Abstract
The prevalence of Parkinson’s disease, which affects millions of people worldwide, is increasing due to the aging population. In addition to the classic motor symptoms caused by the death of dopaminergic neurons, Parkinson’s disease encompasses a wide range of nonmotor symptoms. Although novel disease-modifying medications that slow or stop Parkinson’s disease progression are being developed, drug repurposing, which is the use of existing drugs that have passed numerous toxicity and clinical safety tests for new indications, can be used to identify treatment compounds. This strategy has revealed that tetracyclines are promising candidates for the treatment of Parkinson’s disease. Tetracyclines, which are neuroprotective, inhibit proinflammatory molecule production, matrix metalloproteinase activity, mitochondrial dysfunction, protein misfolding/aggregation, and microglial activation. Two commonly used semisynthetic second-generation tetracycline derivatives, minocycline and doxycycline, exhibit effective neuroprotective activity in experimental models of neurodegenerative/ neuropsychiatric diseases and no substantial toxicity. Moreover, novel synthetic tetracyclines with different biological properties due to chemical tuning are now available. In this review, we discuss the multiple effects and clinical properties of tetracyclines and their potential use in Parkinson’s disease treatment. In addition, we examine the hypothesis that the anti-inflammatory activities of tetracyclines regulate inflammasome signaling. Based on their excellent safety profiles in humans from their use for over 50 years as antibiotics, we propose the repurposing of tetracyclines, a multitarget antibiotic, to treat Parkinson’s disease.
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References
Agnihotri R, Gaur S (2012) Chemically modified tetracyclines: novel therapeutic agents in the management of chronic periodontitis. Indian J Pharmacol 44:161–167. https://doi.org/10.4103/0253-7613.93841
Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006) Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA 103(25):9685–9690. https://doi.org/10.1073/pnas.0600554103
Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Abramson SB (1997) Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett 410(2–3):259–264. https://doi.org/10.1016/S0014-5793(97)00605-4
Andreux PA, Houtkooper RH, Auwerx J (2013) Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 12:465–483. https://doi.org/10.1038/nrd4023
Archer JSM, Archer DF (2002) Oral contraceptive efficacy and antibiotic interaction: a myth debunked. J Am Acad Dermatol 46:917–923. https://doi.org/10.1067/mjd.2002.120448
Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683. https://doi.org/10.1038/nrd1468
Bahrami F, Morris DL, Pourgholami MH (2012) Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem 12(1):44–52. https://doi.org/10.2174/138955712798868977
Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA, Leenders KL (2010) [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 16(1):57–59. https://doi.org/10.1016/j.parkreldis.2009.05.005
Bi F, Li F, Huang C, Zhou H (2013) Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity. Int J Biol Sci 9(2):149–155. https://doi.org/10.7150/ijbs.5617
Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004) Clinical potential of minocycline for neurodegenerative disorders, Neurobiol Dis 17(3):359–366. https://doi.org/10.1016/j.nbd.2004.07.012
Bonelli RM, Hödl AK, Hofmann P, Kapfhammer HP (2004) Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19(6):337–342
Bourgault S, Vaudry D, Ségalas-Milazzo I, Guilhaudis L, Couvineau A, Laburthe M, Vaudry H, Fournier A (2009) Molecular and conformational determinants of pituitary adenylate cyclase-activating polypeptide (PACAP) for activation of the PAC1 receptor. J Med Chem 52(10):3308–3316. https://doi.org/10.1021/jm900291j
Bradaric BD, Patel A, Schneider JA, Carvey PM, Hendey B (2012) Evidence for angiogenesis in Parkinson’s disease, incidental Lewy body disease, and progressive supranuclear palsy. J Neural Transm 119:59–71
Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, Mao X, Shin JH, Lee Y, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Ko HS (2016) Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J Clin Invest 126(8):2970–2988. https://doi.org/10.1172/JCI85456
Carter EL (2003) Antibiotics in Cutaneous medicine: an update. Semin Cutan Med Surg 22:196–211. https://doi.org/10.1016/S1085-5629(03)00046-4
Casarejos MJ, Menéndez J, Solano RM, Rodríguez-Navarro JA, García de Yébenes J, Mena MA (2006) Susceptibility to rotenone is increased in neurons from parkin null mice is reduced by minocycline. J Neurochem 97(4):934–946. https://doi.org/10.1111/j.1471-4159.2006.03777.x
Cathcart JM, Cao J (2015) MMP inhibitors: past, present and future. Front Biosci (Landmark Ed) 20:1164–1178
Cha Y, Erez T, Reynolds IJ, Kumar D, Ross J, Koytiger G, Kusko R, Zeskind B, Risso S, Kagan E, Papapetropoulos S, Grossman I, Laifenfeld D (2018) Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol 175(2):168–180. https://doi.org/10.1111/bph.13798
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7):797–801. https://doi.org/10.1038/77528
Chen H, Zhang SM, Hernán MA, Schwarzschild MA, Willett WC, Colditz GA, Speizer FE, Ascherio A (2003) Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 60(8):1059–1064. https://doi.org/10.1001/archneur.60.8.1059
Cho Y, Son HJ, Kim EM, Choi JH, Kim ST, Ji IJ, Choi DH, Joh TH, Kim YS, Hwang O (2009) Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3. Neurotox Res 16(4):361–371. https://doi.org/10.1007/s12640-009-9078-1
Cho DC, Cheong JH, Yang MS, Hwang SJ, Kim JM, Kim CH (2011) The effect of minocy clineon motor neuron recovery and neuropathic pain in a rat model of spinal cord injury. J Korean Neurosurg Soc 49(2):83–91. https://doi.org/10.3340/jkns.2011.49.2.83
Chopra I, Roberts M (2001) Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 65:232–260. https://doi.org/10.1128/MMBR.65.2.232-260.2001
Chopra I, Hawkey PM, Hinton M, Jordan J, Fernandez-Gomez FJ, Ramos M, Ikuta I, Aguirre N, Galindo MF (2007) Minocycline and cytoprotection: shedding new light on a shadowy controversy. Curr Drug Deliv 4(3):225–331
Chu QS, Forouzesh B, Syed S, Mita M, Schwartz G, Cooper J, Curtright J, Rowinsky EK (2007) A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 25(4):359–367. https://doi.org/10.1007/s10637-006-9031-6
Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I et al (2013) Triggering of inflammasome by aggregated a–Synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8(1):e55375. https://doi.org/10.1371/journal.pone.0055375
Connamacher RH, Mandel HG (1965) Binding of tetracycline to the 30S ribosomes and to polyuridylic acid. Biochem Biophys Res Comm 20:98–103
Cox CA, Amaral J, Salloum R, Guedez L, Reid TW, Jaworski C, John- Aryankalayil M, Freedman KA, Campos MM, Martinez A, Becerra SP, Carper DA (2010) Doxycycline’s effect on ocular angiogenesis: an in vivo analysis. Ophthalmology 117(9):1782–1791
DeClerck YA, Shimada H, Taylor SM, Langley KE (1994) Matrix metalloproteinases and their inhibitors in tumor progression. Ann NY Acad Sci 732:222–232. https://doi.org/10.1111/j.1749-6632.1994.tb24738.x
Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM (2006) Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi’s sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol 24(9):1389–1394. https://doi.org/10.1200/JCO.2005.04.2614
Diguet E, Gross CE, Tison F, Bezard E (2004) Rise and fall of minocycline in neuroprotection: need to promote publication of negative results. Exp Neurol 189(1):1–4. https://doi.org/10.1016/j.expneurol.2004.05.016
Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N et al (2010) Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 25(1):97–107. https://doi.org/10.1002/mds.22732
Domercq M, Matute C (2004) Neuroprotection by tetracyclines. Trends Pharmacol Sci 25(12):609–612. https://doi.org/10.1016/j.tips.2004.10.001
Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR et al (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 98(25):14669–14674. https://doi.org/10.1073/pnas.251341998
Duggar BM (1948) Aureomycin: a product of the continuing search for new antibiotics. Ann N Y Acad Sci 51(Art. 2):177–181. https://doi.org/10.1111/j.1749-6632.1948.tb27262.x
Edan RA, Luqmani YA, Masocha W (2013) COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain. PLoS ONE 8(2):e57827. https://doi.org/10.1371/journal.pone.0057827
Egeberg A, Hansen PR, Gislason GH, Thyssen JP (2016) Exploring the association between rosacea and Parkinson disease: a Danish nationwide cohort study. JAMA Neurol 73(5):529–534. https://doi.org/10.1001/jamaneurol.2016.0022
Esterly NB, Koransky JS, Furey NL, Trevisan M (1984) Neutrophil chemotaxis in patients with acne receiving oral tetracycline therapy. Arch Dermatol 120(10):1308–1313. https://doi.org/10.1001/archderm.1984.01650460048018
Fahn S (2008) How do you treat motor complications in Parkinson’s disease: medicine, surgery, or both? Ann Neurol 64(2):56–64. https://doi.org/10.1002/ana.21453
Faust K, Gehrke S, Yang Y, Yang L, Beal MF, Lu B (2009) Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson’s disease. BMC Neurosci 10:109. https://doi.org/10.1186/1471-2202-10-109
Fingleton B (2003) CMT-3. CollaGenex. Curr Opin Investig Drugs 2003(12):1460–1467
Forloni G, Salmona M, Marcon G, Tagliavini F (2009) Tetracyclines and prion infectivity. Infect Disord Drug Targets 9(1):23–30. https://doi.org/10.2174/1871526510909010023
Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG (2009) Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 4:47. https://doi.org/10.1186/1750-1326-4-47
Furst DE (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Curr Opin Rheumatol 10:123–128
Gabler WL, Creamer HR (1991) Suppression of human neutrophil functions by tetracycline. J Periodontal Res 26:52–58. https://doi.org/10.1111/j.1600-0765.1991.tb01626.x
Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29:357–365. https://doi.org/10.1016/j.it.2008.05.002
Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, Bandez MJ, Fernandez-Gomez FJ, Perez-Alvarez S, De Mera RM, Jordan MJ, Aguirre N, Galindo MF, Villalobos C, Navarro A, Kmita H, Jordan J (2010) Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochem Pharmacol 79:239–250. https://doi.org/10.1016/j.bcp.2009.07.028
Garner SE, Eady EA, Popescu C, Newton J, Li WA (2003) Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev 8:CD002086. https://doi.org/10.1002/14651858.CD002086
Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR (1991) Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2(3):297–321
Golub LM, Soummalainen K, Sorsa T (1992) Host modulation with tetracyclines and their chemically modified analogues. Curr Opin Dent 2:80–90. https://doi.org/10.4103/0972-124X.149934
Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T (1998) Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 12:12–26. https://doi.org/10.1177/08959374980120010501
Golub LM, Ramamurthy NS, Llavaneras A, Ryan ME, Lee HM, Liu Y, Bain S, Sorsa T (1999) A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats. Ann N Y Acad Sci 878:290–310. https://doi.org/10.1111/j.1749-6632.1999.tb07691.x
Golub LM, Elburki MS, Walker C, Ryan M, Sorsa T, Tenenbaum H, Goldberg M, Wolff M, Gu Y (2016) Non-antibacterial tetracycline formulations: host-modulators in the treatment of periodontitis and relevant systemic diseases. Int Dent J 66(3):127–135. https://doi.org/10.1111/idj.12221
Gompels LL, Smith A, Charles PJ, Rogers W, Soon-Shiong J, Mitchell A et al (2006) Single-blind randomized trial of combination antibiotic therapy in rheumatoid arthritis. J Rheumatol 33(2):224–227. https://doi.org/10.1177/08959374980120010501
González-Lizárraga F, Socías SB, Ávila CL, Torres-Bugeau CM, Barbosa LR, Binolfi A, Sepúlveda-Díaz JE, Del-Bel E, Fernandez CO, Papy-Garcia D, Itri R, Raisman-Vozari R, Chehín RN (2017) Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species. Sci Rep 7:41755. https://doi.org/10.1038/srep41755
Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6(12):1045–1053. https://doi.org/10.1016/S1474-4422(07)70270-3
Gordon RA, Mays R, Sambrano B, Mayo T, Lapolla W (2012) Antibiotics used in nonbacterial dermatologic conditions. Dermatol Ther 25(1):38–54. https://doi.org/10.1111/j.1529-8019.2012.01496.x
Greenwald M (1998) Re: the new macrolide antibiotics: use them carefully. Paediatr Child Health 3(4):281–282
Griffin MO, Fricovsky E, Ceballos G, Villarreal F (2010) Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol 299(3):C539–C548. https://doi.org/10.1152/ajpcell.00047.2010
Gu Y, Lee HM, Simon SR, Golub LM (2011) Chemically modified tetracycline-3 (CMT-3): a novel inhibitor of the serine proteinase, elastase. Pharmacol Res 64(6):595–601. https://doi.org/10.1016/j.phrs.2011.05.011
Gupta AK, Gover MD, Abramovits W, Perlmutter A (2006) Solodyn (Minocycline HCl, USP) extended-release tablets. Skinmed 5(6):291–292
Hanemaaijer R, Visser H, Koolwijk P, Sorsa T, Salo T, Golub LM, van Hinsbergh VW (1998) Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res 12(2):114–118. https://doi.org/10.1177/08959374980120010301
He Y, Appel S, Le W (2001) Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909:187–193. https://doi.org/10.1016/S0006-8993(01)02681-6
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. https://doi.org/10.1016/S1353-8020(11)70065-7
Johnston TH, Lacoste AMB, Visanji NP, Lang AE, Fox SH, Brotchie JM (2018) Repurposing drugs to treat l-DOPA-induced dyskinesia in Parkinson’s disease. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2018.05.035)
Jordan J, Fernandez-Gomez FJ, Ramos M, Ikuta I, Aguirre N, Galindo MF (2007) Minocycline and cytoprotection: shedding new light on a shadowy controversy. Curr Drug Deliv 4(3):225–231. https://doi.org/10.2174/156720107781023938
Joshi N, Miller DQ (1997) Doxycycline revisited. Arch Intern Med 157(13):1421–1428. https://doi.org/10.1001/archinte.1997.00440340035003
Kauppinen A, Salminen A, Kaarniranta K (2013) Inflammation as a target of minocycline: special interest in the regulation of inflammasome signaling. Inflammasome 2013:2–14. https://doi.org/10.2478/infl-2013-0002
Keijmel SP, Delsing CE, Bleijenberg G, van der Meer JWM, Donders RT, Leclercq M et al (2017) Effectiveness of long-term doxycycline treatment and cognitive-behavioral therapy on fatigue severity in patients with Q fever fatigue syndrome (Qure study): a randomized controlled trial. Clin Infect Dis 64(8):998–1005. https://doi.org/10.1093/cid/cix013
Keller WR, Kum LM, Wehring HJ, Koola MM, Buchanan RW, Kelly DL (2013) A review of anti-inflammatory agents for symptoms of schizophrenia. J Psychopharmacol 27(4):337–342. https://doi.org/10.1177/0269881112467089
Kelly DL, Sullivan KM, McEvoy JP, McMahon RP, Wehring HJ, Gold JM et al (2015) Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol 35(4):374–381. https://doi.org/10.1097/JCP.0000000000000345
Kim H-S, Suh Y-H (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196(2):168–179. https://doi.org/10.1016/j.bbr.2008.09.040
Kosloski LM, Ha DM, Stone DK, Hutter JAL, Pichler MR, Reynolds AD, Gendelman HE, Mosley RL (2010) Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem 114(5):1261–1276. https://doi.org/10.1111/j.1471-4159.2010.06834.x
Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A (2013) The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord 28:311–318. https://doi.org/10.1002/mds.25292
Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 94(3):819–827. https://doi.org/10.1111/j.1471-4159.2005.03219.x
Langevitz P, Bank I, Zemer D, Book M, Pras M (1992) Treatment of resistant rheumatoid arthritis with minocycline: an open study. J Rheumatol 19(10):1502–1504
Lazzarini M, Martin S, Mitkovski M, Vozari RR, Stühmer W, Bel ED (2013) Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model. Glia 61(7):1084–1100. https://doi.org/10.1002/glia.22496
Lee JK, Tran T, Tansey MG (2009) Neuroinflammation in Parkinson’s disease. J Neuroimmune Pharmacol 4(4):419–429. https://doi.org/10.1007/s11481-009-9176-0
Lewandoski M (2001) Conditional control of gene expression in the mouse. Nat Rev Gene 2:743–755. https://doi.org/10.1038/35093537
LeWitt PA, Nyholm D (2004) New developments in levodopa therapy. Neurology 62(1):9–16. https://doi.org/10.1212/WNL.62.1_suppl_1.S9
Lin C, Zhang J (2017) Inflammasomes in inflammation-induced cancer. Front Immunol 8:271. https://doi.org/10.3389/fimmu.2017.00271
Lleo A, Galea E, Sastre M (2007) Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell Mol Life Sci 64(11):1403–1418. https://doi.org/10.1007/s00018-007-6516-1
Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall A et al (2004) A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc 52(3):381–387. https://doi.org/10.1111/j.1532-5415.2004.52109.x
Maiti P, Manna J, Veleri S, Frautschy S (2014) Molecular chaperone dysfunction in neurodegenerative diseases and effects of curcumin. Biomed Res Int 2014:495091. https://doi.org/10.1155/2014/495091
Mao J, Barrow J, McMahon J, Vaughan J, McMahon AP (2005) An ES cell system for rapid, spatial and temporal analysis of gene function in vitro and in vivo. Nucleic Acids Res 33(18):e155. https://doi.org/10.1093/nar/gni146
Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem 110(3):966–975. https://doi.org/10.1111/j.1471-4159.2009.06189.x
Martin RB (1985) Tetracyclines and daunorubicin in metal ions in biological systems. In: Sigel H (ed) Antibiotics and their complexes. Marcel Dekker, New York, pp 19–40
Martínez C, Arranz A, Juarranz Y, Abad C, García-Gómez M, Rosignoli F, Leceta J, Gomariz RP (2006) PAC1 receptor: emerging target for septic shock therapy. Ann N Y Acad Sci 1070:405–410. https://doi.org/10.1196/annals.1317.053
McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23(4):474–483
Molloy DW, Standish TI, Zhou Q, Guyatt G (2013) A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer’s disease: the DARAD trial. Int J Geriatr Psychiatry 28(5):463–470. https://doi.org/10.1002/gps.3846
Moon A, Gil S, Gill SE, Chen P, Matute-Bello G (2012) Doxycycline impairs neutrophil migration to the airspaces of the lung in mice exposed to intratracheal lipopolysaccharide. J Inflamm 9(1):31. https://doi.org/10.1186/1476-9255-9-31
Nelson ML (1998) Chemical and biological dynamics of tetracyclines. Adv Dent Res 12:5–11. https://doi.org/10.1177/08959374980120011901
Nelson ML, Levy ST (2011) The history of Tetracyclines Ann. N Y Acad Sci 1241:17–32
Nikodemova M, Duncan ID, Watters JJ (2006) Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem 96:314–323. https://doi.org/10.1111/j.1471-4159.2005.03520.x
NINDS NET-PD Investigators (2006) A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66(5):664–671. https://doi.org/10.1212/01.wnl.0000201252.57661.e1
Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger DP, Anderton BH (2009a) Minocycline reduces the development of abnormal tau species in models of Alzheimer’s disease. FASEB J 23(3):739–750. https://doi.org/10.1096/fj.08-113795
Noble W, Garwood CJ, Hanger DP (2009b) Minocycline as a potential therapeutic agent in neurodegenerative disorders characterized by protein misfolding. Prion 3:78–83. https://doi.org/10.4161/pri.3.2.8820
Nordström D, Lindy O, Lauhio A, Sorsa T, Santavirta S, Konttinen YT (1998) Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis. Rheumatol Int 17(5):175–180
Olanow CW (2007) The pathogenesis of cell death in Parkinson’s disease. Mov Disord 22(17):335–342. https://doi.org/10.1002/mds.21675
Olanow CW (2008) Levodopa/dopamine replacement strategies in Parkinson’s disease–future directions. Mov Disord 23(3):613–622. https://doi.org/10.1002/mds.22061
Orsucci D, Calsolaro V, Mancuso M, Siciliano G (2009) Neuroprotective effects of tetracyclines: molecular targets, animal models and human disease. CNS Neurol Disord Drug Targets 8(3):222–231. https://doi.org/10.2174/187152709788680689
Papapetropoulos A, Szabo C (2018) Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br J Pharmacol 175(2):165–167. https://doi.org/10.1111/bph.14081
Parashos SA, Luo S, Biglan KM, Bodis-Wollner I, He B, Liang GS, Ross GW, Tilley BC, Shulman LM (2014) Measuring disease progression in early Parkinson disease: the National Institutes of Health Exploratory Trials in Parkinson disease (NET-PD) experience. JAMA Neurol 71(6):710–716. https://doi.org/10.1001/jamaneurol.2014.391
Pardo CA, Buckley A, Thurm A, Lee LC, Azhagiri A, Neville DM, Swedo SE (2013) A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodev Disord 5(1):9. https://doi.org/10.1186/1866-1955-5-9
Payne JB, Golub LM, Stoner JA, Lee HM, Reinhardt RA, Sorsa T, Slepian MJ (2011) The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. J Am Dent Assoc 142:262–273. https://doi.org/10.14219/jada.archive.2011.0165
Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK (2006) Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration. J Neurosci 26(45):11644–11651. https://doi.org/10.1523/JNEUROSCI.3447-06.2006
Pérez-Trallero E, Iglesias L (2003) Tetracyclines, sulfonamides and metronidazole. Enferm Infecc Microbiol Clin 21(9):520–528. https://doi.org/10.1016/j.eimc.2009.10.002
Plane JM, Joseph DM, Allan BJ, Ashworth SH, Francisco JS (2006) An experimental and theoretical study of the reactions OIO + NO and OIO + OH. J Phys Chem A 110(1):93–100. https://doi.org/10.1021/jp055364y
Plane JM, Shen Y, Pleasure DE, Deng W (2010) Prospects for minocycline neuroprotection. Arch Neurol 67(12):1442–1448. https://doi.org/10.1001/archneurol.2010.191
Pontieri FE, Ricci A, Pellicano C, Benincasa D, Buttarelli FR (2005) Minocycline in amyotrophic lateral sclerosis: a pilot study. Neurol Sci 26(4):285–287. https://doi.org/10.1007/s10072-005-0474-x
Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P (1992) Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 44(6):1165–1170. https://doi.org/10.1016/0006-2952(92)90381-R
Quintero EM, Willis L, Singleton R, Harris N, Huang P, Bhat N, Granholm AC (2006) Behavioral and morphological effects of minocycline in the 6-hydroxydopamine rat model of Parkinson’s disease. Brain Res 1093(1):198–207. https://doi.org/10.1016/j.brainres.2006.03.104
Radad K, Moldzio R, Rausch WD (2010) Minocycline protects dopaminergic neurons against long-term rotenone toxicity. Can J Neurol Sci 37(1):81–85. https://doi.org/10.1017/S0317167100009690
Reglodi D, Maasz G, Pirger Z, Rivnyak A, Balogh D, Jungling A, Fulop B, Mark L et al (2015) Neurochemical changes in different brain regions induced by PACAP—relations to neuroprotection. Springerplus 4(1):L56. https://doi.org/10.1186/2193-1801-4-S1-L56
Reglodi D, Renaud J, Tamas A, Tizabi Y, Socías SB, Del-Bel E, Raisman-Vozari R (2017) Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol 155:120–148. https://doi.org/10.1016/j.pneurobio.2015.10.004
Rifkin BR, Vernillo AT, Golub LM, Ramamurthy NS (1994) Modulation of bone resorption by tetracyclines. Ann NY Acad Sci 732:165–180. https://doi.org/10.1111/j.1749-6632.1994.tb24733.x
Rodríguez-Violante M, Zerón-Martínez R, Cervantes-Arriaga A, Corona T (2017) Who can diagnose Parkinson’s disease first? Role of pre-motor symptoms. Arch Med Res 48(3):221–227. https://doi.org/10.1016/j.arcmed.2017.08.005
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE et al (2005) β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77
Ruzza C, Rizzi A, Malfacini D, Cerlesi MC, Ferrari F, Marzola E, Ambrosio C, Gro C et al (2014) Pharmacological characterization of tachykinin tetrabranched derivatives. Br J Pharmacol 171(17):4125–4137. https://doi.org/10.1111/bph.12727
Sande MA, Mandell GL (1985) Antimicrobial agents, tetracyclines. chloramphenicol, erythromycin, and miscellaneous antibacterial agents. In: Goodman and Gilman’s (ed) The pharmacological basis of therapeutics, 7th edn. McGraw-Hill, New York
Santa-Cecília FV, Socias B, Ouidja MO, Sepulveda-Diaz JE, Acuña L, Silva RL, Michel PP, Del-Bel E, Cunha TM, Raisman-Vozari R (2016) Doxycycline suppresses microglial activation by inhibiting the p38 MAPK and NF-kB signaling pathways. Neurotox Res 29(4):447–459. https://doi.org/10.1007/s12640-015-9592-2
Sapadin AN, Fleischmajer R (2006) Tetracyclines: Nonantibiotic properties and their clinical implications. J Am Acad Dermatol 54:258–265. https://doi.org/10.1016/j.jaad.2005.10.004
Schapira AH (2005) Present and future drug treatment for Parkinson’s disease. J Neurol Neurosurg Psychiatry 76(11):1472–1478. https://doi.org/10.1136/jnnp.2004.035980
Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E et al (2006) Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 5(10):845–854. https://doi.org/10.1038/nrd2087
Seaborn T, Masmoudi-Kouli O, Fournier A, Vaudry H, Vaudry D (2011) Protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against apoptosis. Curr Pharm Des 17(3):204–214. https://doi.org/10.2174/138161211795049679
Skidmore R, Kovach R, Walker C, Thomas J, Bradshaw M, Leyden J, Powala C, Ashley R (2003) Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol 139(4):459–464. https://doi.org/10.1001/archderm.139.4.459
Smith JR, Verwaerde C, Rolling F, Naud MC, Delanoye A, Thillaye-Goldenberg B, Apparailly F, De Kozak Y (2005) Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis. Hum Gene Ther 16(9):1037–1046. https://doi.org/10.1089/hum.2005.16.1037
Smith CJ, Sayles H, Mikuls TR, Michaud K (2011) Minocycline and doxycycline therapy in community patients with rheumatoid arthritis: prescribing patterns, patient-level determinants of use, and patient-reported side effects. Arthritis Res Ther 13(5):R168. https://doi.org/10.1186/ar3491
Socias SB, González-Lizárraga F, Avila CL, Vera C, Acuña L, Sepulveda-Diaz JE, Del-Bel E, Raisman-Vozari R, Chehin RN (2018) Exploiting the therapeutic potential of ready-to-use drugs: repurposing antibiotics against amyloid aggregation in neurodegenerative diseases. Prog Neurobiol. https://doi.org/10.1016/j.pneurobio.2017.12.002
Sriram K, Miller DB, O’Callaghan JP (2006) Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem 96(3):706–718. https://doi.org/10.1111/j.1471-4159.2005.03566.x
Stock ML, Fiedler KJ, Acharya S, Lange JK, Mlynarczyk GS, Anderson SJ, McCormack GR, Kanuri SH, Kondru NC, Brewer MT, Carlson SA (2013) Antibiotics acting as neuroprotectants via mechanisms independent of their anti-infective activities. Neuropharmacology 73:174–182
Stoilova T, Colombo L, Forloni G, Tagliavini F, Salmona M (2013) A new face for old antibiotics: tetracyclines in treatment of amyloidoses. J Med Chem 56(15):5987–6006. https://doi.org/10.1021/jm400161p
Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G, Kulik A, Fakler B, Roeper J (2014) Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci 34(41):13586–13599. https://doi.org/10.1523/JNEUROSCI.5069-13.2014
Sultan S, Gebara E, Toni N (2013) Doxycycline increases neurogenesis and reduces microglia in the adult hippocampus. Front Neurosci 7:131. https://doi.org/10.3389/fnins.2013.00131
Swamy DN, Sanivarapu S, Moogla S, Kapalavai V (2015) Chemically modified tetracyclines: the novel host modulating agents. J Indian Soc Periodontol 19(4):370–374. https://doi.org/10.4103/0972-124X.149934
Tamargo RJ, Bok RA, Brem H (1991) Angiogenesis inhibition by minocycline. Cancer Res 51:672–675
Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37(3):510–518. https://doi.org/10.1016/j.nbd.2009.11.004
Taylor N (2013) Direct current cardioversion causing ventricular fibrillation in Wolff-Parkinson-White syndrome. Emerg Med Australas 25(6):612–614. https://doi.org/10.1111/1742-6723.12150
Thong YH, Ferrante A (1979) Inhibition of mitogen-induced human lymphocyte proliferative responses by tetracycline analogues. Clin Exp Immunol 35(3):443–446
Tikka TM, Koistinaho JE (2001) Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 166:7527–7533. https://doi.org/10.4049/jimmunol.166.12.7527
Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H, Endo N (1996) Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J Biol Chem 271(12):6839–6844
Ton TG, Heckbert SR, Longstreth WT Jr, Rossing MA, Kukull WA, Franklin GM, Swanson PD, Smith-Weller T, Checkoway H (2006) Nonsteroidal anti-inflammatory drugs and risk of Parkinson’s disease. Mov Disord 21(7):964–969. https://doi.org/10.1002/mds.20856
Tufekci KU, Meuwissen R, Genc S, Genc K (2012) Inflammation in Parkinson’s disease. Adv Protein Chem Struct Biol 88:69–132. https://doi.org/10.1016/B978-0-12-398314-5.00004-0
Wachter B, Schürger S, Rolinger J, von Ameln-Mayerhofer A, Berg D, Wagner HJ, Kueppers E (2010) Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes. Cell Tissue Res 342(2):147–160. https://doi.org/10.1007/s00441-010-1061-x
Wang X, Cai H, Yan X, Ye Z (2010) Effect of different tidal volume ventilation on apoptosis and the expression of Bax and Bcl-2 in rat lungs. Zhong Nan Da Xue Xue Bao Yi Xue Ban 35(4):351–357. https://doi.org/10.3969/j.issn.1672-7347.2010.04.012
Wang W, Sidoli S, Zhang W, Wang Q, Wang L, Jensen ON, Guo L, Zhao X, Zheng L (2017) Abnormal levels of histone methylation in the retinas of diabetic rats are reversed by minocycline treatment. Sci Rep 7:45103. https://doi.org/10.1038/srep45103
Whiteman M, Halliwell B (1997) Prevention of peroxynitrite-dependent tyrosine nitration and inactivation of alpha1-antiproteinase by antibiotics. Free Radic Res 26:49–56
Wong YC, Krainc D (2017) α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23(2):1–13. https://doi.org/10.1038/nm.4269
Worlitzer MM, Viel T, Jacobs AH, Schwamborn JC (2013) The majority of newly generated cells in the adult mouse substantia nigra express low levels of Doublecortin, but their proliferation is unaffected by 6-OHDA-induced nigral lesion or Minocycline-mediated inhibition of neuroinflamation. Eur J Neurosci 38:2684–2692. https://doi.org/10.1111/ejn.12269
Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771
Yang L, Sugama S, Chirichigno JW, Gregorio J, Lorenzl S, Shin DH, Browne SE, Shimizu Y, Joh TH, Beal MF, Albers DS (2003) Minocycline enhances MPTP toxicity to dopaminergic neurons. J Neurosci Res 74(2):278–285. https://doi.org/10.1002/jnr.10709
Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM (2004) The promise of minocycline in neurology. Lancet Neurol. 3, 744–751. https://doi.org/10.1016/S1474-4422(04)00937-8
Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774
Yu R, Zheng L, Cui Y, Zhang H, Ye H (2016) Doxycycline exerted neuroprotective activity by enhancing the activation of neuropeptide GPCR PAC1. Neuropharmacology 103:1–15. https://doi.org/10.1016/j.neuropharm.2015.11.032
Zhang W, Narayanan M, Friedlander RM (2003) Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol 53(2):267–270. https://doi.org/10.1002/ana.10476
Zhang GB, Feng YH, Wang PQ, Song JH, Wang P, Wang SA (2015) A study on the protective role of doxycycline upon dopaminergic neuron of LPS-PD rat model rat. Eur Rev Med Pharmacol Sci 19(18):3468–3474
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This publication was funded by Grants from Fundação de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), CAPES (Conselho de Aperfeiçoamento de Pessoal) and Conselho Nacional de Pesquisa (CNPq) to EADB. We would like to dedicate this paper to Professor Walter Stuhmer (Director-Max Planck Institute of Experimental Medicine- Göttingen-Germany) who gave us his never-ceasing support in his proud struggle for the endurance of science in Latin America.
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Bortolanza, M., Nascimento, G.C., Socias, S.B. et al. Tetracycline repurposing in neurodegeneration: focus on Parkinson’s disease. J Neural Transm 125, 1403–1415 (2018). https://doi.org/10.1007/s00702-018-1913-1
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DOI: https://doi.org/10.1007/s00702-018-1913-1