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// Zhouguang Wang 1 , Yan Huang 1 , Yi Cheng 1 , Yi Tan 1,2 , Fenzan Wu 1 , Jiamin Wu 1 , Hongxue Shi 1 , Hongyu Zhang 1 , Xichong Yu 1 , Hongchang Gao 1 , Li Lin 1 , Jun Cai 2 , Jinsan Zhang 1 , Xiaokun Li 1,2 , Lu Cai 1,2 and Jian Xiao 1 1 Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China 2 Department of Pediatrics, Children’s Hospital Research Institute, the University of Louisville, Louisville, Kentucky, USA Correspondence to: Jian Xiao, email: // Lu Cai, email: // Keywords : ER stress, inflammation, apoptosis, p-JNK, diabetes Received : June 09, 2016 Accepted : October 19, 2016 Published : October 26, 2016 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.