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Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice.

Zheng LS, Kaneko N, Sawamoto K - Front Cell Neurosci (2015)

Bottom Line: 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.Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan ; Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University Hangzhou, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

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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Figure 3: 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.

Mentions: We finally tested whether the IFN-α-induced defects in hippocampal neurogenesis and induction of depressive behaviors (Zheng et al., 2014) could be ameliorated by an anti-microglial agent. Mice were treated with minocycline (50 mg/kg) for 2 d prior to and during the IFN-α (4 × 105 IU/kg) treatment (Figure 3A). After the 4-week treatment, brain sections were immunostained for the proliferation marker Ki67 (Figure 3B) and the neuronal progenitor marker TBR2 (Figure 3C). To quantify newly generated neurons, the mice were injected with BrdU once every 8 h for a total of six injections, at the beginning of the 5th week of the IFN-α/minocycline treatment, and the brain sections were immunostained for BrdU and DCX, a marker of immature neurons. The decreased numbers of Ki67+cells (Figure 3D), TBR2+ cells (Figure 3E), and BrdU+DCX+ cells in the IFN-α-treated group (Figures 3F,G) were significantly restored by the simultaneous treatment with minocycline.


Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice.

Zheng LS, Kaneko N, Sawamoto K - Front Cell Neurosci (2015)

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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Related In: Results  -  Collection

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Figure 3: 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.
Mentions: We finally tested whether the IFN-α-induced defects in hippocampal neurogenesis and induction of depressive behaviors (Zheng et al., 2014) could be ameliorated by an anti-microglial agent. Mice were treated with minocycline (50 mg/kg) for 2 d prior to and during the IFN-α (4 × 105 IU/kg) treatment (Figure 3A). After the 4-week treatment, brain sections were immunostained for the proliferation marker Ki67 (Figure 3B) and the neuronal progenitor marker TBR2 (Figure 3C). To quantify newly generated neurons, the mice were injected with BrdU once every 8 h for a total of six injections, at the beginning of the 5th week of the IFN-α/minocycline treatment, and the brain sections were immunostained for BrdU and DCX, a marker of immature neurons. The decreased numbers of Ki67+cells (Figure 3D), TBR2+ cells (Figure 3E), and BrdU+DCX+ cells in the IFN-α-treated group (Figures 3F,G) were significantly restored by the simultaneous treatment with minocycline.

Bottom Line: 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.Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan ; Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University Hangzhou, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus