title: Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy.
abstract: We assumed that diabetic encephalopathy (DEP) may be induced by endoplasmic reticulum (ER)-mediated inflammation and apoptosis in central nervous system. To test this notion, here we investigated the neuronal ER stress and associated inflammation and apoptosis in a type 2 diabetes model induced with high-fat diet/streptozotocin in Sprague-Dawley rats. Elevated expressions of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor-6 (ATF-6), X-box binding protein-1 (XBP-1), and C/EBP homologous protein, and phosphor-Jun N-terminal kinase (p-JNK) were evident in the hippocampus CA1 of diabetic rats. These changes were also accompanied with the activation of NF-κB and the increased levels of inflammatory cytokines, tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6). Mechanistic study with in vitro cultured hippocampus neurons exposed to high glucose (HG), which induced a diabetes-like effects, shown by increased ER stress, JNK and NF-κB activation, and inflammatory response. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) or blockade of JNK activity by specific inhibitor or transfection of DN-JNK attenuated HG-induced inflammation and associated apoptosis. To validate the in vitro finding, in vivo application of 4-PBA resulted in a significant reduction of diabetes-induced neuronal ER stress, inflammation and cell death, leading to the prevention of DEP. These results suggest that diabetes-induced neuronal ER stress plays the critical role for diabetes-induced neuronal inflammation and cell death, leading to the development of DEP.
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Zhouguang
authors: Z
authors: Wang
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Yan
authors: Y
authors: Huang
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Yi
authors: Y
authors: Cheng
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Children's Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA.
authors: Yi
authors: Y
authors: Tan
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Fenzan
authors: F
authors: Wu
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Jiamin
authors: J
authors: Wu
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Hongxue
authors: H
authors: Shi
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Hongyu
authors: H
authors: Zhang
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Xichong
authors: X
authors: Yu
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Hongchang
authors: H
authors: Gao
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Li
authors: L
authors: Lin
authors: Department of Pediatrics, Children's Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA.
authors: Jun
authors: J
authors: Cai
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Jinsan
authors: J
authors: Zhang
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Children's Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA.
authors: Xiaokun
authors: X
authors: Li
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Children's Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA.
authors: Lu
authors: L
authors: Cai
authors: Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Jian
authors: J
authors: Xiao
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal; D001927:Brain Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D003071:Cognition; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051702:Activating Transcription Factor 6; D000893:Anti-Inflammatory Agents; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051742:Transcription Factor CHOP; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; C497113:Atf6 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000605545:Xbp1 protein, rat
keywords: ER stress; apoptosis; diabetes; inflammation; p-JNK