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Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat
Abstract
Activated microglia-induced neuroinflammation can stimulate the hypothalamic- pituitary-adrenal (HPA) axis to release glucocorticoids and suppress astrocyte functions, such as reducing neurotrophin production, which occur in depression. However, the balance between M1 (pro-inflammation) and M2 (anti-inflammation) microglial phenotypes and the interaction between these two glial cells are unclear in the depression. Hence, the chronic unpredictable mild stress (CUMS)-induced depression model was chosen to study depression- and anxiety-like behaviors, the concentration of corticosterone and relevant hippocampal cytokines, mRNA and protein expressions of microglial and astrocyte markers. To demonstrate the role of M1 phenotype activation in depression, the effect of microglial inhibitor minocycline on these aspects was also evaluated. Six weeks after CUMS exposure, behaviors were tested. Compared to the control group, CUMS increased serum corticosterone concentration and depression-like behaviors, like anhedonia, helplessness and anxiety. Moreover, CUMS increased microglia M1 marker CD11b expression and tumor necrosis factor (TNF)-α, interferon (INF)-γ, interleukin (IL)-1β and IL-17 concentrations, but decreased the concentration of M2 cytokines, IL-4, IL-10 and IL-13. Meanwhile, CUMS inhibited the expressions of astrocyte marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrKB. Minocycline (40 mg/kg, 45 days) treatment significantly attenuated CUMS-induced behavioral abnormalities, which were associated with the suppressed M1 response, restored GFAP, BDNF and its receptor expression. In conclusion, CUMS-induced depression- and anxiety-like behavior may result from an imbalance between M1 and M2 and suppressed astrocyte function. Minocycline treatment reversed M1 response, which was associated with behavioral normalization.
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“Preclinical studies in rodents corroborate these findings, showing that IL-17A administration induces depressive-like behaviors [48] and stress exposure elevates IL-17A levels [66,67,68,69].”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [69]
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Metadata
- Authors
- Zhang, C., Zhang, Y.-P., Li, Y.-Y., Liu, B.-P., Wang, H.-Y., Li, K.-W., Zhao, S., & Song, C.
- Affiliations
- Guangdong Ocean University (CN)
- University of Southern California (US)
- Corresponding author
- Song, Cai
- ORCID
- Venue
- Behavioural Brain Research
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 356
- Pages
- 348-357
- ISSN
- 0166-4328 (ISSN-L)
- OpenAlex
- W2871444027
- Cited by
- 172
- References
- 64
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 22 · 2023: 22 · 2022: 25 · 2021: 29 · 2020: 25 · 2019: 13
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Behavioural Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81471223, 81171118)
- Project of Enhancing School with Innovation of Guangdong Ocean University (GDOU2013050110)
- Guangdong Provincial Science and Technology Planning Project of Guangdong Province, China (2016A020215153, 2016B020235001)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- minocycline, depression, chronic unpredictable mild stress, neuroinflammation, astrocyte dysfunction, hippocampus, corticosterone, hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, glial fibrillary acidic protein, cytokines, anxiety-like behavior
- MeSH terms
- Animals, Antidepressive Agents, Anxiety Disorders, Behavior, Animal, Depression, Disease Models, Animal, Female, Hypothalamo-Hypophyseal System, Minocycline, Pituitary-Adrenal System, Stress, Psychological, Rats, Sprague-Dawley, Brain-Derived Neurotrophic Factor
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