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Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy.

Endoplasmic reticulum stress-induced neuronal inflammatory response and apoptosis likely plays a key role in the development of diabetic encephalopathy.
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Wang Z, Huang Y, Cheng Y, Tan Y, Wu F, Wu J, Shi H, Zhang H, Yu X, Gao H, Lin L, Cai J, Zhang J, Li X, Cai L, Xiao J,


Wang Z, Huang Y, Cheng Y, Tan Y, Wu F, Wu J, Shi H, Zhang H, Yu X, Gao H, Lin L, Cai J, Zhang J, Li X, Cai L, Xiao J, (click to view)

Wang Z, Huang Y, Cheng Y, Tan Y, Wu F, Wu J, Shi H, Zhang H, Yu X, Gao H, Lin L, Cai J, Zhang J, Li X, Cai L, Xiao J,

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Oncotarget 2016 Oct 26() doi 10.18632/oncotarget.12925
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.

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