Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat

Cai Zhang; Yong-Ping Zhang; Yu-Yu Li; Bai-Ping Liu; Hao-Yin Wang; Kang-Wei Li; Shannon Zhao; Cai Song

doi:10.1016/j.bbr.2018.07.001

Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat

Behav Brain Res. 2019 Jan 1:356:348-357. doi: 10.1016/j.bbr.2018.07.001. Epub 2018 Jul 9.

Authors

Cai Zhang¹, Yong-Ping Zhang¹, Yu-Yu Li¹, Bai-Ping Liu¹, Hao-Yin Wang¹, Kang-Wei Li¹, Shannon Zhao², Cai Song³

Affiliations

¹ Research Institute for Marine Drug & Nutrition, College of Food Science & Technology, Guangdong Ocean University, Zhanjiang, and Marine Medicine Development Center, Shenzhen Institute, Guangdong Ocean University, Shenzhen, Guangdong, China.
² American Studies and Ethnicity, University of Southern California, Los Angeles, CA, 90089, USA.
³ Research Institute for Marine Drug & Nutrition, College of Food Science & Technology, Guangdong Ocean University, Zhanjiang, and Marine Medicine Development Center, Shenzhen Institute, Guangdong Ocean University, Shenzhen, Guangdong, China. Electronic address: cai.song@dal.ca.

PMID: 30003978
DOI: 10.1016/j.bbr.2018.07.001

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.

Keywords: Behavior; Chronic unpredictable mild stress; Cytokines; Microglial M1; Minocycline; Neurotrophins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / pharmacology*
Anxiety Disorders / drug therapy
Behavior, Animal
Brain-Derived Neurotrophic Factor / metabolism
Depression / drug therapy
Depression / metabolism
Disease Models, Animal
Female
Hypothalamo-Hypophyseal System / drug effects
Hypothalamo-Hypophyseal System / metabolism
Minocycline / pharmacology*
Pituitary-Adrenal System / drug effects
Pituitary-Adrenal System / metabolism
Rats, Sprague-Dawley
Stress, Psychological / drug therapy*
Stress, Psychological / metabolism

Substances

Antidepressive Agents
Brain-Derived Neurotrophic Factor
Minocycline