A new face for old antibiotics: Tetracyclines in treatment of amyloidoses

Journal of Medicinal Chemistry

Volumn 56, Issue 15, 2013, Pages 5987-6006

  Stoilova, Tatiana ^a   Colombo, Laura ^a   Forloni, Gianluigi ^a   Tagliavini, Fabrizio ^b   Salmona, Mario ^a  

^a MARIO NEGRI INSTITUTE FOR PHARMACOLOGICAL RESEARCH   (Italy)

^b DEPARTMENT OF NEUROSURGERY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID PROTEIN; DOXYCYCLINE; INCYCLINIDE; MINOCYCLINE; REACTIVE OXYGEN METABOLITE;

AMYLOIDOSIS; ANTIINFLAMMATORY ACTIVITY; ANTIMICROBIAL ACTIVITY; APOPTOSIS; BACTERIAL STRAIN; DEGRADATION; HUMAN; MOLECULAR MECHANICS; OXIDATIVE STRESS; REVIEW;

AMYLOID; AMYLOIDOGENIC PROTEINS; AMYLOIDOSIS; ANIMALS; ANTI-BACTERIAL AGENTS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; APOPTOSIS; CLINICAL TRIALS AS TOPIC; DRUG ADMINISTRATION SCHEDULE; HUMANS; MATRIX METALLOPROTEINASE INHIBITORS; PROTEIN CONFORMATION; TETRACYCLINES;

EID: 84881396342     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400161p     Document Type: Review

References (152)

1. Gillmore, J. D.; Hawkins, P. N. Drug insight: emerging therapies for amyloidosis Nat. Clin. Pract. Nephrol. 2006, 2, 263-270
2. Sipe, J. D.; Benson, M. D.; Buxbaum, J. N.; Ikeda, S.; Merlini, G.; Saraiva, M. J.; Westermark, P. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis Amyloid 2010, 17, 101-104
3. Pepys, M. B. Amyloidosis Annu. Rev. Med. 2006, 57, 223-241
4. Sunde, M.; Serpell, L. C.; Bartlam, M.; Fraser, P. E.; Pepys, M. B.; Blake, C. C. Common core structure of amyloid fibrils by synchrotron X-ray diffraction J. Mol. Biol. 1997, 273, 729-739
5. Kirschner, D. A.; Gross, A. A.; Hidalgo, M. M.; Inouye, H.; Gleason, K. A.; Abdelsayed, G. A.; Castillo, G. M.; Snow, A. D.; Pozo-Ramajo, A.; Petty, S. A.; Decatur, S. M. Fiber diffraction as a screen for amyloid inhibitors Curr. Alzheimer Res. 2008, 5, 288-307
6. Dobson, C. M. Protein folding and misfolding Nature 2003, 426, 884-890
7. Hardy, J. A.; Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis Science 1992, 256, 184-185
8. Bucciantini, M.; Giannoni, E.; Chiti, F.; Baroni, F.; Formigli, L.; Zurdo, J.; Taddei, N.; Ramponi, G.; Dobson, C. M.; Stefani, M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases Nature 2002, 416, 507-511
9. Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science 2003, 300, 486-489
10. Glabe, C. G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease Neurobiol. Aging 2006, 27, 570-575
11. Ferreira, S. T.; Vieira, M. N.; De Felice, F. G. Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases IUBMB Life 2007, 59, 332-345
12. Budka, H. Neuropathology of prion diseases Br. Med. Bull. 2003, 66, 121-130
13. Haass, C.; Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide Nat. Rev. Mol. Cell Biol. 2007, 8, 101-112
14. Cooper, G. J.; Aitken, J. F.; Zhang, S. Is type 2 diabetes an amyloidosis and does it really matter (to patients)? Diabetologia 2010, 53, 1011-1016
15. Klein, W. L.; Krafft, G. A.; Finch, C. E. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 2001, 2, 219-224
16. Zhao, H. L.; Lai, F. M.; Tong, P. C.; Zhong, D. R.; Yang, D.; Tomlinson, B.; Chan, J. C. Prevalence and clinicopathological characteristics of islet amyloid in Chinese patients with type 2 diabetes Diabetes 2003, 52, 2759-2766
17. Aitken, J. F.; Loomes, K. M.; Scott, D. W.; Reddy, S.; Phillips, A. R.; Prijic, G.; Fernando, C.; Zhang, S.; Broadhurst, R.; L'Huillier, P.; Cooper, G. J. Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/islet amyloid polypeptide transgenic mice Diabetes 2010, 59, 161-171
18. Bhak, G.; Choe, Y. J.; Paik, S. R. Mechanism of amyloidogenesis: nucleation-dependent fibrillation versus double-concerted fibrillation BMB Rep. 2009, 42, 541-551
19. 2-microglobulin monomer and fibrils PLoS One 2011, 6, e27353
20. Stefani, M. Structural features and cytotoxicity of amyloid oligomers: implications in Alzheimer's disease and other diseases with amyloid deposits Prog. Neurobiol. 2012, 99, 226-245
21. Merlini, G.; Bellotti, V. Molecular mechanisms of amyloidosis N. Engl. J. Med. 2003, 349, 583-596
22. Lashuel, H. A.; Hartley, D.; Petre, B. M.; Walz, T.; Lansbury, P. T., Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations Nature 2002, 418, 291
23. Huang, X.; Atwood, C. S.; Hartshorn, M. A.; Multhaup, G.; Goldstein, L. E.; Scarpa, R. C.; Cuajungco, M. P.; Gray, D. N.; Lim, J.; Moir, R. D.; Tanzi, R. E.; Bush, A. I. The Ab peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction Biochemistry 1999, 38, 7609-7616
24. Virok, D. P.; Simon, D.; Bozsó, Z.; Rajkó, R.; Datki, Z.; Bálint, é.; Szegedi, V.; Janáky, T.; Penke, B.; Fülöp, L. Protein array based interactome analysis of amyloid-β indicates an inhibition of protein translation J. Proteome Res. 2011, 10, 1538-1547
25. Manzoni, C.; Colombo, L.; Bigini, P.; Diana, V.; Cagnotto, A.; Messa, M.; Lupi, M.; Bonetto, V.; Pignataro, M.; Airoldi, C.; Sironi, E.; Williams, A.; Salmona, M. The molecular assembly of amyloid Aβ controls its neurotoxicity and binding to cellular proteins PLoS One 2011, 6, e24909
26. Aguzzi, A.; O'Connor, T. Protein aggregation diseases: pathogenicity and therapeutic perspectives Nat. Rev. Drug Discovery 2010, 9, 237-248
27. Gertz, M. A.; Zeldenrust, S. R. Treatment of immunoglobulin light chain amyloidosis Curr. Hematol. Malig. Rep. 2009, 4, 91-98
28. Suhr, O. B.; Herlenius, G.; Friman, S.; Ericzon, B. G. Liver transplantation for hereditary transthyretin amyloidosis Liver Transplant. 2000, 6, 263-276
29. Liepnieks, J. J.; Benson, M. D. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation Amyloid 2007, 14, 277-282
30. Liepnieks, J. J.; Zhang, L. Q.; Benson, M. D. Progression of transthyretin amyloid neuropathy after liver transplantation Neurology 2010, 75, 324-327
31. Hamaguchi, T.; Ono, K.; Yamada, M. Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer's disease Cell. Mol. Life Sci. 2006, 63, 1538-1552
32. Dember, L. M.; Hawkins, P. N.; Hazenberg, B. P.; Gorevic, P. D.; Merlini, G.; Butrimiene, I.; Livneh, A.; Lesnyak, O.; Puéchal, X.; Lachmann, H. J.; Obici, L.; Balshaw, R.; Garceau, D.; Hauck, W.; Skinner, M. Eprodisate for the treatment of renal disease in AA amyloidosis N. Engl. J. Med. 2007, 356, 2349-2360
33. Galimberti, D.; Scarpini, E. Disease-modifying treatments for Alzheimer's disease Ther. Adv. Neurol. Disord. 2011, 4, 203-216
34. Soto, C.; Kascsak, R. J.; Saborío, G. P.; Aucouturier, P.; Wisniewski, T.; Prelli, F.; Kascsak, R.; Mendez, E.; Harris, D. A.; Ironside, J.; Tagliavini, F.; Carp, R. I.; Frangione, B. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides Lancet 2000, 355, 192-197
35. Ratner, M. Spotlight focuses on protein-misfolding therapies Nat. Biotechnol. 2009, 27, 874
36. Planté-Bordeneuve, V.; Said, G. Familial amyloid polyneuropathy Lancet Neurol. 2011, 10, 1086-1097
37. Weiner, H. L.; Lemere, C. A.; Maron, R.; Spooner, E. T.; Grenfell, T. J.; Mori, C.; Issazadeh, S.; Hancock, W. W.; Selkoe, D. J. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease Ann. Neurol. 2000, 48, 567-579
38. Birmingham, K.; Frantz, S. Set back to Alzheimer vaccine studies Nat. Med. 2002, 8, 199-200
39. Mullard, A. Sting of Alzheimer's failures offset by upcoming prevention trials Nat. Rev. Drug Discovery 2012, 11, 657-660
40. Bodin, K.; Ellmerich, S.; Kahan, M. C.; Tennent, G. A.; Loesch, A.; Gilbertson, J. A.; Hutchinson, W. L.; Mangione, P. P.; Gallimo, J. R.; Millar, D. J.; Minogue, S.; Dhillon, A. P.; Taylor, G. W.; Bradwell, A. R.; Petrie, A.; Gillmore, J. D.; Bellotti, V.; Botto, M.; Hawkins, P. N.; Pepys, M. B. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits Nature 2010, 468, 93-97
41. Tagliavini, F.; Forloni, G.; Colombo, L.; Rossi, G.; Girola, L.; Canciani, B.; Angeretti, N.; Giampaolo, L.; Peressini, E.; Awan, T.; De Gioia, L.; Ragg, E.; Bugiani, O.; Salmona, M. Tetracycline affects abnormal properties of synthetic PrP peptides and PrP(Sc) in vitro J. Mol. Biol. 2000, 300, 1309-1322
42. Forloni, G.; Colombo, L.; Girola, L.; Tagliavini, F.; Salmona, M. Anti-amyloidogenic activity of tetracyclines: studies in vitro FEBS Lett. 2001, 487, 404-407
43. Forloni, G.; Salmona, M.; Marcon, G.; Tagliavini, F. Tetracyclines and prion infectivity Infect. Disord.: Drug Targets 2009, 9, 23-30
44. Airoldi, C.; Colombo, L.; Manzoni, C.; Sironi, E.; Natalello, A.; Doglia, S. M.; Forloni, G.; Tagliavini, F.; Del Favero, E.; Cantù, L.; Nicotra, F.; Salmona, M. Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction Org. Biomol. Chem. 2011, 9, 463-472
45. Saivin, S.; Houin, G. Clinical pharmacokinetics of doxycycline and minocycline Clin. Pharmacokinet. 1988, 15, 355-366
46. Griffin, M. O.; Fricovsky, E.; Ceballos, G.; Villarreal, F. Tetracyclines: a pleiotropic family of compounds with promising therapeutic properties. Review of the literature Am. J. Physiol.: Cell Physiol. 2010, 299, C539-C548
47. 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
48. Nelson, M. L. Chemical and biological dynamics of tetracyclines Adv. Dent. Res. 1998, 12, 5-11
49. Kraus, R. L.; Pasieczny, R.; Lariosa-Willingham, K.; Turner, M. S.; Jiang, A.; Trauger, J. W. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity J. Neurochem. 2005, 94, 819-827
50. Cosentino, U.; Varí, M. R.; Saracino, A. A.; Pitea, D.; Moro, G.; Salmona, M. Tetracycline and its analogues as inhibitors of amyloid fibrils: searching for a geometrical pharmacophore by theoretical investigation of their conformational behavior in aqueous solution J. Mol. Model. 2005, 11, 17-25
51. Duarte, H. A.; Carvalho, S.; Paniago, E. B.; Simas, A. M. Importance of tautomers in the chemical behavior of tetracyclines J. Pharm. Sci. 1999, 88, 111-120
52. Hughes, L. J.; Stezowski, J. J.; Hughes, R. E. Chemical-structural properties of tetracycline derivatives. 7. Evidence for coexistence of the zwitterionic and nonionized forms of the free base in solution J. Am. Chem. Soc. 1979, 101, 7655-7657
53. Sapadin, A. N.; Fleischmajer, R. Tetracyclines: nonantibiotic properties and their clinical implications J. Am. Acad. Dermatol. 2006, 54, 258-265
54. 2+ bind tetracycline with distinct stoichiometries and linked deprotonation Biophys. Chem. 2007, 128, 185-196
55. Neuvonen, P. J. Interactions with the absorption of tetracyclines Drugs 1976, 11, 45-54
56. Weinstein, L. The Tetracyclines. In The Pharmacological Basis of Therapeutics, 4 th ed.; Goodman, L. S.; Gilman, A., Eds.; The Macmillan Co.: New York, 1970; pp 1253-1268.
57. Canalis, R. F.; Lechago, J. Tetracycline bone labeling: an improved technique using incident fluorescence Ann. Otol., Rhinol., Laryngol. 1982, 91, 160-162
58. Melsen, F.; Mosekilde, L. Trabecular bone mineralization lag time determined by tetracycline double-labeling in normal and certain pathological conditions Acta Pathol. Microbiol. Scand., Sect. A 1980, 88, 83-88
59. Mellibovsky, L.; Diez, A.; Serrano, S.; Aubia, J.; Pérez-Vila, E.; Mariñoso, M. L.; Nogués, X.; Recker, R. R. Bone remodeling alterations in myelodysplastic syndrome Bone 1996, 19, 401-405
60. Ayala, A. G.; Murray, J. A.; Erling, M. A.; Raymond, A. K. Osteoid-osteoma: intraoperative tetracicline-fluorescence demonstration of the nidus J. Bone Jt. Surg., Am. Vol. 1986, 68, 747-751
61. Brodersen, D. E.; Clemons, W. M., Jr.; Carter, A. P.; Morgan-Warren, R. J.; Wimberly, B. T.; Ramakrishnan, V. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit Cell 2000, 103, 1143-1154
62. Gianni, L.; Bellotti, V.; Gianni, A. M.; Merlini, G. New drug therapy of amyloidoses: resorption of AL-type deposits with 4′-iodo-4′- deoxydoxorubicin Blood 1995, 86, 855-861
63. Merlini, G.; Ascari, E.; Amboldi, N.; Bellotti, V.; Arbustini, E.; Perfetti, V.; Ferrari, M.; Zorzoli, I.; Marinone, M. G.; Garini, P.; Diegoli, M.; Trizio, D.; Ballinari, D. Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2959-2963
64. Tagliavini, F.; McArthur, R. A.; Canciani, B.; Giaccone, G.; Porro, M.; Bugiani, M.; Lievens, P. M.; Bugiani, O.; Peri, E.; Dall'Ara, P.; Rocchi, M.; Poli, G.; Forloni, G.; Bandiera, T.; Varasi, M.; Suarato, A.; Cassutti, P.; Cervini, M. A.; Lansen, J.; Salmona, M.; Post, C. Effectiveness of anthracycline against experimental prion disease in Syrian hamsters Science 1997, 276, 1119-1122
65. Palha, J. A.; Ballinari, D.; Amboldi, N.; Cardoso, I.; Fernandes, R.; Bellotti, V.; Merlini, G.; Saraiva, M. J. 4′-Iodo-4′- deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid Am. J. Pathol. 2000, 156, 1919-1925
66. Forloni, G.; Iussich, S.; Awan, T.; Colombo, L.; Angeretti, N.; Girola, L.; Bertani, I.; Poli, G.; Caramelli, M.; Grazia Bruzzone, M.; Farina, L.; Limido, L.; Rossi, G.; Giaccone, G.; Ironside, J. W.; Bugiani, O.; Salmona, M.; Tagliavini, F. Tetracyclines affect prion infectivity Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 10849-10854
67. Forloni, G.; Angeretti, N.; Chiesa, R.; Monzani, E.; Salmona, M.; Bugiani, O.; Tagliavini, F. Neurotoxicity of a prion protein fragment Nature 1993, 362, 543-546
68. Fioriti, L.; Angeretti, N.; Colombo, L.; De Luigi, A.; Colombo, A.; Manzoni, C.; Morbin, M.; Tagliavini, F.; Salmona, M.; Chiesa, R.; Forloni, G. Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-Sträussler-Scheinker disease amyloid protein J. Neurosci. 2007, 27, 1576-1583
69. Ronga, L.; Langella, E.; Palladino, P.; Marasco, D.; Tizzano, B.; Saviano, M.; Pedone, C.; Improta, R.; Ruvo, M. Does tetracycline bind helix 2 of prion? An integrated spectroscopical and computational study of the interaction between the antibiotic and alpha helix 2 human prion protein fragments Proteins 2007, 66, 707-715
70. Georgieva, D.; Schwark, D.; von Bergen, M.; Redecke, L.; Genov, N.; Betzel, C. Interactions of recombinant prions with compounds of therapeutical significance Biochem. Biophys. Res. Commun. 2006, 344, 463-470
71. De Luigi, A.; Colombo, L.; Diomede, L.; Capobianco, R.; Mangieri, M.; Miccolo, C.; Limido, L.; Forloni, G.; Tagliavini, F.; Salmona, M. The efficacy of tetracyclines in peripheral and intracerebral prion infection PLoS One 2008, 3, e1888
72. Diomede, L.; Cassata, G.; Fiordaliso, F.; Salio, M.; Ami, D.; Natalello, A.; Doglia, S. M.; De Luigi, A.; Salmona, M. Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers Neurobiol. Dis. 2010, 40, 424-431
73. Loeb, M. B.; Molloy, D. W.; Smieja, M.; Standish, T.; Goldsmith, C. H.; Mahony, J.; Smith, S.; Borrie, M.; Decoteau, E.; Davidson, W.; McDougall, A.; Gnarpe, J.; O'Donnell, M.; Chernesky, M. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease J. Am. Geriatr. Soc. 2004, 52, 381-387
74. Molloy, D. W.; Standish, T. I.; Zhou, Q.; Guyatt, G.; The DARAD Study Group. A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer's disease: the DARAD trial Int. J. Geriatr. Psychiatry 2013, 28, 463-470
75. Aitken, J. F.; Loomes, K. M.; Konarkowska, B.; Cooper, G. J. Suppression by polycyclic compounds of the conversion of human amylin into insoluble amyloid Biochem. J. 2003, 374, 779-784
76. Malmo, C.; Vilasi, S.; Iannuzzi, C.; Tacchi, S.; Cametti, C.; Irace, G.; Sirangelo, I. Tetracycline inhibits W7FW14F apomyoglobin fibril extension and keeps the amyloid protein in a pre-fibrillar, highly cytotoxic state FASEB J. 2006, 20, 346-347
77. Cardoso, I.; Merlini, G.; Saraiva, M. J. 4′-Iodo-4′- deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters FASEB J. 2003, 17, 803-809
78. Cardoso, I.; Saraiva, M. J. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model FASEB J. 2006, 20, 234-239
79. Cardoso, I.; Martins, D.; Ribeiro, T.; Merlini, G.; Saraiva, M. J. Synergy of combined doxycycline/TUDCA treatment in lowering transthyretin deposition and associated biomarkers: studies in FAP mouse models J. Transl. Med. 2010, 8, 74
80. Obici, L.; Cortese, A.; Lozza, A.; Lucchetti, J.; Gobbi, M.; Palladini, G.; Perlini, S.; Saraiva, M. J.; Merlini, G. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study Amyloid 2012, 19, 34-36
81. Ono, K.; Yamada, M. Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro J. Neurochem. 2006, 97, 105-115
82. Du, Y.; Ma, Z.; Lin, S.; Dodel, R. C.; Gao, F.; Bales, K. R.; Triarhou, L. C.; Chernet, E.; Perry, K. W.; Nelson, D. L.; Luecke, S.; Phebus, L. A.; Bymaster, F. P.; Paul, S. M. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 14669-14674
83. NINDS NET-PD Investigators. A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results Clin. Neuropharmacol. 2008, 31, 141-150
84. Chen, M.; Ona, V. O.; Li, M.; Ferrante, R. J.; Fink, K. B.; Zhu, S.; Bian, J.; Guo, L.; Farrell, L. A.; Hersch, S. M.; Hobbs, W.; Vonsattel, J. P.; Cha, J. H.; Friedlander, R. M. 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
85. Smith, D. L.; Woodman, B.; Mahal, A.; Sathasivam, K.; Ghazi-Noori, S.; Lowden, P. A.; Bates, G. P.; Hockly, E. Minocycline and doxycycline are not beneficial in a model of Huntington's disease Ann. Neurol. 2003, 54, 186-196
86. Mievis, S.; Levivier, M.; Communi, D.; Vassart, G.; Brotchi, J.; Ledent, C.; Blum, D. Lack of minocycline efficiency in genetic models of Huntington's disease Neuromol. Med. 2007, 9, 47-54
87. Huntington Study Group DOMINO Investigators. A futility study of minocycline in Huntington's disease Mov. Disord. 2010, 25, 2219-2224
88. Davies, J. E.; Wang, L.; Garcia-Oroz, L.; Cook, L. J.; Vacher, C.; O'Donovan, D. G.; Rubinsztein, D. C. Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice Nat. Med. 2005, 11, 672-677
89. Ward, J. E.; Ren, R.; Toraldo, G.; Soohoo, P.; Guan, J.; O'Hara, C.; Jasuja, R.; Trinkaus-Randall, V.; Liao, R.; Connors, L. H.; Seldin, D. C. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis Blood 2011, 118, 6610-6617
90. Zheng, H.; Tang, M.; Zheng, Q.; Kumarapeli, A. R.; Horak, K. M.; Tian, Z.; Wang, X. Doxycycline attenuates protein aggregation in cardiomyocytes and improves survival of a mouse model of cardiac proteinopathy J. Am. Coll. Cardiol. 2010, 56, 1418-1426
91. Giorgetti, S.; Raimondi, S.; Pagano, K.; Relini, A.; Bucciantini, M.; Corazza, A.; Fogolari, F.; Codutti, L.; Salmona, M.; Mangione, P.; Colombo, L.; De Luigi, A.; Porcari, R.; Gliozzi, A.; Stefani, M.; Esposito, G.; Bellotti, V.; Stoppini, M. Effect of tetracyclines on the dynamics of formation and destructuration of β2-microglobulin amyloid fibrils J. Biol. Chem. 2011, 286, 2121-2131
92. Cosentino, U.; Pitea, D.; Moro, G.; Saracino, G. A.; Caria, P.; Varì, R. M.; Colombo, L.; Forloni, G.; Tagliavini, F.; Salmona, M. The anti-fibrillogenic activity of tetracyclines on PrP 106-126: a 3D-QSAR study J. Mol. Model. 2008, 14, 987-994
93. Howlett, D. R.; George, A. R.; Owen, D. E.; Ward, R. V.; Markwell, R. E. Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation Biochem. J. 1999, 343, 419-423
94. Inbar, P.; Bautista, M. R.; Takayama, S. A.; Yang, J. Assay to screen for molecules that associate with Alzheimer's related β-amyloid fibrils Anal. Chem. 2008, 80, 3502-3506
95. Zovo, K.; Helk, E.; Karafin, A.; Tõugu, V.; Palumaa, P. Label-free high-throughput screening assay for inhibitors of Alzheimer's amyloid-β peptide aggregation based on MALDI MS Anal. Chem. 2010, 82, 8558-8565
96. Galimberti, D.; Fenoglio, C.; Scarpini, E. Inflammation in neurodegenerative disorders: friend or foe? Curr. Aging Sci. 2008, 1, 30-41
97. Ferreiro, E.; Baldeiras, I.; Ferreira, I. L.; Costa, R. O.; Rego, A. C.; Pereira, C. F.; Oliveira, C. R. Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer's disease: from pathogenesis to biomarkers Int. J. Cell Biol. 2012, 2012, 735206
98. Bolognin, S.; Messori, L.; Zatta, P. Metal ion physiopathology in neurodegenerative disorders Neuromol. Med. 2009, 11, 223-238
99. Lim, Y. A.; Rhein, V.; Baysang, G.; Meier, F.; Poljak, A.; Raftery, M. J.; Guilhaus, M.; Ittner, L. M.; Eckert, A.; Götz, J. Ab and human amylin share a common toxicity pathway via mitochondrial dysfunction Proteomics 2010, 10, 1621-1633
100. Noble, W.; Garwood, C. J.; Hanger, D. P. Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding Prion 2009, 3, 78-83
101. Gialeli, C.; Theocharis, A. D.; Karamanos, N. K. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting FEBS J. 2011, 278, 16-27
102. Manicone, A. M.; McGuire, J. K. Matrix metalloproteinases as modulators of inflammation Semin. Cell Dev. Biol. 2008, 19, 34-41
103. Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs Cardiovasc. Res. 2006, 69, 562-573
104. Naganuma, T.; Sugimura, K.; Uchida, J.; Tashiro, K.; Yoshimura, R.; Takemoto, Y.; Nakatani, T. Increased levels of serum matrix metalloproteinase-3 in haemodialysis patients with dialysis-related amyloidosis Nephrology (Carlton) 2008, 13, 104-108
105. Sousa, M. M.; do Amaral, J. B.; Guimarães, A.; Saraiva, M. J. Up-regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase-associated lipocalin, and matrix metalloproteinase-9 in familial amyloid polyneuropathy FASEB J. 2005, 19, 124-126
106. Biolo, A.; Ramamurthy, S.; Connors, L. H.; O'Hara, C. J.; Meier-Ewert, H. K.; Soo Hoo, P. T.; Sawyer, D. B.; Seldin, D. C.; Sam, F. Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition Circ.: Heart Failure 2008, 1, 249-257
107. Rosenberg, G. A. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases Lancet Neurol. 2009, 8, 205-216
108. Kim, E. M.; Hwang, O. Role of matrix metalloproteinase-3 in neurodegeneration J. Neurochem. 2011, 116, 22-32
109. Yan, P.; Hu, X.; Song, H.; Yin, K.; Bateman, R. J.; Cirrito, J. R.; Xiao, Q.; Hsu, F. F.; Turk, J. W.; Xu, J.; Hsu, C. Y.; Holtzman, D. M.; Lee, J. M. Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ J. Biol. Chem. 2006, 281, 24566-24574
110. Choi, D. H.; Kim, E. M.; Son, H. J.; Joh, T. H.; Kim, Y. S.; Kim, D.; Flint Beal, M.; Hwang, O. A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells J. Neurochem. 2008, 106, 405-415
111. Golub, L. M.; Lee, H. M.; Lehrer, G.; Nemiroff, A.; McNamara, T. F.; Kaplan, R.; Ramamurthy, N. S. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action J. Periodontal Res. 1983, 18, 516-526
112. Greenwald, R. A.; Golub, L. M.; Lavietes, B.; Ramamurthy, N. S.; Gruber, B.; Laskin, R. S.; McNamara, T. F. Tetracyclines inhibit human synovial collagenase in vivo and in vitro J. Rheumatol. 1987, 14, 28-32
113. Golub, L. M.; Evans, R. T.; McNamara, T. F.; Lee, H. M.; Ramamurthy, N. S. 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
114. Ryan, M. E.; Usman, A.; Ramamurthy, N. S.; Golub, L. M.; Greenwald, R. A. Excessive matrix metalloproteinase activity in diabetes: inhibition by tetracycline analogues with zinc reactivity Curr. Med. Chem. 2001, 8, 305-316
115. Seftor, R. E.; Seftor, E. A.; De Larco, J. E.; Kleiner, D. E.; Leferson, J.; Stetler-Stevenson, W. G.; McNamara, T. F.; Golub, L. M.; Hendrix, M. J. Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis Clin. Exp. Metastasis 1998, 16, 217-225
116. Garcia, R. A.; Pantazatos, D. P.; Gessner, C. R.; Go, K. V.; Woods, V. L., Jr.; Villarreal, F. J. Molecular interactions between matrilysin and the matrix metalloproteinase inhibitor doxycycline investigated by deuterium exchange mass spectrometry Mol. Pharmacol. 2005, 67, 1128-1136
117. Smith, G. N., Jr.; Mickler, E. A.; Hasty, K. A.; Brandt, K. D. Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme Arthritis Rheum. 1999, 42, 1140-1146
118. Golub, L. M. Introduction and background Pharmacol. Res. 2011, 63, 99-101
119. Greenwald, R. A. The road forward: the scientific basis for tetracycline treatment of arthritic disorders Pharmacol. Res. 2011, 64, 610-613
120. Fang, J.; Seki, T.; Maeda, H. Therapeutic strategies by modulating oxygen stress in cancer and inflammation Adv. Drug Delivery Rev. 2009, 61, 290-302
121. Schildknecht, S.; Pape, R.; Müller, N.; Robotta, M.; Marquardt, A.; Bürkle, A.; Drescher, M.; Leist, M. Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite J. Biol. Chem. 2011, 286, 4991-5002
122. Kummer, M. P.; Hermes, M.; Delekarte, A.; Hammerschmidt, T.; Kumar, S.; Terwel, D.; Walter, J.; Pape, H. C.; König, S.; Roeber, S.; Jessen, F.; Klockgether, T.; Korte, M.; Heneka, M. T. Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation Neuron 2011, 71, 833-844
123. Sousa, M. M.; Du Yan, S.; Fernandes, R.; Guimaraes, A.; Stern, D.; Saraiva, M. J. Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways J. Neurosci. 2001, 21, 7576-7586
124. Manczak, M.; Park, B. S.; Jung, Y.; Reddy, P. H. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage Neuromol. Med. 2004, 5, 147-162
125. Miyachi, Y.; Yoshioka, A.; Imamura, S.; Niwa, Y. Effect of antibiotics on the generation of reactive oxygen species J. Invest. Dermatol. 1986, 86, 449-453
126. Akamatsu, H.; Asada, M.; Komura, J.; Asada, Y.; Niwa, Y. Effect of doxycycline on the generation of reactive oxygen species: a possible mechanism of action of acne therapy with doxycycline Acta Derm.-Venereol. 1992, 72, 178-179
127. Romero-Perez, D.; Fricovsky, E.; Yamasaki, K. G.; Griffin, M.; Barraza-Hidalgo, M.; Dillmann, W.; Villarreal, F. Cardiac uptake of minocycline and mechanisms for in vivo cardioprotection J. Am. Coll. Cardiol. 2008, 52, 1086-1094
128. Zeydanli, E. N.; Kandilci, H. B.; Turan, B. Doxycycline ameliorates vascular endothelial and contractile dysfunction in the thoracic aorta of diabetic rats Cardiovasc. Toxicol. 2011, 11, 134-147
129. Lai, H. C.; Yeh, Y. C.; Ting, C. T.; Lee, W. L.; Lee, H. W.; Wang, L. C.; Wang, K. Y.; Lai, H. C.; Wu, A.; Liu, T. J. Doxycycline suppresses doxorubicin-induced oxidative stress and cellular apoptosis in mouse hearts Eur. J. Pharmacol. 2010, 644, 176-187
130. Hoyt, J. C.; Ballering, J.; Numanami, H.; Hayden, J. M.; Robbins, R. A. Doxycycline modulates nitric oxide production in murine lung epithelial cells J. Immunol. 2006, 176, 567-572
131. Huang, T. Y.; Chu, H. C.; Lin, Y. L.; Lin, C. K.; Hsieh, T. Y.; Chang, W. K.; Chao, Y. C.; Liao, C. L. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases Toxicol. Appl. Pharmacol. 2009, 237, 69-82
132. Amin, A. R.; Attur, M. G.; Thakker, G. D.; Patel, P. D.; Vyas, P. R.; Patel, R. N.; Patel, I. R.; Abramson, S. B. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14014-14019
133. Milano, S.; Arcoleo, F.; D'Agostino, P.; Cillari, E. Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood Antimicrob. Agents Chemother. 1997, 41, 117-121
134. Krakauer, T.; Buckley, M. Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines Antimicrob. Agents Chemother. 2003, 47, 3630-3633
135. Lau, A. C.; Duong, T. T.; Ito, S.; Wilson, G. J.; Yeung, R. S. Inhibition of matrix metalloproteinase-9 activity improves coronary outcome in an animal model of Kawasaki disease Clin. Exp. Immunol. 2009, 157, 300-309
136. Prall, A. K.; Longo, G. M.; Mayhan, W. G.; Waltke, E. A.; Fleckten, B.; Thompson, R. W.; Baxter, B. T. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice J. Vasc. Surg. 2002, 35, 923-929
137. Lindeman, J. H.; Abdul-Hussien, H.; van Bockel, J. H.; Wolterbeek, R.; Kleemann, R. Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells Circulation 2009, 119, 2209-2216
138. Miyazaki, E.; Ando, M.; Fukami, T.; Nureki, S.; Eishi, Y.; Kumamoto, T. Minocycline for the treatment of sarcoidosis: Is the mechanism of action immunomodulating or antimicrobial effect? Clin. Rheumatol. 2008, 27, 1195-1197
139. Del Rosso, J. Q.; Webster, G. F.; Jackson, M.; Rendon, M.; Rich, P.; Torok, H.; Bradshaw, M. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea J. Am. Acad. Dermatol. 2007, 56, 791-802
140. Golub, L. M.; McNamara, T. F.; Ryan, M. E.; Kohut, B.; Blieden, T.; Payonk, G.; Sipos, T.; Baron, H. J. Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis J. Clin. Periodontol. 2001, 28, 146-156
141. Sagar, J.; Sales, K.; Seifalian, A.; Winslet, M. Doxycycline in mitochondrial mediated pathway of apoptosis: a systematic review Anti-Cancer Agents Med. Chem. 2010, 10, 556-563
142. Wang, X.; Zhu, S.; Drozda, M.; Zhang, W.; Stavrovskaya, I. G.; Cattaneo, E.; Ferrante, R. J.; Kristal, B. S.; Friedlander, R. M. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10483-10487
143. 2+-dependent ion channels J. Bioenerg. Biomembr. 2010, 42, 151-163
144. Du Buy, H. G.; Showacre, J. L. Selective localization of tetracycline in mitochondria of living cells Science 1961, 133, 196-197
145. Riesbeck, K.; Bredberg, A.; Forsgren, A. Ciprofloxacin does not inhibit mitochondrial functions but other antibiotics do Antimicrob. Agents Chemother. 1990, 34, 167-169
146. Nadanaciva, S.; Dillman, K.; Gebhard, D. F.; Shrikhande, A.; Will, Y. High-content screening for compounds that affect mtDNA-encoded protein levels in eukaryotic cells J. Biomol. Screening 2010, 15, 937-948
147. Van der Bogert, C.; Melis, T. E.; Kroon, A. M. Mitochondrial biogenesis during the activation of lymphocytes by mitogens: the immunosuppressive action of tetracyclines J. Leukocyte Biol. 1989, 46, 128-133
148. Shieh, J. M.; Huang, T. F.; Hung, C. F.; Chou, K. H.; Tsai, Y. J.; Wu, W. B. Activation of c-Jun N-terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells Br. J. Pharmacol. 2010, 160, 1171-1184
149. Brown, T. M.; Clark, H. W.; Bailey, J. S.; Gray, C. W. Relationship between mycoplasma antibodies and rheumatoid factors Arthritis Rheum. 1970, 13, 309-310
150. Paulus, H. E. Minocycline treatment of rheumatoid arthritis Ann. Intern. Med. 1995, 122, 147-148
151. Ossola, B.; Lantto, T. A.; Puttonen, K. A.; Tuominen, R. K.; Raasmaja, A.; Männistö, P. T. Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death J. Neurosci. Res. 2012, 90, 682-690
152. Yong, V. W.; Wells, J.; Giuliani, F.; Casha, S.; Power, C.; Metz, L. M. The promise of minocycline in neurology Lancet Neurol. 2004, 3, 744-751