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Minocycline Treatment Ameliorates Interferon-Alpha- Induced Neurogenic Defects and Depression-Like Behaviors in Mice


Minocycline Treatment Ameliorates Interferon-Alpha- Induced Neurogenic Defects and Depression-Like Behaviors in Mice

Lian-Shun Zheng et al. Front Cell Neurosci.


Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

Keywords: depression; hippocampus; interferon; microglia; neurogenesis.


Chronic treatment with minocycline inhibits IFN-α-induced proinflammatory cytokine expression in the hippocampus. (A) Time-dependent alteration of IFN-α, IL-1β, IL-6, and TNF-α mRNA levels in the hippocampus at 2, 6, and 24 h following the final IFN-α injection of the 5-week treatment. The mRNAs were quantified by real-time PCR, and the results are expressed as relative values, compared to the PBS-treated control group. n = 3 mice per group. *P < 0.05, **P < 0.01 versus the PBS-treated group. (B) Experimental design of the minocycline study. (C–E) Effect of minocycline on IFN-α-induced microglial activation in the hippocampus. Coronal brain sections prepared after the 5-week treatment with IFN-α in the presence or absence of minocycline, immunostained for Iba1, a microglial marker (red) with Hoechst nuclear staining (blue) (C). Density of Iba1+ microglia in the DG and hilus (D). Relative IFN-α, IL-1β, IL-6, and TNF-α mRNA levels in the hippocampus quantified by real-time PCR (E). n = 5 mice per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM; Scale bar, 25 μm.
IFN-α-stimulated microglia suppress proliferation of hippocampal NSCs by production and release of IFN-α. (A) Experimental design. (B) Proinflammatory cytokine levels in the conditioned media (CM) of microglia following incubation with IFN-α. The CM samples were collected before (control) or 6, 12, 18, 24, and 48 h after the 6 h incubation with IFN-α. The concentrations of IFN-α, IL-1β, IL-6, and TNF-α were quantified by ELISA and are expressed as relative values compared to the control. n = 6 cultures per group; Cnt, control. (C,D) Proliferation of the cultured hippocampal NSCs incubated with the CM from PBS or IFN-α-stimulated microglia (PBS-CM or IFN-CM, respectively), or with IFN-CM supplemented with an IFN-α neutralizing antibody (IFN-CM + IFN-α ab). NSCs were immunostained for Nestin and BrdU (C), then the percentage of BrdU+ cells in the Nestin+ population was quantified (D). n = 6 cultures per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM, Scale bar, 20 μm.
Minocycline treatment ameliorates IFN-α-induced neurogenic defects and depressive behaviors. (A) Experimental design. (B–E) Quantification of proliferating cells in the SGZ following the 4-week treatment with PBS or IFN-α, in the absence or presence of minocycline (Mino). The brain sections were immunostained for the proliferation marker, Ki67 (B) and neuronal progenitor marker, TBR2 (C), and then the Ki67+ and TBR2+ cells in the SGZ were counted and compared among the treatment groups (Ki67, D; TBR2, E). n = 7 mice per group. (F,G) Quantification of newly generated neurons in the DG after the 5-week IFN-α treatment. The new neurons were labeled with BrdU administered at the beginning at the 5th week of the IFN-α treatment and visualized by immunostaining for BrdU and DCX, a marker of immature neurons (F) The number of BrdU+DCX+ cells in the DG was counted and compared among the groups. n = 5 mice per group. (H,I) The effects of IFN-α and minocycline on depression-like behaviors in mice. After the final injection of IFN-α and/or minocycline, the mice were subjected to the tail suspension (H) and forced swimming test (I). The immobility times observed in these tests were quantified and compared among the groups. n = 10 mice per group. *P < 0.05; **P < 0.01; Error bars: means ± SEM; Scale bars: (B,C) = 100 μm; (F) = 25 μm.

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