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Modulating Microglial Activation As a Possible Therapeutic Target for Depression

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Understanding Depression

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Abstract

Microglia have recently been highlighted to understand the pathophysiology of various psychiatric disorders including depression. In this brief review article, we have shown up-to-date knowledge about the effects of psychotropic drugs, especially aripiprazole, on microglial modulation and the relationship between microglia and neurotransmitters such as serotonin and noradrenaline, to understand the cross talk between microglia and neuronal systems. Finally, we have introduced a novel translational research tool, induced microglia-like (iMG) cells from human peripheral blood (monocytes). Further translational studies combining human tissue studies and animal experiences are needed to dig up the microglial roles in the underlying biological mechanisms of depression and other psychiatric disorders.

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References

  • Acarin L, Peluffo H, Gonzalez B, Castellano B. Expression of inducible nitric oxide synthase and cyclooxygenase-2 after excitotoxic damage to the immature rat brain. J Neurosci Res. 2002;68(6):745–54.

    Article  CAS  Google Scholar 

  • Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci. 2009;34(1):4–20.

    PubMed  PubMed Central  Google Scholar 

  • Baptiste DC, Fehlings MG. Pharmacological approaches to repair the injured spinal cord. J Neurotrauma. 2006;23(3–4):318–34.

    Article  Google Scholar 

  • Bartels AL, Leenders KL. Cyclooxygenase and neuroinflammation in Parkinson’s disease neurodegeneration. Curr Neuropharmacol. 2010;8(1):62–8.

    Article  CAS  Google Scholar 

  • Bian Q, Kato T, Monji A, Hashioka S, Mizoguchi Y, Horikawa H, Kanba S. The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32(1):42–8.

    Article  CAS  Google Scholar 

  • Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883–97.

    Article  CAS  Google Scholar 

  • Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26(9):1185–93.

    Article  Google Scholar 

  • Chijiwa T, Oka T, Lkhagvasuren B, Yoshihara K, Sudo N. Prior chronic stress induces persistent polyI:C-induced allodynia and depressive-like behavior in rats: possible involvement of glucocorticoids and microglia. Physiol Behav. 2015;147:264–73.

    Article  CAS  Google Scholar 

  • Choi SH, Joe EH, Kim SU, Jin BK. Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. J Neurosci. 2003;23(13):5877–86.

    Article  CAS  Google Scholar 

  • Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L, TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    Article  CAS  Google Scholar 

  • Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113(504):1237–64.

    Article  CAS  Google Scholar 

  • De Simone R, Ajmone-Cat MA, Minghetti L. Atypical antiinflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol Neurobiol. 2004;29(2):197–212.

    Article  Google Scholar 

  • Dean OM, Data-Franco J, Giorlando F, Berk M. Minocycline: therapeutic potential in psychiatry. CNS Drugs. 2012;26(5):391–401.

    Article  CAS  Google Scholar 

  • Dello Russo C, Boullerne AI, Gavrilyuk V, Feinstein DL. Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production. J Neuroinflammation. 2004;1(1):9.

    Article  Google Scholar 

  • di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, Mauro G, De Lucia C, Battaglia G, Bruno V, Fabene PF, Nicoletti F. Antidepressant activity of fingolimod in mice. Pharmacol Res Perspect. 2015;3(3):e00135.

    Article  Google Scholar 

  • Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–57.

    Article  CAS  Google Scholar 

  • Eyre HA, Air T, Proctor S, Rositano S, Baune BT. A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2015;57:11–6.

    Article  CAS  Google Scholar 

  • Farmer P, Pugin J. Beta-adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells through the IkappaB/NF-kappaB pathway. Am J Physiol Lung Cell Mol Physiol. 2000;279(4):L675–82.

    Article  CAS  Google Scholar 

  • Gilbert DF, Stebbing MJ, Kuenzel K, Murphy RM, Zacharewicz E, Buttgereit A, Stokes L, Adams DJ, Friedrich O. Store-operated Ca2+ entry (SOCE) and Purinergic receptor-mediated Ca2+ homeostasis in murine bv2 microglia cells: early cellular responses to ATP-mediated microglia activation. Front Mol Neurosci. 2016;9:111.

    Article  Google Scholar 

  • Glebov K, Lochner M, Jabs R, Lau T, Merkel O, Schloss P, Steinhauser C, Walter J. Serotonin stimulates secretion of exosomes from microglia cells. Glia. 2015;63(4):626–34.

    Article  Google Scholar 

  • Gyoneva S, Traynelis SF. Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J Biol Chem. 2013;288(21):15291–302.

    Article  CAS  Google Scholar 

  • Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL, Kanba S. Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol. 2007;206(1):33–42.

    Article  CAS  Google Scholar 

  • Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15.

    Article  Google Scholar 

  • Hinwood M, Morandini J, Day TA, Walker FR. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex. 2012;22(6):1442–54.

    Article  CAS  Google Scholar 

  • Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR. Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex. 2013;23(8):1784–97.

    Article  Google Scholar 

  • Horikawa H, Kato TA, Mizoguchi Y, Monji A, Seki Y, Ohkuri T, Gotoh L, Yonaha M, Ueda T, Hashioka S, Kanba S. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog Neuro-Psychopharmacol Biol Psychiatry. 2010;34(7):1306–16.

    Article  CAS  Google Scholar 

  • Hurlock EC. Interferons: potential roles in affect. Med Hypotheses. 2001;56(5):558–66.

    Article  CAS  Google Scholar 

  • Hwang J, Zheng LT, Ock J, Lee MG, Kim SH, Lee HW, Lee WH, Park HC, Suk K. Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants. Neuropharmacology. 2008;55(5):826–34.

    Article  CAS  Google Scholar 

  • Ishii Y, Yamaizumi A, Kawakami A, Islam A, Choudhury ME, Takahashi H, Yano H, Tanaka J. Anti-inflammatory effects of noradrenaline on LPS-treated microglial cells: suppression of NFkappaB nuclear translocation and subsequent STAT1 phosphorylation. Neurochem Int. 2015;90:56–66.

    Article  CAS  Google Scholar 

  • Jiang L, Chen SH, Chu CH, Wang SJ, Oyarzabal E, Wilson B, Sanders V, Xie K, Wang Q, Hong JS. A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis. Glia. 2015;63(6):1057–72.

    Article  Google Scholar 

  • Kaizaki A, Tien LT, Pang Y, Cai Z, Tanaka S, Numazawa S, Bhatt AJ, Fan LW. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. J Neuroinflammation. 2013;10:45.

    Article  CAS  Google Scholar 

  • Kamijima K, Higuchi T, Ishigooka J, Ohmori T, Ozaki N, Kanba S, Kinoshita T, Koyama T, ADMIRE Study Group. Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: a randomized, double-blind, placebo-controlled study (ADMIRE study). J Affect Disord. 2013;151(3):899–905.

    Article  CAS  Google Scholar 

  • Kato TA, Hayakawa K, Monji A, Kanba S. Missing and possible link between neuroendocrine factors, neuropsychiatric disorders, and microglia. Front Integr Neurosci. 2013a;7:53.

    Article  Google Scholar 

  • Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y, Iwaki T, Hashioka S, Kanba S. Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro. J Neurochem. 2008;106(2):815–25.

    Article  CAS  Google Scholar 

  • Kato T, Monji A, Hashioka S, Kanba S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res. 2007;92(1–3):108–15.

    Article  Google Scholar 

  • Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, Kasai M, Utsumi H, Kanba S. Anti-inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a ‘fire extinguisher’ in the brain of schizophrenia? Mini Rev Med Chem. 2011a;11(7):565–74.

    Article  CAS  Google Scholar 

  • Kato TA, Monji A, Yasukawa K, Mizoguchi Y, Horikawa H, Seki Y, Hashioka S, Han YH, Kasai M, Sonoda N, Hirata E, Maeda Y, Inoguchi T, Utsumi H, Kanba S. Aripiprazole inhibits superoxide generation from phorbol-myristate-acetate (PMA)-stimulated microglia in vitro: implication for antioxidative psychotropic actions via microglia. Schizophr Res. 2011b;129(2–3):172–82.

    Article  Google Scholar 

  • Kato TA, Watabe M, Kanba S. Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry. Front Psych. 2013b;4:139.

    Google Scholar 

  • Kato TA, Watabe M, Tsuboi S, Ishikawa K, Hashiya K, Monji A, Utsumi H, Kanba S. Minocycline modulates human social decision-making: possible impact of microglia on personality-oriented social behaviors. PLoS One. 2012;7(7):e40461.

    Article  CAS  Google Scholar 

  • Kato TA, Yamauchi Y, Horikawa H, Monji A, Mizoguchi Y, Seki Y, Hayakawa K, Utsumi H, Kanba S. Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry. Curr Med Chem. 2013c;20(3):331–44.

    CAS  PubMed  Google Scholar 

  • Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–27.

    Article  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91(2):461–553.

    Article  CAS  Google Scholar 

  • Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res. 2009;196(2):168–79.

    Article  CAS  Google Scholar 

  • Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiat. 2014;71(12):1381–91.

    Article  Google Scholar 

  • Kohler-Forsberg O, Buttenschon HN, Tansey KE, Maier W, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, Rietschel M, McGuffin P, Aitchison KJ, Uher R, Mors O. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav Immun. 2017;62:344–50.

    Article  CAS  Google Scholar 

  • Kolodziejczak M, Bechade C, Gervasi N, Irinopoulou T, Banas SM, Cordier C, Rebsam A, Roumier A, Maroteaux L. Serotonin modulates developmental microglia via 5-HT2B receptors: potential implication during synaptic refinement of retinogeniculate projections. ACS Chem Neurosci. 2015;6(7):1219–30.

    Article  CAS  Google Scholar 

  • Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HW, Kettenmann H. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun. 2012;26(3):419–28.

    Article  CAS  Google Scholar 

  • Lee CH, Park JH, Yoo KY, Choi JH, Hwang IK, Ryu PD, Kim DH, Kwon YG, Kim YM, Won MH. Pre- and post-treatments with escitalopram protect against experimental ischemic neuronal damage via regulation of BDNF expression and oxidative stress. Exp Neurol. 2011;229(2):450–9.

    Article  CAS  Google Scholar 

  • Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A. Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology. 2011;61(4):592–9.

    Article  CAS  Google Scholar 

  • Madrigal JL, Feinstein DL, Dello Russo C. Norepinephrine protects cortical neurons against microglial-induced cell death. J Neurosci Res. 2005;81(3):390–6.

    Article  CAS  Google Scholar 

  • Markus T, Hansson SR, Cronberg T, Cilio C, Wieloch T, Ley D. Beta-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices. J Neuroinflammation. 2010;7:94.

    Article  CAS  Google Scholar 

  • Marrie RA, Reingold S, Cohen J, Stuve O, Trojano M, Sorensen PS, Cutter G, Reider N. The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review. Mult Scler. 2015;21(3):305–17.

    Article  Google Scholar 

  • McNamee EN, Griffin EW, Ryan KM, Ryan KJ, Heffernan S, Harkin A, Connor TJ. Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. Neuropharmacology. 2010;59(1-2):37–48.

    Article  CAS  Google Scholar 

  • Meltzer HY, Massey BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol. 2011;11(1):59–67.

    Article  CAS  Google Scholar 

  • Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol. 2004;63(9):901–10.

    Article  CAS  Google Scholar 

  • Miyaoka T, Wake R, Furuya M, Liaury K, Ieda M, Kawakami K, Tsuchie K, Taki M, Ishihara K, Araki T, Horiguchi J. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;37(2):222–6.

    Article  CAS  Google Scholar 

  • Monji A, Kato T, Kanba S. Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63(3):257–65.

    Article  CAS  Google Scholar 

  • Monji A, Kato TA, Mizoguchi Y, Horikawa H, Seki Y, Kasai M, Yamauchi Y, Yamada S, Kanba S. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:115–21.

    Article  CAS  Google Scholar 

  • Mori K, Ozaki E, Zhang B, Yang L, Yokoyama A, Takeda I, Maeda N, Sakanaka M, Tanaka J. Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. Neuropharmacology. 2002;43(6):1026–34.

    Article  CAS  Google Scholar 

  • Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005;1044(1):8–15.

    Article  CAS  Google Scholar 

  • Muller N. The role of anti-inflammatory treatment in psychiatric disorders. Psychiatr Danub. 2013;25(3):292–8.

    PubMed  Google Scholar 

  • Muller N. Immunology of major depression. Neuroimmunomodulation. 2014;21(2-3):123–30.

    Article  Google Scholar 

  • Myint AM, Bondy B, Baghai TC, Eser D, Nothdurfter C, Schule C, Zill P, Muller N, Rupprecht R, Schwarz MJ. Tryptophan metabolism and immunogenetics in major depression: a role for interferon-gamma gene. Brain Behav Immun. 2013;31:128–33.

    Article  CAS  Google Scholar 

  • Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, Correll CU. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39(6):1230–41.

    Article  Google Scholar 

  • Ohgidani M, Kato TA, Haraguchi Y, Matsushima T, Mizoguchi Y, Murakawa-Hirachi T, Sagata N, Monji A, Kanba S. Microglial CD206 gene has potential as a state marker of bipolar disorder. Front Immunol. 2017;7:676.

    Article  Google Scholar 

  • Ohgidani M, Kato TA, Kanba S. Introducing directly induced microglia-like (iMG) cells from fresh human monocytes: a novel translational research tool for psychiatric disorders. Front Cell Neurosci. 2015;9:184.

    Article  Google Scholar 

  • Ohgidani M, Kato TA, Sagata N, Hayakawa K, Shimokawa N, Sato-Kasai M, Kanba S. TNF-alpha from hippocampal microglia induces working memory deficits by acute stress in mice. Brain Behav Immun. 2016;55:17–24.

    Article  CAS  Google Scholar 

  • Ohgidani M, Kato TA, Setoyama D, Sagata N, Hashimoto R, Shigenobu K, Yoshida T, Hayakawa K, Shimokawa N, Miura D, Utsumi H, Kanba S. Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci Rep. 2014;4:4957.

    Article  CAS  Google Scholar 

  • Piontkewitz Y, Assaf Y, Weiner I. Clozapine administration in adolescence prevents postpubertal emergence of brain structural pathology in an animal model of schizophrenia. Biol Psychiatry. 2009;66(11):1038–46.

    Article  CAS  Google Scholar 

  • Qian L, Hu X, Zhang D, Snyder A, Wu HM, Li Y, Wilson B, Lu RB, Hong JS, Flood PM. Beta2 adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway. Glia. 2009;57(15):1600–9.

    Article  Google Scholar 

  • Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiat. 2013;70(1):31–41.

    Article  CAS  Google Scholar 

  • Ramirez K, Sheridan JF. Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like behaviors. Brain Behav Immun. 2016;57:293–303.

    Article  CAS  Google Scholar 

  • Rossetti AC, Papp M, Gruca P, Paladini MS, Racagni G, Riva MA, Molteni R. Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: restorative effect of pharmacological intervention. Pharmacol Res. 2016;103:1–12.

    Article  CAS  Google Scholar 

  • Sato-Kasai M, Kato TA, Ohgidani M, Mizoguchi Y, Sagata N, Inamine S, Horikawa H, Hayakawa K, Shimokawa N, Kyuragi S, Seki Y, Monji A, Kanba S. Aripiprazole inhibits polyI:C-induced microglial activation possibly via TRPM7. Schizophr Res. 2016;178(1–3):35–43.

    Article  Google Scholar 

  • Schwarz MJ, Chiang S, Muller N, Ackenheil M. T-helper-1 and T-helper-2 responses in psychiatric disorders. Brain Behav Immun. 2001;15(4):340–70.

    Article  CAS  Google Scholar 

  • Seki Y, Kato TA, Monji A, Mizoguchi Y, Horikawa H, Sato-Kasai M, Yoshiga D, Kanba S. Pretreatment of aripiprazole and minocycline, but not haloperidol, suppresses oligodendrocyte damage from interferon-gamma-stimulated microglia in co-culture model. Schizophr Res. 2013;151(1–3):20–8.

    Article  Google Scholar 

  • Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL, Rekkas PV, Houle S, Meyer JH. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiat. 2015;72(3):268–75.

    Article  Google Scholar 

  • Setoyama D, Kato TA, Hashimoto R, Kunugi H, Hattori K, Hayakawa K, Sato-Kasai M, Shimokawa N, Kaneko S, Yoshida S, Goto YI, Yasuda Y, Yamamori H, Ohgidani M, Sagata N, Miura D, Kang D, Kanba S. Plasma metabolites predict severity of depression and suicidal ideation in psychiatric patients-a Multicenter pilot analysis. PLoS One. 2016;11(12):e0165267.

    Article  Google Scholar 

  • Soczynska JK, Mansur RB, Brietzke E, Swardfager W, Kennedy SH, Woldeyohannes HO, Powell AM, Manierka MS, McIntyre RS. Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res. 2012;235(2):302–17.

    Article  CAS  Google Scholar 

  • Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414–9.

    Article  CAS  Google Scholar 

  • Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42(2):151–7.

    Article  Google Scholar 

  • Steiner J, Gos T, Bogerts B, Bielau H, Drexhage HA, Bernstein HG. Possible impact of microglial cells and the monocyte-macrophage system on suicidal behavior. CNS Neurol Disord Drug Targets. 2013;12(7):971–9.

    Article  CAS  Google Scholar 

  • Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol. 2006;112(3):305–16.

    Article  CAS  Google Scholar 

  • Tynan RJ, Naicker S, Hinwood M, Nalivaiko E, Buller KM, Pow DV, Day TA, Walker FR. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun. 2010;24(7):1058–68.

    Article  CAS  Google Scholar 

  • Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012;26(3):469–79.

    Article  CAS  Google Scholar 

  • Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97–120.

    Article  CAS  Google Scholar 

  • Walker FR, Nilsson M, Jones K. Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr Drug Targets. 2013;14(11):1262–76.

    Article  CAS  Google Scholar 

  • Watabe M, Kato TA, Monji A, Horikawa H, Kanba S. Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction? Psychopharmacology. 2012;220(3):551–7.

    Article  CAS  Google Scholar 

  • Watabe M, Kato TA, Tsuboi S, Ishikawa K, Hashiya K, Monji A, Utsumi H, Kanba S. Minocycline, a microglial inhibitor, reduces ‘honey trap’ risk in human economic exchange. Sci Rep. 2013;3:1685.

    Article  Google Scholar 

  • Weber J, Lyseng-Williamson KA, Scott LJ. Aripiprazole: in major depressive disorder. CNS Drugs. 2008;22(10):807–13.

    Article  CAS  Google Scholar 

  • Xiang YQ, Zheng W, Wang SB, Yang XH, Cai DB, Ng CH, Ungvari GS, Kelly DL, Xu WY, Xiang YT. Adjunctive minocycline for schizophrenia: a meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2017;27(1):8–18.

    Article  CAS  Google Scholar 

  • Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A. 1998;95(26):15769–74.

    Article  CAS  Google Scholar 

  • Zheng LS, Kaneko N, Sawamoto K. Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci. 2015;9:5.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported in part by Grant-in-Aid for Scientific Research on (1) the Japan Agency for Medical Research and Development (AMED) (Yugo-No to T.A.K. & Syogaisya-Taisaku-Sogo-Kenkyu-Kaihatsu-Jigyo to S.K.), (2) Japan Society for the Promotion of Science—KAKENHI (Grant-in-Aid 26713039 for Young Scientists (A) to T.A.K., Grant-in-Aid 26860933 for Young Scientists (B) to M.O.), (3) Innovative Areas of The Ministry of Education, Culture, Sports, Science, and Technology, Japan (“Will Dynamics” 16H06403 to T.A.K. & “Glia Assembly” 25117011 to S.K.), (4) Young Principal Investigators’ Research Grant of Innovation Center for Medical Redox Navigation, Kyushu University (to T.A.K.), (5) Takeda Medical Research Foundation (to TAK), and (6) SENSHIN Medical Research Foundation (to T.A.K., M.O. & S.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors report no financial relationships with commercial interests.

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Authors and Affiliations

  1. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Mina Sato-Kasai, Takahiro A. Kato, Masahiro Ohgidani, Hideki Horikawa & Shigenobu Kanba

  2. Department of Psychiatry, Graduate School of Medical Sciences, Saga University, Saga, Japan

    Yoshito Mizoguchi & Akira Monji

Authors
  1. Mina Sato-Kasai
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  2. Takahiro A. Kato
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  3. Masahiro Ohgidani
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Correspondence to Takahiro A. Kato .

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  1. College of Medicine, Korea University, Kyonggi-do, Korea (Republic of)

    Yong-Ku Kim

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Sato-Kasai, M. et al. (2018). Modulating Microglial Activation As a Possible Therapeutic Target for Depression. In: Kim, YK. (eds) Understanding Depression . Springer, Singapore. https://doi.org/10.1007/978-981-10-6580-4_18

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