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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

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.
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Figure 1: 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.

Mentions: Previously, we found that mice subjected to peripheral IFN-α treatment (4 × 105 IU/kg, i.p., once daily for 5 weeks) exhibited suppressed neurogenesis (Zheng et al., 2014). To determine if peripheral IFN-α treatment leads to hippocampal inflammation, mice were subjected to the same IFN-α treatment regimen, the hippocampal tissues were collected at 2, 6, and 24 h after the final injection of IFN-α, and the expression of proinflammatory cytokines was quantified by real-time PCR (Figure 1A). IFN-α treatment was previously shown to increase the IL-1β, IL-6, and TNF-α levels in the brain (Kaneko et al., 2006; Raison et al., 2009). Consistent with these reports, the mRNA levels of these cytokines in the hippocampus were significantly upregulated by IFN-α administration, exhibiting ∼2-, 3-, and 8-fold increases compared with the control PBS-treated group at 6 h after treatment (Figure 1A), suggesting that our treatment protocol efficiently stimulated hippocampal inflammation in the mouse. We also found that our IFN-α treatment protocol increased the IFN-α mRNA level in the hippocampus, resulting in a greater than fourfold increase over background levels after 6 h of treatment, suggesting that peripherally administered IFN-α can enhance IFN-α signaling in the hippocampus.


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

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

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.
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Figure 1: 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.
Mentions: Previously, we found that mice subjected to peripheral IFN-α treatment (4 × 105 IU/kg, i.p., once daily for 5 weeks) exhibited suppressed neurogenesis (Zheng et al., 2014). To determine if peripheral IFN-α treatment leads to hippocampal inflammation, mice were subjected to the same IFN-α treatment regimen, the hippocampal tissues were collected at 2, 6, and 24 h after the final injection of IFN-α, and the expression of proinflammatory cytokines was quantified by real-time PCR (Figure 1A). IFN-α treatment was previously shown to increase the IL-1β, IL-6, and TNF-α levels in the brain (Kaneko et al., 2006; Raison et al., 2009). Consistent with these reports, the mRNA levels of these cytokines in the hippocampus were significantly upregulated by IFN-α administration, exhibiting ∼2-, 3-, and 8-fold increases compared with the control PBS-treated group at 6 h after treatment (Figure 1A), suggesting that our treatment protocol efficiently stimulated hippocampal inflammation in the mouse. We also found that our IFN-α treatment protocol increased the IFN-α mRNA level in the hippocampus, resulting in a greater than fourfold increase over background levels after 6 h of treatment, suggesting that peripherally administered IFN-α can enhance IFN-α signaling in the hippocampus.

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