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Minocycline Directly Enhances the Self-Renewal of Adult Neural Precursor Cells

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Abstract

Minocycline not only has antibacterial action but also produces a variety of pharmacological effects. It has drawn considerable attention as a therapeutic agent for symptoms caused by inflammation in many neurological disorders, leading to several clinical trials. Although some of these effects are mediated through its function of suppressing microglial activation, it is not clear whether minocycline acts on other cell types in the adult brain. In this study, we utilized a colony-forming neurosphere assay, in which neural stem cells (NSCs) clonally proliferate to form floating colonies, called neurospheres. We found that minocycline (at therapeutically relevant concentrations in cerebrospinal fluid) enhances the self-renewal capability of NSCs derived from the subependymal zone of adult mouse brain and facilitates their differentiation into oligodendrocytes. Importantly, these effects were independent of a suppression of microglial activation and were specifically observed with minocycline (among tetracycline derivatives). In addition, the size of the NSC population in the adult brain was increased when minocycline was infused into the lateral ventricle by an osmotic minipump in vivo. While precise molecular mechanisms of how minocycline alters the behavior of adult NSCs remain unknown, our data provide a basis for the clinical use of minocycline to treat neurodegenerative and demyelinating diseases.

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References

  1. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM (2004) The promise of minocycline in neurology. Lancet Neurol 3:744–751

    PubMed  Google Scholar 

  2. Garrido-Mesa N, Zarzuelo A, Gálvez J (2013) Minocycline: far beyond an antibiotic. Br J Pharmacol 169:337–352

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sato K (2015) Effects of microglia on neurogenesis. Glia 63:1394–1405

    PubMed  PubMed Central  Google Scholar 

  4. Möller T, Bard F, Bhattacharya A, Biber K, Campbell B, Dale E, Eder C, Gan L, Garden GA, Hughes ZA, Pearse DD, Staal RG, Sayed FA, Wes PD, Boddeke HW (2016) Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64:1788–1794

    PubMed  Google Scholar 

  5. Temple S (2001) The development of neural stem cells. Nature 414:112–117

    CAS  PubMed  Google Scholar 

  6. Naruse M, Ishizaki Y, Ikenaka K, Tanaka A, Hitoshi S (2017) Origin of oligodendrocytes in mammalian forebrains: a revised perspective. J Physiol Sci 67:63–70

    CAS  PubMed  Google Scholar 

  7. Seaberg RM, van der Kooy D (2002) Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22:1784–1793

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7:a018812

    PubMed  PubMed Central  Google Scholar 

  9. Klempin F, Kempermann G (2007) Adult hippocampal neurogenesis and aging. Eur Arch Psychiatry Clin Neurosci 257:271–280

    PubMed  Google Scholar 

  10. Schoenfeld TJ, Gould E (2012) Stress, stress hormones, and adult neurogenesis. Exp Neurol 233:12–21

    CAS  PubMed  Google Scholar 

  11. Jacobs BL (2002) Adult brain neurogenesis and depression. Brain Behav Immun 16:602–609

    CAS  PubMed  Google Scholar 

  12. Malberg JE (2004) Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci 29:196–205

    PubMed  PubMed Central  Google Scholar 

  13. Hitoshi S, Maruta N, Higashi M, Kumar A, Kato N, Ikenaka K (2007) Antidepressant drugs reverse the loss of adult neural stem cells following chronic stress. J Neurosci Res 85:3574–3585

    CAS  PubMed  Google Scholar 

  14. Higashi M, Maruta N, Bernstein A, Ikenaka K, Hitoshi S (2008) Mood stabilizing drugs expand the neural stem cell pool in the adult brain through activation of notch signaling. Stem Cells 26:1758–1767

    CAS  PubMed  Google Scholar 

  15. Zheng L-S, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S, Ikenaka K, Sawamoto K (2014) Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. Stem Cell Rep 3:73–84

    CAS  Google Scholar 

  16. Zheng L-S, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha-induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:5

    PubMed  PubMed Central  Google Scholar 

  17. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    CAS  PubMed  Google Scholar 

  18. Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hitoshi S, Seaberg RM, Koscik C, Alexson T, Kusunoki S, Kanazawa I, Tsuji S, van der Kooy D (2004) Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling. Genes Dev 18:1806–1811

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Shi P, Grobe JL, Desland FA, Zhou G, Shen XZ, Shan Z, Liu M, Raizada MK, Sumners C (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS ONE 9:e92937

    PubMed  PubMed Central  Google Scholar 

  21. Shibata K, Hanai T, Kato T, Ito T, Fujii M (1969) Laboratory and clinical studies on minocycline in the surgical field. Jpn J Antibiot 22:458–462

    CAS  PubMed  Google Scholar 

  22. Nakamura Y, Sakakibara S-i, Miyata T, Ogawa M, Shimazaki T, Weiss S, Kageyama R, Okano H (2000) The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. J Neurosci 20:283–293

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chojnacki A, Shimazaki T, Gregg C, Weinmaster G, Weiss S (2003) Glycoprotein 130 signaling regulates Notch1 expression and activation in the self-renewal of mammalian forebrain neural stem cells. J Neurosci 23:1730–1741

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hirota Y, Sawada M, Huang SH, Ogino T, Ohata S, Kubo A, Sawamoto K (2016) Roles of Wnt signaling in the neurogenic niche of the adult mouse ventricular-subventricular zone. Neurochem Res 41:222–230

    CAS  PubMed  Google Scholar 

  25. Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel auqporin-1. FASEB J 19:76–78

    CAS  PubMed  Google Scholar 

  26. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774

    PubMed  Google Scholar 

  27. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 98:14669–14674

    CAS  PubMed  Google Scholar 

  28. Keller AF, Gravel M, Kriz J (2011) Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice. Exp Neurol 228:69–79

    CAS  PubMed  Google Scholar 

  29. Barza M, Brown RB, Shanks C, Gamble C, Weinstein L (1975) Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother 8:713–720

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Naruse M, Ishino Y, Kumar A, Ono K, Takebayashi H, Yamaguchi M, Ishizaki Y, Ikenaka K, Hitoshi S (2016) The dorsoventral boundary of the germinal zone is a specialized niche for the generation of cortical oligodendrocytes during a restricted temporal window. Cereb Cortex 26:2800–2810

    PubMed  Google Scholar 

  31. Martens DJ, Tropepe V, van der Kooy D (2000) Separate proliferation kinetics of fibroblast growth factor-responsive and epidermal growth factor-responsive neural stem cells within the embryonic forebrain germinal zone. J Neurosci 20:1085–1095

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082

    CAS  PubMed  Google Scholar 

  33. Sanosaka T, Imamura T, Hamazaki N, Chai M, Igarashi K, Ideta-Otsuka M, Miura F, Ito T, Fujii N, Ikeo K, Nakashima K (2017) DNA methylome analysis identifies transcription factor-based epigenomic signatures of multilineage competence in neural stem/progenitor cells. Cell Rep 20:2992–3003

    CAS  PubMed  Google Scholar 

  34. Sakata H, Niizuma K, Yoshioka H, Kim GS, Jung JE, Katsu M, Narasimhan P, Maier CM, Nishiyama Y, Chan PH (2012) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32:3462–3473

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rueger MA, Muesken S, Walberer M, Jantzen SU, Schnakenburg K, Backes H, Graf R, Neumaier B, Hoehn M, Fink GR, Schroeter M (2012) Effects of minocycline on endogenous neural stem cells after experimental stroke. Neuroscience 215:174–183

    CAS  PubMed  Google Scholar 

  36. Liu X, Su H, Chu TH, Guo A, Wu W (2013) Minocycline inhibited the pro-apoptotic effect of microglia on neural progenitor cells and protected their neuronal differentiation in vitro. Neurosci Lett 542:30–36

    CAS  PubMed  Google Scholar 

  37. Agwuh KN, MacGowan A (2006) Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother 58:256–265

    CAS  PubMed  Google Scholar 

  38. Zhang Q, Wu HH, Wang Y, Gu GJ, Zhang W, Xia R (2016) Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer’s disease. J Neurochem 136:815–825

    CAS  PubMed  Google Scholar 

  39. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125:1297–1308

    PubMed  Google Scholar 

  40. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–223

    CAS  PubMed  Google Scholar 

  41. Rasmussen S, Imitola J, Ayuso-Sacido A, Wang Y, Starossom SC, Kivisäkk P, Zhu B, Meyer M, Bronson RT, Garcia-Verdugo JM, Khoury SJ (2011) Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol 69:878–891

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand’Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team (2017) Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 376:2122–2133

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Ono for O4 antibody, N. Kaneko and K. Sawamoto for discussion, and M. Mori and M. Tomoeda for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (B) (16H04671) and for challenging Exploratory Research (16K14578) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S. H.).

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Authors and Affiliations

  1. Department of Integrative Physiology, Shiga University of Medical Science, Otsu, 520-2192, Japan

    Anri Kuroda, Takahiro Fuchigami, Satoshi Fuke, Natsu Koyama & Seiji Hitoshi

  2. Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan

    Kazuhiro Ikenaka & Seiji Hitoshi

  3. Department of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies, Okazaki, 444-8787, Japan

    Kazuhiro Ikenaka & Seiji Hitoshi

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  1. Anri Kuroda
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  2. Takahiro Fuchigami
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  5. Kazuhiro Ikenaka
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Correspondence to Seiji Hitoshi.

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Kuroda, A., Fuchigami, T., Fuke, S. et al. Minocycline Directly Enhances the Self-Renewal of Adult Neural Precursor Cells. Neurochem Res 43, 219–226 (2018). https://doi.org/10.1007/s11064-017-2422-6

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  • DOI: https://doi.org/10.1007/s11064-017-2422-6

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