Conclusion
This study supports the prominent anti-inflammatory profile of the
promising tetracycline with no antibacterial activity, COL-3, on
microglial cells activated by ether LPS or αSa. These anti-inflammatory
effects derive from the inhibition of glucose uptake and NADPH
synthesis-dependent mechanism, which culminates in the production of ROS
by NADPH oxidase, necessary for the change of microglial cells into
their pro-inflammatory state. Thus, the complex and multifaceted action
of COL-3 can be useful in clinical trials in addition to those already
carried out for cancer studies, including different neuroinflammatory
conditions of the central nervous system.
REFERENCES
1. Protasoni, M.; Kroon, A.M.; Taanman, J.W. Mitochondria as oncotarget:
a comparison between the tetracycline analogs doxycycline and COL-3.Oncotarget 2018 , 9 , 33818-33831,
doi:10.18632/oncotarget.26107.
2. Bortolanza, M.; Nascimento, G.C.; Socias, S.B.; Ploper, D.; Chehin,
R.N.; Raisman-Vozari, R.; Del-Bel, E. Tetracycline repurposing in
neurodegeneration: focus on Parkinson’s disease. Journal of neural
transmission 2018 , 125 , 1403-1415,
doi:10.1007/s00702-018-1913-1.
3. Orsucci, D.; Calsolaro, V.; Mancuso, M.; Siciliano, G.
Neuroprotective effects of tetracyclines: molecular targets, animal
models and human disease. CNS & neurological disorders drug
targets 2009 , 8 , 222-231,
doi:10.2174/187152709788680689.
4. Orsucci, D.; Mancuso, M.; Filosto, M.; Siciliano, G. Tetracyclines
and neuromuscular disorders. Current neuropharmacology2012 , 10 , 134-138, doi:10.2174/157015912800604498.
5. Cho, Y.; Son, H.J.; Kim, E.M.; Choi, J.H.; Kim, S.T.; Ji, I.J.; Choi,
D.H.; Joh, T.H.; Kim, Y.S.; Hwang, O. Doxycycline is neuroprotective
against nigral dopaminergic degeneration by a dual mechanism involving
MMP-3. Neurotoxicity research 2009 , 16 , 361-371,
doi:10.1007/s12640-009-9078-1.
6. Lazzarini, M.; Martin, S.; Mitkovski, M.; Vozari, R.R.; Stuhmer, W.;
Bel, E.D. Doxycycline restrains glia and confers neuroprotection in a
6-OHDA Parkinson model. Glia 2013 , 61 , 1084-1100,
doi:10.1002/glia.22496.
7. Gonzalez-Lizarraga, F.; Socias, S.B.; Avila, C.L.; Torres-Bugeau,
C.M.; Barbosa, L.R.; Binolfi, A.; Sepulveda-Diaz, J.E.; Del-Bel, E.;
Fernandez, C.O.; Papy-Garcia, D.; et al. Repurposing doxycycline for
synucleinopathies: remodelling of alpha-synuclein oligomers towards
non-toxic parallel beta-sheet structured species. Scientific
reports 2017 , 7 , 41755, doi:10.1038/srep41755.
8. Medina, L.; Gonzalez-Lizarraga, F.; Dominguez-Meijide, A.; Ploper,
D.; Parrales, V.; Sequeira, S.; Cima-Omori, M.S.; Zweckstetter, M.; Del
Bel, E.; Michel, P.P.; et al. Doxycycline Interferes With Tau
Aggregation and Reduces Its Neuronal Toxicity. Front Aging
Neurosci 2021 , 13 , 635760,
doi:10.3389/fnagi.2021.635760.
9. Santa-Cecilia, F.V.; Socias, B.; Ouidja, M.O.; Sepulveda-Diaz, J.E.;
Acuna, L.; Silva, R.L.; Michel, P.P.; Del-Bel, E.; Cunha, T.M.;
Raisman-Vozari, R. Doxycycline Suppresses Microglial Activation by
Inhibiting the p38 MAPK and NF-kB Signaling Pathways.Neurotoxicity research 2016 , 29 , 447-459,
doi:10.1007/s12640-015-9592-2.
10. Bortolanza, M.; Nascimento, G.C.D.; Raisman-Vozari, R.; Del-Bel, E.
Doxycycline and its derivative, COL-3, decrease dyskinesia induced by
L-DOPA in hemiparkinsonian rats. British journal of pharmacology2021 , doi:10.1111/bph.15439.
11. Golub, L.M.; Lee, H.M.; Ryan, M.E.; Giannobile, W.V.; Payne, J.;
Sorsa, T. Tetracyclines inhibit connective tissue breakdown by multiple
non-antimicrobial mechanisms. Adv Dent Res 1998 ,12 , 12-26, doi:10.1177/08959374980120010501.
12. Golub, L.M.; Ramamurthy, N.S.; Llavaneras, A.; Ryan, M.E.; Lee,
H.M.; Liu, Y.; Bain, S.; Sorsa, T. A chemically modified
nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix
metalloproteinases, periodontal breakdown, and extra-oral bone loss in
ovariectomized rats. Annals of the New York Academy of Sciences1999 , 878 , 290-310,
doi:10.1111/j.1749-6632.1999.tb07691.x.
13. Golub, L.M.; Suomalainen, K.; Sorsa, T. Host modulation with
tetracyclines and their chemically modified analogues. Curr Opin
Dent 1992 , 2 , 80-90.
14. Sapadin, A.N.; Fleischmajer, R. Tetracyclines: nonantibiotic
properties and their clinical implications. Journal of the
American Academy of Dermatology 2006 , 54 , 258-265,
doi:10.1016/j.jaad.2005.10.004.
15. Gu, Y.; Lee, H.M.; Sorsa, T.; Salminen, A.; Ryan, M.E.; Slepian,
M.J.; Golub, L.M. Non-antibacterial tetracyclines modulate mediators of
periodontitis and atherosclerotic cardiovascular disease: a mechanistic
link between local and systemic inflammation. Pharmacological
research 2011 , 64 , 573-579,
doi:10.1016/j.phrs.2011.06.023.
16. Golub, L.M.; Ramamurthy, N.S.; McNamara, T.F.; Greenwald, R.A.;
Rifkin, B.R. Tetracyclines inhibit connective tissue breakdown: new
therapeutic implications for an old family of drugs. Crit Rev Oral
Biol Med 1991 , 2 , 297-321,
doi:10.1177/10454411910020030201.
17. Gonzalez-Lizarraga, F.; Ploper, D.; Avila, C.L.; Socias, S.B.;
Dos-Santos-Pereira, M.; Machin, B.; Del-Bel, E.; Michel, P.P.;
Pietrasanta, L.I.; Raisman-Vozari, R.; et al. CMT-3 targets different
alpha-synuclein aggregates mitigating their toxic and inflammogenic
effects. Scientific reports 2020 , 10 , 20258,
doi:10.1038/s41598-020-76927-0.
18. Zhang, H.; Chang, M.; Hansen, C.N.; Basso, D.M.; Noble-Haeusslein,
L.J. Role of matrix metalloproteinases and therapeutic benefits of their
inhibition in spinal cord injury. Neurotherapeutics : the journal
of the American Society for Experimental NeuroTherapeutics2011 , 8 , 206-220, doi:10.1007/s13311-011-0038-0.
19. Islam, M.M.; Franco, C.D.; Courtman, D.W.; Bendeck, M.P. A
nonantibiotic chemically modified tetracycline (CMT-3) inhibits intimal
thickening. The American journal of pathology 2003 ,163 , 1557-1566, doi:10.1016/S0002-9440(10)63512-2.
20. Syed, S.; Takimoto, C.; Hidalgo, M.; Rizzo, J.; Kuhn, J.G.; Hammond,
L.A.; Schwartz, G.; Tolcher, A.; Patnaik, A.; Eckhardt, S.G.; et al. A
phase I and pharmacokinetic study of Col-3 (Metastat), an oral
tetracycline derivative with potent matrix metalloproteinase and
antitumor properties. Clin Cancer Res 2004 , 10 ,
6512-6521, doi:10.1158/1078-0432.CCR-04-0804.
21. Rudek, M.A.; Figg, W.D.; Dyer, V.; Dahut, W.; Turner, M.L.;
Steinberg, S.M.; Liewehr, D.J.; Kohler, D.R.; Pluda, J.M.; Reed, E.
Phase I clinical trial of oral COL-3, a matrix metalloproteinase
inhibitor, in patients with refractory metastatic cancer. J Clin
Oncol 2001 , 19 , 584-592, doi:10.1200/JCO.2001.19.2.584.
22. Chu, Q.S.; Forouzesh, B.; Syed, S.; Mita, M.; Schwartz, G.; Cooper,
J.; Curtright, J.; Rowinsky, E.K. A phase II and pharmacological study
of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with
advanced soft tissue sarcomas. Invest New Drugs 2007 ,25 , 359-367, doi:10.1007/s10637-006-9031-6.
23. Dezube, B.J.; Krown, S.E.; Lee, J.Y.; Bauer, K.S.; Aboulafia, D.M.
Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in
AIDS-related Kaposi’s sarcoma: an AIDS Malignancy Consortium Study.J Clin Oncol 2006 , 24 , 1389-1394,
doi:10.1200/JCO.2005.04.2614.
24. Fingleton, B. CMT-3. CollaGenex. Current opinion in
investigational drugs 2003 , 4 , 1460-1467.
25. Greenwald, R.A.; Golub, L.M.; Ramamurthy, N.S.; Chowdhury, M.; Moak,
S.A.; Sorsa, T. In vitro sensitivity of the three mammalian collagenases
to tetracycline inhibition: relationship to bone and cartilage
degradation. Bone 1998 , 22 , 33-38,
doi:10.1016/s8756-3282(97)00221-4.
26. Edan, R.A.; Luqmani, Y.A.; Masocha, W. COL-3, a chemically modified
tetracycline, inhibits lipopolysaccharide-induced microglia activation
and cytokine expression in the brain. PloS one 2013 ,8 , e57827, doi:10.1371/journal.pone.0057827.
27. Couch, Y.; Alvarez-Erviti, L.; Sibson, N.R.; Wood, M.J.; Anthony,
D.C. The acute inflammatory response to intranigral alpha-synuclein
differs significantly from intranigral lipopolysaccharide and is
exacerbated by peripheral inflammation. Journal of
neuroinflammation 2011 , 8 , 166,
doi:10.1186/1742-2094-8-166.
28. Lema Tome, C.M.; Tyson, T.; Rey, N.L.; Grathwohl, S.; Britschgi, M.;
Brundin, P. Inflammation and alpha-synuclein’s prion-like behavior in
Parkinson’s disease–is there a link? Molecular neurobiology2013 , 47 , 561-574, doi:10.1007/s12035-012-8267-8.
29. Zhang, W.; Wang, T.; Pei, Z.; Miller, D.S.; Wu, X.; Block, M.L.;
Wilson, B.; Zhang, W.; Zhou, Y.; Hong, J.S.; et al. Aggregated
alpha-synuclein activates microglia: a process leading to disease
progression in Parkinson’s disease. FASEB journal : official
publication of the Federation of American Societies for Experimental
Biology 2005 , 19 , 533-542, doi:10.1096/fj.04-2751com.
30. Dos-Santos-Pereira, M.; Acuna, L.; Hamadat, S.; Rocca, J.;
Gonzalez-Lizarraga, F.; Chehin, R.; Sepulveda-Diaz, J.; Del-Bel, E.;
Raisman-Vozari, R.; Michel, P.P. Microglial glutamate release evoked by
alpha-synuclein aggregates is prevented by dopamine. Glia2018 , 66 , 2353-2365, doi:10.1002/glia.23472.
31. Rousseau, E.; Michel, P.P.; Hirsch, E.C. The iron-binding protein
lactoferrin protects vulnerable dopamine neurons from degeneration by
preserving mitochondrial calcium homeostasis. Molecular
pharmacology 2013 , 84 , 888-898,
doi:10.1124/mol.113.087965.
32. Dos-Santos-Pereira, M.; Guimaraes, F.S.; Del-Bel, E.;
Raisman-Vozari, R.; Michel, P.P. Cannabidiol prevents LPS-induced
microglial inflammation by inhibiting ROS/NF-kappaB-dependent signaling
and glucose consumption. Glia 2020 , 68 , 561-573,
doi:10.1002/glia.23738.
33. Sepulveda-Diaz, J.E.; Ouidja, M.O.; Socias, S.B.; Hamadat, S.;
Guerreiro, S.; Raisman-Vozari, R.; Michel, P.P. A simplified approach
for efficient isolation of functional microglial cells: Application for
modeling neuroinflammatory responses in vitro. Glia2016 , 64 , 1912-1924, doi:10.1002/glia.23032.
34. Hoyer, W.; Antony, T.; Cherny, D.; Heim, G.; Jovin, T.M.;
Subramaniam, V. Dependence of alpha-synuclein aggregate morphology on
solution conditions. Journal of molecular biology 2002 ,322 , 383-393.
35. Acuna, L.; Hamadat, S.; Corbalan, N.S.; Gonzalez-Lizarraga, F.;
Dos-Santos-Pereira, M.; Rocca, J.; Diaz, J.S.; Del-Bel, E.; Papy-Garcia,
D.; Chehin, R.N.; et al. Rifampicin and Its Derivative Rifampicin
Quinone Reduce Microglial Inflammatory Responses and Neurodegeneration
Induced In Vitro by alpha-Synuclein Fibrillary Aggregates. Cells2019 , 8 , doi:10.3390/cells8080776.
36. Doring, C.; Regen, T.; Gertig, U.; van Rossum, D.; Winkler, A.;
Saiepour, N.; Bruck, W.; Hanisch, U.K.; Janova, H. A presumed
antagonistic LPS identifies distinct functional organization of TLR4 in
mouse microglia. Glia 2017 , 65 , 1176-1185,
doi:10.1002/glia.23151.
37. Ghosh, S.; Castillo, E.; Frias, E.S.; Swanson, R.A. Bioenergetic
regulation of microglia. Glia 2018 , 66 ,
1200-1212, doi:10.1002/glia.23271.
38. Richards, C.; Pantanowitz, L.; Dezube, B.J. Antimicrobial and
non-antimicrobial tetracyclines in human cancer trials.Pharmacological research 2011 , 63 , 151-156,
doi:10.1016/j.phrs.2010.10.008.
39. Lee, H.M.; Golub, L.M.; Cao, J.; Teronen, O.; Laitinen, M.; Salo,
T.; Zucker, S.; Sorsa, T. CMT-3, a non-antimicrobial tetracycline (TC),
inhibits MT1-MMP activity: relevance to cancer. Curr Med Chem2001 , 8 , 257-260, doi:10.2174/0929867013373660.
40. Cianfrocca, M.; Cooley, T.P.; Lee, J.Y.; Rudek, M.A.; Scadden, D.T.;
Ratner, L.; Pluda, J.M.; Figg, W.D.; Krown, S.E.; Dezube, B.J. Matrix
metalloproteinase inhibitor COL-3 in the treatment of AIDS-related
Kaposi’s sarcoma: a phase I AIDS malignancy consortium study. J
Clin Oncol 2002 , 20 , 153-159,
doi:10.1200/JCO.2002.20.1.153.
41. Parvathy, S.S.; Masocha, W. Matrix metalloproteinase inhibitor COL-3
prevents the development of paclitaxel-induced hyperalgesia in mice.Med Princ Pract 2013 , 22 , 35-41,
doi:10.1159/000341710.
42. Cazalis, J.; Tanabe, S.; Gagnon, G.; Sorsa, T.; Grenier, D.
Tetracyclines and chemically modified tetracycline-3 (CMT-3) modulate
cytokine secretion by lipopolysaccharide-stimulated whole blood.Inflammation 2009 , 32 , 130-137,
doi:10.1007/s10753-009-9111-9.
43. Hsieh, C.F.; Liu, C.K.; Lee, C.T.; Yu, L.E.; Wang, J.Y. Acute
glucose fluctuation impacts microglial activity, leading to inflammatory
activation or self-degradation. Scientific reports 2019 ,9 , 840, doi:10.1038/s41598-018-37215-0.
44. Dai, C.; Ciccotosto, G.D.; Cappai, R.; Wang, Y.; Tang, S.; Xiao, X.;
Velkov, T. Minocycline attenuates colistin-induced neurotoxicity via
suppression of apoptosis, mitochondrial dysfunction and oxidative
stress. J Antimicrob Chemother 2017 , 72 ,
1635-1645, doi:10.1093/jac/dkx037.
45. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the
Warburg effect: the metabolic requirements of cell proliferation.Science 2009 , 324 , 1029-1033,
doi:10.1126/science.1160809.
46. Jurcovicova, J. Glucose transport in brain - effect of inflammation.Endocr Regul 2014 , 48 , 35-48,
doi:10.4149/endo_2014_01_35.
47. Fodelianaki, G.; Lansing, F.; Bhattarai, P.; Troullinaki, M.;
Zeballos, M.A.; Charalampopoulos, I.; Gravanis, A.; Mirtschink, P.;
Chavakis, T.; Alexaki, V.I. Nerve Growth Factor modulates LPS - induced
microglial glycolysis and inflammatory responses. Exp Cell Res2019 , 377 , 10-16, doi:10.1016/j.yexcr.2019.02.023.
48. Koo, S.J.; Szczesny, B.; Wan, X.; Putluri, N.; Garg, N.J. Pentose
Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide
Production Controlling Trypanosoma cruzi in Macrophages. Front
Immunol 2018 , 9 , 202, doi:10.3389/fimmu.2018.00202.
49. TeSlaa, T.; Teitell, M.A. Techniques to monitor glycolysis.Methods Enzymol 2014 , 542 , 91-114,
doi:10.1016/B978-0-12-416618-9.00005-4.
50. Gong, H.; Liu, L.; Ni, C.X.; Zhang, Y.; Su, W.J.; Lian, Y.J.; Peng,
W.; Zhang, J.P.; Jiang, C.L. Dexamethasone rapidly inhibits glucose
uptake via non-genomic mechanisms in contracting myotubes. Arch
Biochem Biophys 2016 , 603 , 102-109,
doi:10.1016/j.abb.2016.05.020.
51. Liu, Y.; Ramamurthy, N.; Marecek, J.; Lee, H.M.; Chen, J.L.; Ryan,
M.E.; Rifkin, B.R.; Golub, L.M. The lipophilicity, pharmacokinetics, and
cellular uptake of different chemically-modified tetracyclines (CMTs).Curr Med Chem 2001 , 8 , 243-252,
doi:10.2174/0929867013373525.
52. di Penta, A.; Moreno, B.; Reix, S.; Fernandez-Diez, B.; Villanueva,
M.; Errea, O.; Escala, N.; Vandenbroeck, K.; Comella, J.X.; Villoslada,
P. Oxidative stress and proinflammatory cytokines contribute to
demyelination and axonal damage in a cerebellar culture model of
neuroinflammation. PloS one 2013 , 8 , e54722,
doi:10.1371/journal.pone.0054722.
53. Bird, L. Microglial memory. Nat Rev Immunol 2018 ,18 , 358-359, doi:10.1038/s41577-018-0015-5.
54. Stefanska, J.; Pawliczak, R. Apocynin: molecular aptitudes.Mediators of inflammation 2008 , 2008 , 106507,
doi:10.1155/2008/106507.
55. Lúcio, M.; Nunes, C.; Gaspar, D.; Ferreira, H.; Lima, J.L.F.C.;
Reis, S. Antioxidant Activity of Vitamin E and Trolox: Understanding of
the Factors that Govern Lipid Peroxidation Studies In Vitro. Food
Biophysics 2009 , 4 , 312-320,
doi:10.1007/s11483-009-9129-4.
56. Bedard, K.; Krause, K.H. The NOX family of ROS-generating NADPH
oxidases: physiology and pathophysiology. Physiological reviews2007 , 87 , 245-313, doi:10.1152/physrev.00044.2005.
57. Gloire, G.; Legrand-Poels, S.; Piette, J. NF-kappaB activation by
reactive oxygen species: fifteen years later. Biochemical
pharmacology 2006 , 72 , 1493-1505,
doi:10.1016/j.bcp.2006.04.011.
58. Shabab, T.; Khanabdali, R.; Moghadamtousi, S.Z.; Kadir, H.A.; Mohan,
G. Neuroinflammation pathways: a general review. The International
journal of neuroscience 2017 , 127 , 624-633,
doi:10.1080/00207454.2016.1212854.
59. Onoda, T.; Ono, T.; Dhar, D.K.; Yamanoi, A.; Nagasue, N.
Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent
and -independent apoptosis in human colon cancer cells.International journal of cancer 2006 , 118 ,
1309-1315, doi:10.1002/ijc.21447.