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

ABSTRACT: Interferon-alpha (IFN-?) 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-? treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-?-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-? 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-? administration induces IFN-? signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-?-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-? treatment induced the secretion of endogenous IFN-? from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-? for 5 weeks increased the production of proinflammatory cytokines, including IFN-?, 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-?-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-?-induced depression, and that minocycline is a promising drug for the treatment of IFN-?-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

SUBMITTER: Zheng LS

PROVIDER: S-EPMC4309184 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Zheng Lian-Shun LS Kaneko Naoko N Sawamoto Kazunobu K

Frontiers in cellular neuroscience 20150128

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, an ...[more]

PMID: 25674053

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Project description:Hypericin, one of the major antidepressant constituents of St. John's wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

Dataset Information

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

Publications

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

Similar Datasets

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