Minocycline for the management of multiple sclerosis: repositioning potential, opportunities, and challenges

References

• Kobelt G, Thompson A, Berg J, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler J. 2017;23:1123–1136.
   PubMed Web of Science ®Google Scholar
• Newman TA, Wooley ST, Hughes PM, et al. T-cell-and macrophage mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases. Brain. 2001;124:2203–2214.
   PubMed Web of Science ®Google Scholar
• Bando Y. Myelin morphology and axon pathology in demyelination during experimental autoimmune encephalomyelitis. Neural Regen Res. 2015;10:1584–1585.
   PubMed Web of Science ®Google Scholar
• Chandler SM, Miller KM, Clements JM, et al. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol. 1997;72:155–161.
   PubMed Web of Science ®Google Scholar
• Goodwin SJ. Multiple sclerosis: integration of modeling with biology, clinical and imaging measures to provide better monitoring of disease progression and prediction of outcome. Neural Regen Res. 2016;11:1900–1903.
   PubMed Web of Science ®Google Scholar
• Traka M, Podojil JR, McCarthy DP, et al. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat Neurosci. 2016;19:65–74.
   PubMed Web of Science ®Google Scholar
• Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46(4):907–911.
   PubMed Web of Science ®Google Scholar
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–286.
   PubMed Web of Science ®Google Scholar
• Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol. 2001;2(9):762–764.
   PubMed Web of Science ®Google Scholar
• Burtchell J, Fetty K, Miller K, et al. Two sides to every story: perspectives from four patients and a healthcare professional on multiple sclerosis disease progression. Neurol Ther. 2019;8:185–205.
   PubMed Web of Science ®Google Scholar
• Greenfield AL, Hauser SL. B-cell therapy for multiple sclerosis: entering an era. Ann Neurol. 2018;83:13–26.
   PubMed Web of Science ®Google Scholar
• Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci. 2013;333:1–4.
   PubMed Web of Science ®Google Scholar
• Wang Q, Mao-Draayer Y. Interferon beta (IFN-β) treatment exerts potential neuroprotective effects through neurotrophic factors and novel neurotensin/neurotensin high affinity receptor 1 pathway. Neural Regen Res. 2015;10:1932–1933.
   PubMed Web of Science ®Google Scholar
• Dasari H, Wootla B, Warrington AE, et al. Concomitant use of neuroprotective drugs in neuro rehabilitation of multiple sclerosis. Int J Phys Med Rehabil. 2016;4:348.
   PubMedGoogle Scholar
• Castro-Borrero W, Graves D, Frohman TC, et al. Current and emerging therapies in multiple sclerosis: a systematic review. Ther Adv Neurol Disord. 2012;5:205–220.
   PubMed Web of Science ®Google Scholar
• Racke MK. Challenges in developing new multiple sclerosis therapies. Ther Adv Neurol Disord. 2008;1:1–3.
   PubMedGoogle Scholar
• Küry P, Kremer D, Göttle P. Drug repurposing for neuroregeneration in multiple sclerosis. Neural Regen Res. 2018;13:1366–1367.
   PubMed Web of Science ®Google Scholar
• Kakkar AK, Singh H, Medhi B. Old wines in new bottles: repurposing opportunities for Parkinson’s disease. Eur J Pharmacol. 2018;830:115–127.
   PubMed Web of Science ®Google Scholar
• Gautam CS, Mahajan SS, Sharma J, et al. Repurposing potential of ketamine: opportunities and challenges. Indian J Psychol Med. 2020;42:22–29.
   PubMedGoogle Scholar
• Benešová Y, Vašků A, Novotná H, et al. Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis. Mult Scler J. 2009;15:316–322.
   PubMed Web of Science ®Google Scholar
• Leppert D, Ford J, Stabler G, et al. Matrix mettaloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain. 1998;121:2327–2334.
   PubMed Web of Science ®Google Scholar
• Gijbels K, Galardy RE, Steinman L. Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Invest. 1994;94(6):2177–2182.
   PubMed Web of Science ®Google Scholar
• Moreno B, Villoslada P. Neuroprotective therapies for multiple sclerosis. Eur Neurol Rev. 2012;7:189–195.
   Google Scholar
• Mix E, Meyer-Rienecker H, Hartung HP, et al. Animal models of multiple sclerosis-potentials and limitations. Prog Neurobiol. 2010;92:386–404.
   PubMed Web of Science ®Google Scholar
• Agrawal SM, Yong VW. Immunopathogenesis of multiple sclerosis. Int Rev Neurobiol. 2007;79:99–126.
   PubMed Web of Science ®Google Scholar
• Gasche Y, Soccal PM, Kanemitsu M, et al. Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain. Front Biosci. 2006;11:1289–1301.
   PubMed Web of Science ®Google Scholar
• Blum D, Chtarto A, Tenenbaum L, et al. Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis. 2004;17:359–366.
   PubMed Web of Science ®Google Scholar
• Yong VW, Zabad RK, Agrawal S, et al. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci. 2007;259:79–84.
   PubMed Web of Science ®Google Scholar
• Brundula V, Rewcastle NB, Metz LM, et al. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain. 2002;125:1297–1308.
   PubMed Web of Science ®Google Scholar
• Niimi N, Khyama K, Matsumoto Y. Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases. Neuropathology. 2023;33:612–620.
   Google Scholar
• Fan R, Xu F, Previti ML, et al. Minocycline reduces microglial activation and improves behavioural deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci Res. 2007;7:3057–3063.
   Google Scholar
• Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Ann Neurol. 2013;74:317–327.
   PubMed Web of Science ®Google Scholar
• Hou Y, Heon Ryu C, Jun JA, et al. Interferon ß-secreting mesenchymal stem cells combined with minocycline attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014;274:20–27.
   PubMed Web of Science ®Google Scholar
• Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation. Neurobiol Dis. 2007;25:514–525.
   PubMed Web of Science ®Google Scholar
• Metz LM, Li DKB, Traboulsee AL, et al. Minocycline in MS study team. trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376:2122–2133.
   PubMed Web of Science ®Google Scholar
• Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA. 2001;98:14669–14674.
   PubMed Web of Science ®Google Scholar
• Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000;6:797–801.
   PubMed Web of Science ®Google Scholar
• Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002;10:268–278.
   PubMed Web of Science ®Google Scholar
• Popovic N, Schubart A, Goetz BD, et al. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol. 2002;51:215–223.
   PubMed Web of Science ®Google Scholar
• Garwood CJ, Cooper JD, Hanger DP, et al. Anti-inflammatory impact of minocycline in a mouse model of taupathy. Front Psychiatry. 2010;1:136.
   PubMedGoogle Scholar
• Cankaya S, Cankaya B, Kilic U, et al. The therapeutic role of minocycline in Parkinson’s disease. Drugs Context. 2019;8:212553.
   PubMedGoogle Scholar
• Cuello AC, Ferretti MT, Leon WC, et al. Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. Neurodegener Dis. 2010;7:96–98.
   PubMed Web of Science ®Google Scholar
• Thomas M, Le WD. Minocycline: neuroprotective mechanisms in Parkinson’s disease. Curr Pharm Des. 2004;10:679–686.
   PubMed Web of Science ®Google Scholar
• Fan LW, Lin S, Pang Y, et al. Minocycline attenuates hypoxia-ischemia-induced neurological dysfunction and brain injury in the juvenile rat. Eur J Neurosci. 2006;24:341–350.
   PubMed Web of Science ®Google Scholar
• Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res. 2009;196:168–179.
   PubMed Web of Science ®Google Scholar
• Chen X, Ma X, Jiang Y, et al. The prospects of minocycline in multiple sclerosis. J Neuroimmunol. 2011;235:1–8.
   PubMed Web of Science ®Google Scholar
• Chen X, Pi R, Liu M, et al. Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in C57 BL/6 mice. J Neuroimmunol. 2010;14(226):104–109.
   Google Scholar
• Giuliani F, Metz LM, Wilson T, et al. Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J Neuroimmunol. 2005;158:213–221.
   PubMed Web of Science ®Google Scholar
• Faissner S, Mahjoub Y, Mishra MH, et al. Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: prospective combination treatment for progressive disease? Mult Scler J. 2018;24:1543–1556.
   PubMed Web of Science ®Google Scholar
• Tikka T, Fiebich BL, Goldsteins G, et al. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21(8):2580–2588.
   PubMed Web of Science ®Google Scholar
• Defaux A, Zurich MG, Honegger P, et al. Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-γ plus lipopolysaccharide-induced demyelination. Neuroscience. 2011;187:84–92.
   PubMed Web of Science ®Google Scholar
• Howell OW, Rundle JL, Garg A, et al. Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J Neuropathol Exp Neurol. 2010;69(10):1017–1033.
   PubMed Web of Science ®Google Scholar
• Filippo M, De Iure A, Giampà C, et al. Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis. Sci Rep. 2016;6(1):1–6.
   PubMedGoogle Scholar
• Planche V, Panatier A, Hiba B, et al. Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis. Brain Behav Immun. 2017;60:240–254.
   PubMed Web of Science ®Google Scholar
• Stoop MP, Rosenling T, Attali A, et al. Minocycline effects on the cerebrospinal fluid proteome of experimental autoimmune encephalomyelitis rats. J Proteome Res. 2012;11:4315–4325.
   PubMed Web of Science ®Google Scholar
• Hahn JN, Kaushik DK, Mishra MK, et al. Impact of minocycline on extracellular matrix metalloproteinase inducer, a factor implicated in multiple sclerosis immunopathogenesis. J Immunol. 2016;197:3850–3860.
   PubMed Web of Science ®Google Scholar
• Chen X, Ma L, Jiang Y, et al. Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis. Eur J Pharmacol. 2012;686(1–3):124–129.
   PubMed Web of Science ®Google Scholar
• Tanaka T, Murakami K, Bando Y, et al. Minocycline reduces remyelination by suppressing ciliary neurotrophic factor expression after cuprizone-induced demyelination. J Neurochem. 2013;127:259–270.
   PubMed Web of Science ®Google Scholar
• Yrjänheikki J, Keinänen R, Pellikka M, et al. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA. 1998;95:15769–15774.
   PubMed Web of Science ®Google Scholar
• Kloppenburg M, Verweij CL, Miltenburg AMM, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol. 1995;102:635–641.
   PubMed Web of Science ®Google Scholar
• Kloppenburg M, Brinkman BMN, DeRooijDijk HH, et al. The tetracycline derivative minocycline differentially affects cytokine production by monocytes and T lymphocytes. Antimicrob Agents Chemother. 1996;40:934–940.
   PubMed Web of Science ®Google Scholar
• Månsson R, Hansson MJ, Morota S, et al. Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline. Neurobiol Dis. 2007;25:198–205.
   PubMed Web of Science ®Google Scholar
• Yamaguchi H, Haranaga S, Widen R, et al. Chlamydia pneumoniae infection induces differentiation of monocytes into macrophages. Infect Immun. 2002;70:2392–2398.
   PubMed Web of Science ®Google Scholar
• Chen X, Hu X, Zou Y, et al. Combined treatment with minocycline and prednisone attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice [published correction appears in J Neuroimmunol.2009;215:130]. J Neuroimmunol. 2009;210:22–29.
   PubMed Web of Science ®Google Scholar
• Luccarini I, Ballerini C, Biagioli T, et al. Combined treatment with atorvastatin and minocycline suppresses severity of EAE. Exp Neurol. 2008;211:214–226.
   PubMed Web of Science ®Google Scholar
• Metz LM, Li D, Traboulsee A, et al. 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.
   PubMed Web of Science ®Google Scholar
• Lampl Y, Boaz M, Gilad R, et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007;69:1404–1410.
   PubMed Web of Science ®Google Scholar
• Plane JM, Shen Y, Pleasure DE, et al. Prospects for minocycline neuroprotection. Arch Neurol. 2010;67:1442–1448.
   PubMedGoogle Scholar
• Ruggieri M, Pica C, Lia A, et al. Combination treatment of glatiramer acetate and minocycline affects phenotype expression of blood monocyte-derived dendritic cells in multiple sclerosis patients. J Neuroimmunol. 2008;197:140–146.
   PubMed Web of Science ®Google Scholar
• Metz LM, Zhang Y, Yeung M, et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004;55:756.
   PubMed Web of Science ®Google Scholar
• Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. Mult Scler. 2007;13:517–526.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Metz LM, Yong VW, et al. Pilot study of minocycline in relapsing-remitting multiple sclerosis. Can J Neurol Sci. 2008;35:185–191.
   PubMed Web of Science ®Google Scholar
• Sørensen PS, Sellebjerg F, Lycke J, et al. Minocycline added to subcutaneous interferon β-1a in multiple sclerosis: randomized RECYCLINE study. Eur J Neurol. 2016;23:861–870.
   PubMed Web of Science ®Google Scholar
• Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169:337–352.
   PubMed Web of Science ®Google Scholar
• Singh H, Kakkar AK, Chauhan P. Repurposing minocycline for COVID-19 management: mechanisms, opportunities, and challenges [published online ahead of print, 2020 Jul 1]. Expert Rev Anti Infect Ther. 2020;1–7. DOI:10.1080/14787210.2020.1782190
   PubMed Web of Science ®Google Scholar
• Diana G, Strollo R, Diana D, et al. Cardiac safety and potential efficacy: two reasons for considering minocycline in place of azithromycin in COVID-19 management [published online ahead of print, 2020 May 7]. Eur Heart J Cardiovasc Pharmacother. 2020;pvaa049. DOI:10.1093/ehjcvp/pvaa049
   PubMedGoogle Scholar
• Minocycline Hydrochloride Capsules (minocycline hydrochloride) dose, indications, adverse effects, interactions … from PDR.net [Internet]. [ cited 2020 June 6]. Available from: https://www.pdr.net/drug-summary/Minocycline-Hydrochloride-Capsules-minocycline-hydrochloride–3396
   Google Scholar
• Kieseier BC, Wiendl H. Oral disease-modifying treatments for multiple sclerosis. CNS Drugs. 2007;21:483–502.
   PubMed Web of Science ®Google Scholar
• Marchand DK, Butcher R (2004). Minocycline for relapsing-remitting multiple sclerosis and clinically isolated syndrome: a review of clinical effectiveness and guidelines [Internet]. [cited 2020 May 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK549544/
   Google Scholar
• Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27:1329–1342.
   PubMed Web of Science ®Google Scholar
• Matsuura H, Senoo A, Saito M, et al. Minocycline-Induced Hyperpigmentation. QJM. 2017;110:323.
   PubMed Web of Science ®Google Scholar
• Nisar MS, Iyer K, Brodell RT, et al. Minocycline-induced hyperpigmentation: comparison of 3Q-switched lasers to reverse its effects. Clin Cosmet Investig Dermatol. 2013;6:159–162.
   PubMedGoogle Scholar
• Grossman TH. Tetracycline antibiotics and resistance. Cold Spring Harb Perspect Med. 2016;64:a025387. Published 2016 Apr 1.
   PubMed Web of Science ®Google Scholar
• Paul M, Ike I. Don’t use minocycline as first line oral antibiotic in acne. BMJ. 2007;334:154.
   PubMedGoogle Scholar
• Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum. 1999;28:392–397.
   PubMed Web of Science ®Google Scholar
• El-Hallak M, Giani T, Yeniay BS, et al. Chronic minocycline-induced autoimmunity in children. J Pediatr. 2008;153:314–319.
   PubMed Web of Science ®Google Scholar
• Brown RJ, Rother KI, Artman H, et al. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol. 2009;145:63–66.
   PubMed Web of Science ®Google Scholar