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

Zhouguang Wang,Hongchang Gao,Jiamin Wu,Hongyu Zhang,Jun Cai,Xiaokun Li,Yan Huang,Li Lin,Hongxue Shi,Yi Cheng,Jinsan Zhang,Lu Cai,Xichong Yu,Fenzan Wu,Jian Xiao,Yi Tan

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.

Highlights

Diabetes associated cerebral atrophy and electrophysiological changes may lead to a diverse of neurological disabilities, including deficits in learning, memory, attention, as well as motor as psychomotor dysfunction
A pilot study showed that in vivo administration of thapsigargin a chemical endoplasmic reticulum (ER) inducer exacerbates diabetic encephalopathy (Supplement Figure 4). These results demonstrate that the neuroprotective role of 4-PBA in T2DM-induced hippocampus neurons injury is mediated by its inhibition of ER stress-activated JNK-dependent inflammatory response and nerve cells apoptosis
Accumulating evidence has described a diverse of neurological disabilities, including cognitive impairment and memory loss, in T1DM children and long-duration T1DM and T2DM adults

Summary

Introduction

Diabetes associated cerebral atrophy and electrophysiological changes may lead to a diverse of neurological disabilities, including deficits in learning, memory, attention, as well as motor as psychomotor dysfunction. A growing body of evidence has identified that both type I and type II diabetic (T1DM and T2DM) patients exhibit a variety of neuropathological and neurobehavioral changes, including brain infarcts, cerebral white matter hyperintensities, poorer visuospatial construction, planning, visual memory, and speed [4,5,6,7]. It is appreciated that diabetes-induced changes observed in the ageing brain is associated with accelerated ageing and is the main risk factor for neurodegenerative disorders such as Alzheimer’s disease [12]

Methods

Results

Conclusion