NLRP3 inflammasome-dependent pyroptosis and apoptosis in hippocampus neurons mediates depressive-like behavior in diabetic mice
| Autor: | Yu-Jian Liu, Lai Jiang, Yan Wang, Dong-Xia Li, Xiao-Yan Zhu, Chang-Lin Ye, Chang-Nan Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Programmed cell death Inflammasomes Caspase 3 Apoptosis Hippocampal formation medicine.disease_cause Hippocampus Streptozocin Cell Line Diabetes Mellitus Experimental 03 medical and health sciences Behavioral Neuroscience Mice 0302 clinical medicine Internal medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Pyroptosis Animals 030304 developmental biology Neurons 0303 health sciences integumentary system business.industry Depression Intracellular Signaling Peptides and Proteins Inflammasome Streptozotocin Mice Inbred C57BL Disease Models Animal Endocrinology business Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress medicine.drug Signal Transduction |
| Zdroj: | Behavioural brain research. 391 |
| ISSN: | 1872-7549 |
| Popis: | A relatively large number of diabetic patients risk complications of clinical depression that lead to poorer quality of life, however the precise mechanisms for diabetes-associated depression are not fully understood. Links between hyperglycemia-induced oxidative stress and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation have been reported in the pathogenesis of diabetes. The present study aimed to elucidate the contribution of NLRP3-mediated apoptotic/pyroptotic neuronal cell death to diabetes-associated depression. We found that depressive-like behavior in streptozotocin (STZ)-induced diabetic mice was associated with hippocampal NLRP3 inflammasome activation. Hyperglycemia increased reactive oxygen species (ROS) production, thus leading to NLRP3 inflammasome activation in hippocampal neurons. It was found that STZ treatment induced apoptotic and pyroptotic cell death in the hippocampus as evidenced by increases of cleaved caspase 3 positive hippocampal neurons, TUNEL-positive cells, protein levels of p53, Bax, Puma, and the cleaved GSDMD N-terminal fragment, all of which were decreased in NLRP3 deficient mice. Using murine hippocampal neuronal cell line HT22, we found that high glucose induced apoptotic and pyroptotic cell death in a NLRP3 inflammasome-dependent manner in vitro. In addition, NLRP3 deficiency alleviated depressive-like behavior in STZ-induced diabetic mice. Our results suggest that hyperglycemia results in apoptosis and pyroptosis of hippocampal neuron cells in a NLRP3-dependent manner, which was associated with the depressive phenotypes evoked by STZ-induced diabetes. The study identifies a novel function of NLRP3 activation in high glucose-induced neuronal cell death, which sheds further light on the pathogenesis and new therapeutic targets of diabetes-associated depression. |
| Databáze: | OpenAIRE |
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