Reduced AKT phosphorylation contributes to endoplasmic reticulum stress-mediated hippocampal neuronal apoptosis in rat recurrent febrile seizure

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• 作者：Yang Zhao^a ; Ying Han^a ; ^{hanying1568@126.com" class="auth_mail" title="E-mail the corresponding author} ; Ding-Fang Bu^a ; Jing Zhang^a ; Qin-Rui Li^a ; Hong-Fang Jin^a ; Jun-Bao Du^a ; Jiong Qin^b ; ^{qinjiong@pkuph.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Febrile seizure ; ERS ; TRIB3 ; AKT ; Apoptosis
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：153
• 期：Complete
• 页码：153-162
• 全文大小：2030 K

文摘

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.

Main 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.

Key findings

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.

Significance

These results show that recurrent FS may induce injury of hippocampal cell by interfering with AKT activation through ERS-mediated up-regulation of TRIB3.