein 3 (TRIB3), which thus inhibits the activity of AKT. The current study assessed whether ERS, TRIB3 and AKT signalling is involved in the hippocampus injury following recurrent FS.
  
  
  METHODS
  Recurrent FS was induced in Sprague-Dawley (SD) rats by using a heated water-bath. TdT-mediated dUTP nick-end labeling (TUNEL) assay was performed to assess hippocampus apoptosis, and electron microscopy was used to examine ultrastructural changes. Protein expression and localization of TRIB3, glucose-regulated protein 78(GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) as well as AKT were examined by using western blot and double immunofluorescence staining. Knockdown of TRIB3 was studied in primary cultured neurons treated with hyperthermia.
  
  
  RESULTS
  As compared with control, apoptosis of hippocampus was significantly induced in FS group. Abundance of TRIB3, GRP78 and CHOP was remarkably elevated, while phosphor-AKT decreased significantly in hippocampus of rats with recurrent FS. Double immunofluorescence indicated that phosphor-AKT was not detected in cells with induction of TRIB3 in FS rats. Hyperthermia-treated cells showed up-regulates TRIB3 expression and that TRIB3 reduces AKT phosphorylation.
  
  
  CONCLUSIONS
  These results show that recurrent FS may induce injury of hippocampal cell by interfering with AKT activation through ERS-mediated up-regulation of TRIB3.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China. Electronic address: hanying1568@126.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Ding-Fang
authors.initials: DF
authors.lastname: Bu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Qin-Rui
authors.initials: QR
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Hong-Fang
authors.initials: HF
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No. 1, Xi-An Men Street, Beijing 100034, PR China.
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Du
authors.affiliation: Department of Pediatrics, Peking University People's Hospital, No. 11, Xi Zhi Men Street, Beijing 100044, PR China. Electronic address: qinjiong@pkuph.edu.cn.
authors.forename: Jiong
authors.initials: J
authors.lastname: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis; D059865:Endoplasmic Reticulum Stress; D006624:Hippocampus / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D003294:Seizures, Febrile / Q000473:pathology*
chemical_list: C502443:Trib3 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Apoptosis; ERS; Febrile seizure; TRIB3