1. Academic Validation
  2. Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis

Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis

  • Brain Behav Immun. 2021 Jan;91:519-530. doi: 10.1016/j.bbi.2020.11.009.
Ben Bassett 1 Selvaraj Subramaniyam 2 Yang Fan 2 Seth Varney 1 Hope Pan 1 Ana M D Carneiro 1 Chang Y Chung 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
  • 2 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
  • 3 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; Division of Natural Science, Duke Kunshan University, Kunshan 215316, China. Electronic address: chang.chung@vanderbilt.edu.
Abstract

Clinical studies examining the potential of anti-inflammatory agents, specifically of minocycline, as a treatment for depression has shown promising results. However, mechanistic insights into the neuroprotective and anti-inflammatory actions of minocycline need to be provided. We evaluated the effect of minocycline on chronic mild stress (CMS) induced depressive-like behavior, and behavioral assays revealed minocycline ameliorate depressive behaviors. Multiple studies suggest a role of microglia in depression, revealing that microglia activation correlates with a decrease in neurogenesis and increased depressive-like behavior. The effect of minocycline on microglia activation in different areas of the dorsal or ventral hippocampus in stressed mice was examined by immunohistochemistry. We observed the increase in the number of activated microglia expressing CD68 after exposure to three weeks of chronic stress, whereas no changes in total microglia number were observed. These changes were observed throughout the DG, CA1 and CA2 regions in dorsal hippocampus but restricted to the DG of the ventral hippocampus. In vitro experiments including western blotting and phagocytosis assay were used to investigate the effect of minocycline on microglia activation. Activation of primary microglia by LPS in vitro causes and ERK1/2 activation, enhancement of iNOS expression and phagocytic activity, and alterations in cellular morphology that are reversed by minocycline exposure, suggesting that minocycline directly acts on microglia to reduce phagocytic potential. Our results suggest the most probable mechanism by which minocycline reverses the pathogenic phagocytic potential of neurotoxic M1 microglia, and reduces the negative phenotypes associated with reduced neurogenesis caused by exposure to chronic stress.

Keywords

Chronic stress; Depression; Microglia; Minocycline; Neurogenesis.

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