miR-182 mediated the inhibitory effects of NF-κB on the GPR39/CREB/BDNF pathway in the hippocampus of mice with depressive-like behaviors
| Autor: | Jianxin Yang, Yuxiao Tang, Chuyang Ye, Hui Shen, Mengyu Cai, Fengfeng Mo, Hongxia Li, Yinyin Zhang, Hongtao Lu, Xin Xu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Restraint Physical medicine.medical_specialty Hippocampus Hippocampal formation CREB Neuroprotection Receptors G-Protein-Coupled Behavioral Neuroscience chemistry.chemical_compound Mice Corticosterone Internal medicine medicine Animals Chronic stress Cyclic AMP Response Element-Binding Protein Neuroinflammation biology Chemistry Depression Brain-Derived Neurotrophic Factor Neurogenesis NF-kappa B Computational Biology Disease Models Animal MicroRNAs Endocrinology biology.protein Stress Psychological Signal Transduction |
| Zdroj: | Behavioural brain research. 418 |
| ISSN: | 1872-7549 |
| Popis: | Background Chronic stress is one of the most important causes of depression, accompanied by neuroinflammation and hippocampal injuries. Long-term elevation of glucocorticoid leads to activation of NF-κB and inhibition of GPR39/CREB/BDNF pathway, which is pivotal for neuroprotection and neurogenesis. The present study thus was designed to determine the relationship between NF-κB and GPR39/CREB/BDNF pathway. Methods Depressive-like behaviors were induced by chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) in mice. Corticosterone, inflammatory cytokines, and GPR39/CREB/BDNF pathway were determined by ELISA and Western Blot assays. The activation of NF-κB and inhibition of GPR39 were connected by bioinformatic analysis and experimentally validated in hippocampus cells by knock-in and knock-down techniques. Results CUMS and CRS led to an elevation of serum corticosterone and depressive-like behaviors in mice, with activation of NF-κB subunit p65 in the hippocampus and elevations of TNFα and IL-6. The expression of GPR39/CREB/BDNF pathway in the hippocampus was inhibited. Bioinformatic analysis revealed that four miRNAs, miR-96, miR-143, miR-150, and miR-182, were potentially transcribed by NF-κB and bound with GPR39 mRNA. NF-κB overexpression increased miR-182 expression and decreased GPR39 expression in hippocampus cells. Its inhibitor led to reverse effects. miR-182 mimics or inhibitors also regulated GPR39 expression in hippocampus cells and more importantly, blocked the regulation of NF-κB on GPR39. Conclusions The results suggested that activation of NF-κB inhibited GPR39/CREB/BDNF pathway through increasing miR-182 in chronic stress-induced depressive-like behaviors. The negative-regulation features of miRNAs might be important for neuroinflammation-induced inhibition of neurofunction in depression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect