Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons

Bo Wang; Xiao Huang; Xiao Pan; Ting Zhang; Cheng Hou; Wen-Jun Su; Lin-Lin Liu; Jia-Mei Li; Yun-Xia Wang

doi:10.1016/j.bbi.2020.06.019

Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons

Brain Behav Immun. 2020 Aug:88:132-143. doi: 10.1016/j.bbi.2020.06.019. Epub 2020 Jun 15.

Authors

Bo Wang¹, Xiao Huang², Xiao Pan³, Ting Zhang⁴, Cheng Hou⁵, Wen-Jun Su⁶, Lin-Lin Liu⁶, Jia-Mei Li⁶, Yun-Xia Wang⁷

Affiliations

¹ Department of Nautical Psychology, Faculty of Psychology, Second Military Medical University, Shanghai 200433, China; Department of Stress Medicine, Faculty of Psychology, Second Military Medical University, Shanghai 200433, China; Department of Medicine, The Unit 31641 of PLA, Xishuangbanna 666100, China.
² Department of Anaesthesiology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201112, China.
³ Department of Medical Psychology, Changzheng Hospital, Navy Medical University, Shanghai 200003, China.
⁴ Department of Nautical Psychology, Faculty of Psychology, Second Military Medical University, Shanghai 200433, China.
⁵ Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
⁶ Department of Stress Medicine, Faculty of Psychology, Second Military Medical University, Shanghai 200433, China.
⁷ Department of Nautical Psychology, Faculty of Psychology, Second Military Medical University, Shanghai 200433, China; Department of Medical Psychology, Changzheng Hospital, Navy Medical University, Shanghai 200003, China. Electronic address: yunxiawang@smmu.edu.cn.

PMID: 32553784
DOI: 10.1016/j.bbi.2020.06.019

Abstract

Background: Our previous study reports the causal role of high mobility group box 1 (HMGB1) in the development of depression; and we find glycyrrhizic acid (GZA) can be a potential treatment for major depressive disorder (MDD) considering its inhibition of HMGB1 activity. This study aims to further explore the exact cell types that release HMGB1 in the hippocampus.

Methods: We detected the effects of microglia conditioned medium on primary astrocytes and neurons. The effects of minocycline on depressive-like behaviors were tested in BABLB/c mice after four weeks of chronic unpredictable mild stress (CUMS) exposure. Furthermore, the immunofluorescence (IF) assays, hematoxylin-eosin (HE) and TUNEL staining were used to observe hippocampal slices to evaluate the release of HMGB1. The cytoplasmic translocations of HMGB1 protein were assayed by western-blot.

Results: Exposure to CUMS caused an active release of HMGB1 from microglia and neurons in the hippocampus. After minocycline administration for inhibiting the activation of microglia, both microglia and neurons reduced the release of HMGB1 and the protein level of central and peripheral HMGB1 recovered accordingly. Along with blocking the release of HMGB1, behavioral and cognitive deficits induced by CUMS were improved significantly by minocycline. In addition, the supernatant of primary microglia stimulated the secretion of HMGB1 in primary neurons, not in astrocytes, at 24 h after 4 h-LPS treatment.

Conclusion: All the evidence supported our hypotheses that microglia and neurons are the main cell sources of HMGB1 release under CUMS condition, and that the release of HMGB1 by microglia may play an important role in the development of depressive-like behavior.

Keywords: Chronic unpredictable mild stress; Depression; HMGB1; Microglia; Minocycline; Neuron.

Publication types

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

MeSH terms

Animals
Depression / drug therapy
Depressive Disorder, Major*
Disease Models, Animal
HMGB1 Protein* / metabolism
Hippocampus / metabolism
Mice
Microglia / metabolism
Minocycline / pharmacology
Neurons / metabolism
Stress, Psychological

Substances

HMGB1 Protein
Minocycline