Acknowledgement
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2020R1A2C1009484, MRC-2017R1A5A2015541).
References
- Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232-260. https://doi.org/10.1128/MMBR.65.2.232-260.2001
- Saleha T, Syed Faheem AR, Ummar A. Tetracycline: classification, structure activity relationship and mechanism of action as a theranostic agent for infectious lesions-a mini review. Biomed J Sci Tech Res 2018;7:5787-5796.
- Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004;3:744-751. https://doi.org/10.1016/S1474-4422(04)00937-8
- Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009;196:168-179. https://doi.org/10.1016/j.bbr.2008.09.040
- Santa-Cecilia FV, Leite CA, Del-Bel E, Raisman-Vozari R. The neuroprotective effect of doxycycline on neurodegenerative diseases. Neurotox Res 2019;35:981-986. https://doi.org/10.1007/s12640-019-00015-z
- Bahrami F, Morris DL, Pourgholami MH. Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem 2012;12:44-52. https://doi.org/10.2174/138955712798868977
- Garrido-Mesa N, Zarzuelo A, Galvez J. What is behind the non-antibiotic properties of minocycline? Pharmacol Res 2013;67:18-30. https://doi.org/10.1016/j.phrs.2012.10.006
- Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti-inflammatory agent: updates in dermatology. J Eur Acad Dermatol Venereol 2017;31:1800-1808. https://doi.org/10.1111/jdv.14345
- Ali I, Alfarouk KO, Reshkin SJ, Ibrahim ME. Doxycycline as potential anti-cancer agent. Anticancer Agents Med Chem 2017;17:1617-1623.
- Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol 2005;78:135-143. https://doi.org/10.1189/jlb.0804477
- Leite LM, Carvalho AG, Ferreira PL, Pessoa IX, Goncalves DO, Lopes Ade A, Goes JG, Alves VC, Leal LK, Brito GA, et al. Anti-inflammatory properties of doxycycline and minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmacology 2011;19:99-110. https://doi.org/10.1007/s10787-011-0077-5
- Ataie-Kachoie P, Morris DL, Pourgholami MH. Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies. PLoS One 2013;8:e60817.
- Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci 2006;7:56.
- Hahn JN, Kaushik DK, Mishra MK, Wang J, Silva C, Yong VW. Impact of minocycline on extracellular matrix metalloproteinase inducer, a factor implicated in multiple sclerosis immunopathogenesis. J Immunol 2016;197:3850-3860. https://doi.org/10.4049/jimmunol.1600436
- Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/ betaII. J Biol Chem 2007;282:15208-15216. https://doi.org/10.1074/jbc.M611907200
- Kloppenburg M, Brinkman BM, de Rooij-Dijk HH, Miltenburg AM, Daha MR, Breedveld FC, Dijkmans BA, Verweij C. The tetracycline derivative minocycline differentially affects cytokine production by monocytes and T lymphocytes. Antimicrob Agents Chemother 1996;40:934-940. https://doi.org/10.1128/AAC.40.4.934
- Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215-223. https://doi.org/10.1002/ana.10092
- Kim N, Park CS, Im SA, Kim JW, Lee JH, Park YJ, Song S, Lee CK. Minocycline promotes the generation of dendritic cells with regulatory properties. Oncotarget 2016;7:52818-52831. https://doi.org/10.18632/oncotarget.10810
- Lee JH, Park CS, Jang S, Kim JW, Kim SH, Song S, Kim K, Lee CK. Tolerogenic dendritic cells are efficiently generated using minocycline and dexamethasone. Sci Rep 2017;7:15087.
- Thong YH, Ferrante A. Effect of tetracycline treatment on immunological responses in mice. Clin Exp Immunol 1980;39:728-732.
- Ingham E, Turnbull L, Kearney JN. The effects of minocycline and tetracycline on the mitotic response of human peripheral blood-lymphocytes. J Antimicrob Chemother 1991;27:607-617. https://doi.org/10.1093/jac/27.5.607
- Kloppenburg M, Verweij CL, Miltenburg AM, Verhoeven AJ, Daha MR, Dijkmans BA, Breedveld FC. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995;102:635-641. https://doi.org/10.1111/j.1365-2249.1995.tb03864.x
- Szeto GL, Pomerantz JL, Graham DR, Clements JE. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem 2011;286:11275-11282. https://doi.org/10.1074/jbc.M110.210518
- Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to human T cells: additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol 2004;113:270-277. https://doi.org/10.1016/j.clim.2004.07.012
- Clark WM, Lessov N, Lauten JD, Hazel K. Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat. J Mol Neurosci 1997;9:103-108. https://doi.org/10.1007/BF02736854
- 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 USA 1998;95:15769-15774. https://doi.org/10.1073/pnas.95.26.15769
- Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297-1308. https://doi.org/10.1093/brain/awf133
- He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 2001;909:187-193. https://doi.org/10.1016/S0006-8993(01)02681-6
- Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763-1771. https://doi.org/10.1523/JNEUROSCI.22-05-01763.2002
- Mei XP, Xu H, Xie C, Ren J, Zhou Y, Zhang H, Xu LX. Post-injury administration of minocycline: an effective treatment for nerve-injury induced neuropathic pain. Neurosci Res 2011;70:305-312. https://doi.org/10.1016/j.neures.2011.03.012
- Kielian T, Esen N, Liu S, Phulwani NK, Syed MM, Phillips N, Nishina K, Cheung AL, Schwartzman JD, Ruhe JJ. Minocycline modulates neuroinflammation independently of its antimicrobial activity in Staphylococcus aureus-induced brain abscess. Am J Pathol 2007;171:1199-1214. https://doi.org/10.2353/ajpath.2007.070231
- Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 2001;21:2580-2588. https://doi.org/10.1523/JNEUROSCI.21-08-02580.2001
- Cazalis J, Bodet C, Gagnon G, Grenier D. Doxycycline reduces lipopolysaccharide-induced inflammatory mediator secretion in macrophage and ex vivo human whole blood models. J Periodontol 2008;79:1762-1768. https://doi.org/10.1902/jop.2008.080051
- Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agent. Neuroscientist 2005;11:308-322. https://doi.org/10.1177/1073858405275175
- Bernardino AL, Kaushal D, Philipp MT. The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. J Infect Dis 2009;199:1379-1388. https://doi.org/10.1086/597807
- Jantzie LL, Todd KG. Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia-ischemia in neonatal rats. J Psychiatry Neurosci 2010;35:20-32. https://doi.org/10.1503/jpn.090061
- Patel A, Khande H, Periasamy H, Mokale S. Immunomodulatory effect of doxycycline ameliorates systemic and pulmonary inflammation in a murine polymicrobial sepsis model. Inflammation 2020;43:1035-1043. https://doi.org/10.1007/s10753-020-01188-y
- Castro JE, Vado-Solis I, Perez-Osorio C, Fredeking TM. Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever. Clin Dev Immunol 2011;2011:370872.
- Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, Kaplan R, Ramamurthy NS. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res 1983;18:516-526. https://doi.org/10.1111/j.1600-0765.1983.tb00388.x
- Golub LM, Evans RT, McNamara TF, Lee HM, Ramamurthy NS. A non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone loss in Porphyromonas gingivalis-induced periodontitis in rats. Ann N Y Acad Sci 1994;732:96-111. https://doi.org/10.1111/j.1749-6632.1994.tb24728.x
- Smith GN Jr, Mickler EA, Hasty KA, Brandt KD. Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme. Arthritis Rheum 1999;42:1140-1146. https://doi.org/10.1002/1529-0131(199906)42:6<1140::AID-ANR10>3.0.CO;2-7
- Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 2018;81:241-330. https://doi.org/10.1016/bs.apha.2017.08.002
- Kim YS, Joh TH. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol Ther (Seoul) 2012;20:133-143. https://doi.org/10.4062/biomolther.2012.20.2.133
- Baugh MD, Perry MJ, Hollander AP, Davies DR, Cross SS, Lobo AJ, Taylor CJ, Evans GS. Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 1999;117:814-822. https://doi.org/10.1016/S0016-5085(99)70339-2
- Niimi N, Kohyama K, Matsumoto Y. Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases. Neuropathology 2013;33:612-620. https://doi.org/10.1111/neup.12039
- Schmidt HH, Walter U. NO at work. Cell 1994;78:919-925. https://doi.org/10.1016/0092-8674(94)90267-4
- Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 1995;96:2357-2363. https://doi.org/10.1172/JCI118292
- Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A 1996;93:14014-14019. https://doi.org/10.1073/pnas.93.24.14014
- D'Agostino P, Arcoleo F, Barbera C, Di Bella G, La Rosa M, Misiano G, Milano S, Brai M, Cammarata G, Feo S, et al. Tetracycline inhibits the nitric oxide synthase activity induced by endotoxin in cultured murine macrophages. Eur J Pharmacol 1998;346:283-290. https://doi.org/10.1016/S0014-2999(98)00046-6
- Huang TY, Chu HC, Lin YL, Lin CK, Hsieh TY, Chang WK, Chao YC, Liao CL. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases. Toxicol Appl Pharmacol 2009;237:69-82. https://doi.org/10.1016/j.taap.2009.02.026
- Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44:1165-1170. https://doi.org/10.1016/0006-2952(92)90381-R
- Dalm D, Palm GJ, Aleksandrov A, Simonson T, Hinrichs W. Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2. J Mol Biol 2010;398:83-96. https://doi.org/10.1016/j.jmb.2010.02.049
- Hsieh CT, Lee YJ, Dai X, Ojeda NB, Lee HJ, Tien LT, Fan LW. Systemic lipopolysaccharide-induced pain sensitivity and spinal inflammation were reduced by minocycline in neonatal rats. Int J Mol Sci 2018;19:2947.
- Attur MG, Patel RN, Patel PD, Abramson SB, Amin AR. Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol 1999;162:3160-3167. https://doi.org/10.4049/jimmunol.162.6.3160
- Metz LM, Li D, Traboulsee A, Myles ML, Duquette P, Godin J, Constantin M, Yong VWGA/minocycline study investigators. Glatiramer acetate in combination with minocycline in patients with relapsing-- remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler 2009;15:1183-1194. https://doi.org/10.1177/1352458509106779
- Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017;376:2122-2133. https://doi.org/10.1056/NEJMoa1608889
- Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol 2008;65:199-204. https://doi.org/10.1001/archneurol.2007.41
- Mazdeh M, Mobaien AR. Efficacy of doxycycline as add-on to interferon beta-1a in treatment of multiple sclerosis. Iran J Neurol 2012;11:70-73.
- Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BA. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1994;37:629-636. https://doi.org/10.1002/art.1780370505
- O'Dell JR, Blakely KW, Mallek JA, Eckhoff PJ, Leff RD, Wees SJ, Sems KM, Fernandez AM, Palmer WR, Klassen LW, et al. Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 2001;44:2235-2241. https://doi.org/10.1002/1529-0131(200110)44:10<2235::AID-ART385>3.0.CO;2-A
- Snijders GF, van den Ende CH, van Riel PL, van den Hoogen FH, den Broeder AANOAC study group. The effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple-blinded randomised controlled trial. Ann Rheum Dis 2011;70:1191-1196. https://doi.org/10.1136/ard.2010.147967
- O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, Blakely KM, Hausch R, Leff RD. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 2006;54:621-627. https://doi.org/10.1002/art.21620
- Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, Wolfe F, Schnitzer TJ, Moreland LW, Manzi S, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum 2005;52:2015-2025. https://doi.org/10.1002/art.21122
- Joks R, Durkin HG. Effect of tetracyclines on IgE allergic responses and asthma. Recent Pat Inflamm Allergy Drug Discov 2011;5:221-228. https://doi.org/10.2174/187221311797264919
- Prins HJ, Daniels JM, Lindeman JH, Lutter R, Boersma WG. Effects of doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial. Respir Med 2016;110:46-52. https://doi.org/10.1016/j.rmed.2015.10.009
- Pardo CA, Buckley A, Thurm A, Lee LC, Azhagiri A, Neville DM, Swedo SE. A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodev Disord 2013;5:9.
- Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc 2004;52:381-387. https://doi.org/10.1111/j.1532-5415.2004.52109.x
- Yulug B, Hanoglu L, Ozansoy M, Isik D, Kilic U, Kilic E, Schabitz WR. Therapeutic role of rifampicin in Alzheimer's disease. Psychiatry Clin Neurosci 2018;72:152-159. https://doi.org/10.1111/pcn.12637
- Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D'Argenio DZ. Pharmacokinetics of doxycycline in adults with cystic fibrosis. Antimicrob Agents Chemother 2012;56:70-74. https://doi.org/10.1128/AAC.05710-11
- Xu X, Abdalla T, Bratcher PE, Jackson PL, Sabbatini G, Wells JM, Lou XY, Quinn R, Blalock JE, Clancy JP, et al. Doxycycline improves clinical outcomes during cystic fibrosis exacerbations. Eur Respir J 2017;49:1601102.
- Lin M, Mao Y, Ai S, Liu G, Zhang J, Yan J, Yang H, Li A, Zou Y, Liang D. Efficacy of subantimicrobial dose doxycycline for moderate-to-severe and active Graves' orbitopathy. Int J Endocrinol 2015;2015:285698.
- Frankwich K, Tibble C, Torres-Gonzalez M, Bonner M, Lefkowitz R, Tyndall M, Schmid-Schonbein GW, Villarreal F, Heller M, Herbst K. Proof of concept: matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. J Inflamm (Lond) 2012;9:35.