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DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA.
- Source :
-
Brain, behavior, and immunity [Brain Behav Immun] 2018 Oct; Vol. 73, pp. 482-492. Date of Electronic Publication: 2018 Jun 18. - Publication Year :
- 2018
-
Abstract
- Type 2 diabetes mellitus (T2DM) complicated with obstructive sleep apnea (OSA) may cause neuronal apoptosis and cognitive deficits, but the underlying mechanisms remain unclear. We aimed to determine the relationship between the activation of microglia and the apoptosis of hippocampal neurons, specifically in terms of high mobility group box-1 (HMGB1), after high glucose (HG) and intermittent hypoxia (IH) exposure. Diabetic KK-Ay mice and non-diabetic C57BL/6J mice (C57 mice) underwent IH or normoxia (control) exposure for 4 weeks. Cognitive function, microglial activation and hippocampal neuronal apoptosis were assessed after IH or normoxia exposure. Compared with C57 control mice, KK-Ay control mice exhibited increased cognitive dysfunction, microglial activation and hippocampal neuronal apoptosis. There were no differences between untreated KK-Ay control mice and C57 mice that had been exposed to IH. The abovementioned responses were aggravated in IH-exposed KK-Ay mice compared with control KK-Ay mice. In vitro, a cellular co-culture experiment showed that HG combined with IH could activate BV2 microglia, leading to the release of neuroinflammatory factors (ROS, TNF-α, IL-1β) and mediating the apoptosis of HT22 cells via the PI3K/Akt/GSK-3β signaling pathway. Meanwhile, HMGB1 was actively secreted into the extracellular environment from activated BV2 microglia. As a proinflammatory factor, it was able to sustain microglial activation by directly acting on those cells. The activation promoted positive feedback and aggravated neuronal damage further. In a cellular monoculture or co-culture system, HMGB1 siRNA was able to alleviate the activation of BV2 cells and the apoptosis of HT22 cells induced by HG combined with IH. Our object is to show that inhibition of HMGB1 may break the vicious cycle to prevent or treat neuroinflammation and hippocampal neuronal apoptosis caused by T2DM complicated with OSA.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Diabetes Complications metabolism
Diabetes Mellitus, Type 2 complications
Glycogen Synthase Kinase 3 beta metabolism
HMGB1 Protein metabolism
Hippocampus metabolism
Hippocampus physiology
Hypoxia metabolism
Inflammation metabolism
Interleukin-1beta metabolism
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Microglia metabolism
Microglia physiology
Neurons metabolism
Neurons physiology
Phosphatidylinositol 3-Kinases metabolism
Signal Transduction
Sleep Apnea, Obstructive metabolism
Sleep Apnea, Obstructive physiopathology
Tumor Necrosis Factor-alpha metabolism
Apoptosis physiology
HMGB1 Protein physiology
Hypoxia physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2139
- Volume :
- 73
- Database :
- MEDLINE
- Journal :
- Brain, behavior, and immunity
- Publication Type :
- Academic Journal
- Accession number :
- 29920330
- Full Text :
- https://doi.org/10.1016/j.bbi.2018.06.012