nach oben

Erschienen in:

01.04.2011 | Research Article

Anti-inflammatory properties of Doxycycline and Minocycline in experimental models: an in vivo and in vitro comparative study

verfasst von: Liz M. Leite, Antônio Germano G. Carvalho, Pollyanna L. F. Tavares Ferreira, Igor Xavier Pessoa, Danilo O. Gonçalves, Amanda de Araújo Lopes, Jean Guilherme dos Santos Góes, Victor Costa de Castro Alves, Luzia Kalyne A. M. Leal, Gerly Anne Brito, Glauce S. B. Viana

Erschienen in: Inflammopharmacology | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Aims and methods

Minocycline (Mino) and doxycycline (Dox) are second generation tetracyclines known to present several other effects, which are independent from their antimicrobial activities. We studied in a comparative way the anti-inflammatory effects of Mino and Dox, on acute models of peripheral inflammation in rodents (formalin test and peritonitis in mice, and carrageenan-induced paw oedema in rats). Immunohistochemical assays for TNF-alpha and iNOS in rat paws of carrageenan-induced oedema were also carried out as well as in vitro assays for myeloperoxidase (MPO) and lactate dehydrogenase (LDH). Furthermore, antioxidant activities were evaluated by the DPPH assay.

Results

In the formalin test although Mino and Dox (1, 5, 10 and 25 mg/kg, i.p.) inhibited the first phase, they acted predominantly on the second phase of the test, where inhibition of the licking time close to 80% were observed. Mino and Dox were very efficacious in reducing the carrageenan-induced paw oedema in rats (10, 25 and 50 mg/kg, i.p.) and carrageenan-induced leucocyte migration (1 and 5 mg/kg, i.p.) to mice peritoneal cavities. Besides, they also significantly inhibited MPO and LDH releases at doses ranging from 0.001 to 1 μg/ml. Thus, in general, the anti-inflammatory activity of Dox was higher as compared to that of Mino, although the radical scavenging activity of Mino was of a magnitude 10 times higher.

Conclusions

Our data indicate that anti-inflammatory and antioxidant effects, involve the inhibition of iNOS and TNF-alpha, among other properties, and these encourage clinical studies of these compounds for new therapeutic applications, especially those were inflammation plays a role.

Aladakatti SV, Patil PA, Vivek V (2008) Influence of tetracyclines on inflammation and their interaction with aspirin in male Wistar rats. Pharmacology online 3:808–819

Alano CC, Kauppinen TM, Valls AV, Swanson RA (2006) Minocycline inhibits poly (ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci USA 103:9685–9690PubMedCrossRef

Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB (1996) A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA 93:14014–14019PubMedCrossRef

Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 52:54–61PubMedCrossRef

Attur MG, Patel RN, Patel PD, Abramson SB, Amin AR (1999) Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol 162:3160–3167PubMed

Bastos LF, Merlo LA, Rocha LT, Coelho MM (2007) Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models. Eur J Pharmacol 576:171–179PubMedCrossRef

Bombardier S, Cattani P, Giabattoni G, Di Munno O, Paero G, Patrono C, Pinca E, Pugliese F (1981) The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and non-steroidal antiinfammatory drugs. Br J Pharmacol 73:893–901

Cai ZY, Yan Y, Sun SQ, Zhang J, Huang LG, Yan NN, Wu F, Li JY (2008) Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull 24:305–313PubMedCrossRef

Cazalis J, Tanabe S, Gagnon G, Sorsa T, Grenier D (2009) Tetracyclines and chemically modified tetracycline-3 (CMT-3) modulate cytokine secretion by lipopolysaccharide-stimulated whole blood. Inflammation 32:130–137PubMedCrossRef

Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Biau J, Gno L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801PubMedCrossRef

Cho IH, Chung YM, Park CK, Li HY, Kim D, Plao ZH, Choi SY, Lee SJ, Park K, Kim JS, Jung SJ, Oh SB (2006) Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat. Brain Res 1072:208–214PubMedCrossRef

Daher JB, Tonussi CR (2003) A spinal mechanism for the peripheral anti-inflammatory action of indomethacin. Brain Res 962:207–212PubMedCrossRef

Davies P, MacIntyre DE (1992) Prostaglandins and inflammation. In: Gallin JI, Goldstein IM, Snyderman R (eds) Inflammation: basic principles and clinical correlates. Raven Press, New York, pp 123–138

Davies P, Bailey PJ, Goldenberg MM, Ford-Hutchinson AW (1984) The role of arachidonic acid oxygenation products in pain and inflammation. Ann Rev Immunol 2:235–257CrossRef

De Young LM, Kheifets JB, Ballaron SJ, Young JM (1989) Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions 26:335–341PubMedCrossRef

DeClerk YA, Shimada H, Taylor SM, Langley KE (1994) Matrix metalloproteinases and their inhibitors in tumor progression. Ann NY Acad Sci 732:222–232CrossRef

El Kebir D, József L, Pan W, Filep JG (2008) Myeloperoxidase delays neutrophil apoptosis through CD11b/CD18 integrins and prolongs inflammation. Circ Res 103:352–359PubMedCrossRef

Faith M, Sukumaran A, Pulimood AB, Jacob M (2008) How reliable an indicator of inflammation is myeloperoxidase activity? Clin Chim Acta 396:23–25PubMedCrossRef

Foster SJ, McCormick ME, Howarth A, Aked D (1986) Leukocyte recruitment in the subcutaneous sponge implant model of acute inflammation in the rat is not mediated by leukotriene B1. Biochem Pharmacol 35:1709–1717PubMedCrossRef

Fu KY, Light AR, Maixner W (2000) Relationship between nociceptor activity, peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin. Neuroscience 101:1127–1135PubMedCrossRef

Gilbertson-Beadling S, Powers EA, Stamp-Cole M, Scott PS, Wallace TL, Copeland J, Petzold G, Mitchell M, Ledbetter S, Poorman R (1995) The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism. Cancer Chemother Pharmacol 36:418–424PubMedCrossRef

Giuliani F, Hader W, Yong VW (2005) Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol 78:135–143PubMedCrossRef

Greenwald RA (1994) Treatment of destructive arthritic disorders with MMP inhibitors. Potential role of tetracyclines. Ann N Y Acad Sci 732:181–198

Guay J, Bateman K, Gordon R, Mancini J, Riendeau D (2004) Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1. J Biol Chem 279:24866–24872PubMedCrossRef

Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior and anhedonia. J Neuroinflamm 13:5–15

Hsu SM, Raine L (1981) Protein a, avidin, and biotin in immunohistochemistry. J Histochem Cytochem 29:1349–1353PubMed

Hua XY, Svensson CI, Matsui T, Fitzsimmons B, Yaksh TL, Webb M (2005) Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci 22:2431–2440PubMedCrossRef

Hunskaar S, Fasmer OB, Hole K (1985) Formalin test in mice, a useful technique for evaluating mild analgesics. J Neurosci Methods 14:69–75PubMedCrossRef

Ichitani Y, Shi T, Haeggstrom JZ, Samuelsson B, Hökfelt T (1997) Increased levels of cyclooxygenase-2 mRNA in the rat spinal cord after peripheral inflammation: an in situ hybridization study. Neuroreport 8:2949–2952PubMedCrossRef

Kelly KJ, Sutton TA, Weathered N, Ray N, Caldwell EJ, Plotkin Z, Dagher PC (2004) Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. Am J Physiol Renal Physiol 287:F760–F766PubMedCrossRef

Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress and direct radical-scavenging activity. J Neurochem 94:819–827PubMedCrossRef

Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maler SF, Watkins LR (2005) Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115:71–83PubMedCrossRef

Leppert D, Lindberg RL, Kappos L, Leib SL (2001) Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res. Brain Res. Rev 36:249–257PubMedCrossRef

Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65:S140–S146PubMedCrossRef

Lucisano YM, Mantovani B (1984) Lysosomal enzyme release from polymorphonuclear leukocytes induced by immune complexes of IgM and of IgG. J Immunol 132(4):2015–2020PubMed

Nieman GF, Zerler BR (2001) A role for the anti-inflammatory properties of tetracyclines in the prevention of acute lung injury. Curr Med Chem 8:317–325PubMed

Omote K, Hozama K, Kawamata T, Kawamata M, Nakayaka Y, Toriyabe M, Namiki A (2001) Peripheral nitric oxide in carraggenan-induced inflammation. Brain Res 912:171–175PubMedCrossRef

Padi SS, Kulkarni SK (2008) Minocycline prevents the development of neurophatic pain, but not acute pain: possible anti-inflammatory and amtioxidant mechanisms. Eur J Pharmacol 601:79–87PubMedCrossRef

Ramamurthy NS, Greenwald RA, Moak SA, Scuibba J, Goren A, Turner G, Rifkin B, Golub LM, Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ (2008) Microglial activation and TNF-alpha production mediate altered CNS excitability following peripheral inflammation. PNAS 105:17151–17156CrossRef

Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ (2008) Microglial activation and TNF-alpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA 105:15151–17156CrossRef

Rifkin B, Vermillo AT, Golub LM (1993) Blocking periodontal disease progression by inhibiting tissue-destructive enzymes: a potential therapeutic role for tetracyclines and their chemically-modified analogs. J Periodontol 64:819–827PubMed

Saint-Cricq de Gaulejac NS, Provost C, Vivas N (1999) Comparative study of polyphenol scavenging activities assessed by different methods. J Agric Food Chem 47:425–431PubMedCrossRef

Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1 beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–475PubMedCrossRef

Sweitzer SM, Colbum RW, Rutkowski M, DeLeo JA (1999) Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res 829:209–221PubMedCrossRef

Tjolsen A, Berge O-G, Hunskaar S et al (1992) The formalin test: an evaluation of the method. Pain 51:5–17PubMedCrossRef

Uitto VJ, Firth JD, Nip L, Golub LM (1994) Doxycycline and chemically modified tetracyclines inhibit gelatinase A (MMP-2) gene expression in human skin keratinocytes. Ann NY Acad Sci 732:140–151PubMedCrossRef

Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J (2003) Early short-term treatment with doxycycline modulates postinfarction left ventricular remodelling. Circulation 108:1487–1492PubMedCrossRef

Wang AL, Yu AC, Lau LT, Lee C, Wu IM, Zhu X, Tso MO (2005) Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47:152–158PubMedCrossRef

Winter CA, Risley EA, Nuss GW (1962) Carrageenen-induced oedema in hind paw of rat: an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–547PubMed

Xiao QG, Liu ZG, Zhang M, Zheng JL, Zhang ZH, Chen JQ (2005) Effect of doxycycline on inflammation-related cytokines and apoptosis in human conjunctival epthelial cells. Zhonghua Yan Ke Za Zhi 41:842–846PubMed

Zhang ZY, Zhang Z, Fauser U, Schluesener HJ (2009) Improved outcome of EAN, an animal model of GBS, through amelioration of peripheral and central inflammation by minocycline. J Cell Mol Med 13:341–351PubMedCrossRef

Zhu S, Stavrosvskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu du C, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78

Titel: Anti-inflammatory properties of Doxycycline and Minocycline in experimental models: an in vivo and in vitro comparative study
verfasst von: Liz M. Leite
Antônio Germano G. Carvalho
Pollyanna L. F. Tavares Ferreira
Igor Xavier Pessoa
Danilo O. Gonçalves
Amanda de Araújo Lopes
Jean Guilherme dos Santos Góes
Victor Costa de Castro Alves
Luzia Kalyne A. M. Leal
Gerly Anne Brito
Glauce S. B. Viana
Publikationsdatum: 01.04.2011
Verlag: SP Birkhäuser Verlag Basel
Erschienen in: Inflammopharmacology / Ausgabe 2/2011
Print ISSN: 0925-4692
Elektronische ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-011-0077-5

Springer Medizin

Abstract

Aims and methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2011

Hughes syndrome (the antiphospholipid syndrome): a disease of our time

The potential of the immunological markers of sarcoidosis in exhaled breath and peripheral blood as future diagnostic and monitoring techniques

Analgesic and anti-inflammatory activities of 18-acetoxy-ent-kaur-16-ene from Annona squamosa L. bark

Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis

Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase