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Published in: Archives of Dermatological Research 10/2016

01-12-2016 | Original Paper

Topically applied manganese-porphyrins BMX-001 and BMX-010 display a significant anti-inflammatory response in a mouse model of allergic dermatitis

Authors: Kelsey Stover, Tomoki Fukuyama, Ashlyn T. Young, Michael A. Daniele, Rebecca Oberley, James D. Crapo, Wolfgang Bäumer

Published in: Archives of Dermatological Research | Issue 10/2016

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Abstract

In this study, we topically administered two antioxidant compounds, the manganese-porphyrin-derivatives BMX-001 and BMX-010, in a mouse model of allergic dermatitis and compared the efficacy for reduction of itch and inflammation. In vitro effects of BMX-001 and BMX-010 on keratinocytes, bone marrow derived dendritic cells (BMDCs) and T-cells were initially analysed. For assessment of scratching behaviour, BMX-001 and BMX-010 (0.01 and 0.1 %) were topically applied 16 h and/or 1 h before compound 48/80 or toluene-2,4,-diisocyanate (TDI) challenge in a TDI induced mouse dermatitis model. Additionally, assessment of allergic skin inflammation was performed in a similar manner in the TDI model. Post-treatment ear thickness was measured 24 h after TDI challenge and compared to basal values. The mice were sacrificed and the ear auricle was removed for further analysis. In vitro, both BMX substances significantly inhibited cytokine production of keratinocytes as well as of BMDC and T-cell proliferation. Topical treatment with BMX cream resulted in a significant decrease in scratching behaviour in the compound 48/80 model, but not in the TDI model. Mice treated with BMX-001 and BMX-010 showed a moderate dose dependent decrease in ear thickness, and interestingly, the concentration of the cytokines IL-1β and IL-4 in inflamed skin was reduced by 80–90 % by all treatment options. These first results suggest the potential benefit of a BMX-001 and BMX-010 cream for the treatment of allergic-inflammatory skin diseases.
Literature
1.
go back to reference Aikawa T, Ito S, Shinohara M, Kaneko M, Kondo T, Yuasa M (2015) A drug formulation using an alginate hydrogel matrix for efficient oral delivery of the manganese porphyrin-based superoxide dismutase mimic. Biomater Sci 3(6):861–869CrossRefPubMed Aikawa T, Ito S, Shinohara M, Kaneko M, Kondo T, Yuasa M (2015) A drug formulation using an alginate hydrogel matrix for efficient oral delivery of the manganese porphyrin-based superoxide dismutase mimic. Biomater Sci 3(6):861–869CrossRefPubMed
3.
go back to reference Archambeau JO, Tovmasyan A, Pearlstein RD, Crapo JD, Batinic-Haberle I (2013) Superoxide dismutase mimic, MnTE-2-PyP(5+) ameliorates acute and chronic proctitis following focal proton irradiation of the rat rectum. Redox Biol 1:599–607CrossRefPubMedPubMedCentral Archambeau JO, Tovmasyan A, Pearlstein RD, Crapo JD, Batinic-Haberle I (2013) Superoxide dismutase mimic, MnTE-2-PyP(5+) ameliorates acute and chronic proctitis following focal proton irradiation of the rat rectum. Redox Biol 1:599–607CrossRefPubMedPubMedCentral
4.
go back to reference Batinic-Haberle I, Rajic Z, Tovmasyan A, Reboucas JS, Ye X, Leong KW, Dewhirst MW, Vujaskovic Z, Benov L, Spasojevic I (2011) Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics. Free Radic Biol Med 51(5):1035–1053CrossRefPubMedPubMedCentral Batinic-Haberle I, Rajic Z, Tovmasyan A, Reboucas JS, Ye X, Leong KW, Dewhirst MW, Vujaskovic Z, Benov L, Spasojevic I (2011) Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics. Free Radic Biol Med 51(5):1035–1053CrossRefPubMedPubMedCentral
5.
go back to reference Batinic-Haberle I, Reboucas JS, Spasojevic I (2010) Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal 13(6):877–918CrossRefPubMedPubMedCentral Batinic-Haberle I, Reboucas JS, Spasojevic I (2010) Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal 13(6):877–918CrossRefPubMedPubMedCentral
6.
go back to reference Batinic-Haberle I, Tovmasyan A, Roberts ER, Vujaskovic Z, Leong KW, Spasojevic I (2014) SOD therapeutics: latest insights into their structure-activity relationships and impact on the cellular redox-based signaling pathways. Antioxid Redox Signal 20(15):2372–2415CrossRefPubMedPubMedCentral Batinic-Haberle I, Tovmasyan A, Roberts ER, Vujaskovic Z, Leong KW, Spasojevic I (2014) SOD therapeutics: latest insights into their structure-activity relationships and impact on the cellular redox-based signaling pathways. Antioxid Redox Signal 20(15):2372–2415CrossRefPubMedPubMedCentral
7.
go back to reference Baumer W, Kietzmann M (2007) Effects of cyclosporin A and cilomilast on activated canine, murine and human keratinocytes. Vet Dermatol 18(2):107–114CrossRefPubMed Baumer W, Kietzmann M (2007) Effects of cyclosporin A and cilomilast on activated canine, murine and human keratinocytes. Vet Dermatol 18(2):107–114CrossRefPubMed
8.
go back to reference Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M (2004) TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol 151(4):823–830CrossRefPubMed Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M (2004) TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol 151(4):823–830CrossRefPubMed
9.
go back to reference Baumer W, Tschernig T, Sulzle B, Seegers U, Luhrmann A, Kietzmann M (2003) Effects of cilomilast on dendritic cell function in contact sensitivity and dendritic cell migration through skin. Eur J Pharmacol 481(2–3):271–279CrossRefPubMed Baumer W, Tschernig T, Sulzle B, Seegers U, Luhrmann A, Kietzmann M (2003) Effects of cilomilast on dendritic cell function in contact sensitivity and dendritic cell migration through skin. Eur J Pharmacol 481(2–3):271–279CrossRefPubMed
10.
go back to reference Baumer W, Wlaz P, Jennings G, Rundfeldt C (2010) The putative lipid raft modulator miltefosine displays immunomodulatory action in T-cell dependent dermal inflammation models. Eur J Pharmacol 628(1–3):226–232CrossRefPubMed Baumer W, Wlaz P, Jennings G, Rundfeldt C (2010) The putative lipid raft modulator miltefosine displays immunomodulatory action in T-cell dependent dermal inflammation models. Eur J Pharmacol 628(1–3):226–232CrossRefPubMed
11.
go back to reference Fukuyama T, Ehling S, Cook E, Baumer W (2015) Topically administered Janus-Kinase inhibitors tofacitinib and oclacitinib display impressive antipruritic and anti-inflammatory responses in a model of allergic dermatitis. J Pharmacol Exp Ther 354(3):394–405CrossRefPubMed Fukuyama T, Ehling S, Cook E, Baumer W (2015) Topically administered Janus-Kinase inhibitors tofacitinib and oclacitinib display impressive antipruritic and anti-inflammatory responses in a model of allergic dermatitis. J Pharmacol Exp Ther 354(3):394–405CrossRefPubMed
12.
go back to reference Liu T, Ji RR (2013) New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch 465(12):1671–1685CrossRefPubMed Liu T, Ji RR (2013) New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch 465(12):1671–1685CrossRefPubMed
13.
go back to reference Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223(1):77–92CrossRefPubMed Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223(1):77–92CrossRefPubMed
14.
go back to reference Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183CrossRefPubMed Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47:143–183CrossRefPubMed
15.
go back to reference Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje AP, Schafer T, Schwennesen T, Seidenari S, Simon D, Stander S, Stingl G, Szalai S, Szepietowski JC, Taieb A, Werfel T, Wollenberg A, Darsow U (2012) Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol 26(9):1176–1193CrossRefPubMed Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje AP, Schafer T, Schwennesen T, Seidenari S, Simon D, Stander S, Stingl G, Szalai S, Szepietowski JC, Taieb A, Werfel T, Wollenberg A, Darsow U (2012) Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol 26(9):1176–1193CrossRefPubMed
16.
go back to reference Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje AP, Schafer T, Schwennesen T, Seidenari S, Simon D, Stander S, Stingl G, Szalai S, Szepietowski JC, Taieb A, Werfel T, Wollenberg A, Darsow U (2012) Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J Eur Acad Dermatol Venereol 26(8):1045–1060CrossRefPubMed Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje AP, Schafer T, Schwennesen T, Seidenari S, Simon D, Stander S, Stingl G, Szalai S, Szepietowski JC, Taieb A, Werfel T, Wollenberg A, Darsow U (2012) Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J Eur Acad Dermatol Venereol 26(8):1045–1060CrossRefPubMed
17.
go back to reference Shim M, Powers KL, Ewing SJ, Zhu S, Smart RC (2005) Diminished expression of C/EBPalpha in skin carcinomas is linked to oncogenic Ras and reexpression of C/EBPalpha in carcinoma cells inhibits proliferation. Cancer Res 65(3):861–867PubMed Shim M, Powers KL, Ewing SJ, Zhu S, Smart RC (2005) Diminished expression of C/EBPalpha in skin carcinomas is linked to oncogenic Ras and reexpression of C/EBPalpha in carcinoma cells inhibits proliferation. Cancer Res 65(3):861–867PubMed
18.
go back to reference Steinhoff M, Brzoska T, Luger TA (2001) Keratinocytes in epidermal immune responses. Curr Opin Allergy Clin Immunol 1(5):469–476PubMed Steinhoff M, Brzoska T, Luger TA (2001) Keratinocytes in epidermal immune responses. Curr Opin Allergy Clin Immunol 1(5):469–476PubMed
19.
go back to reference Steinman RM (2007) Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med 13(10):1155–1159CrossRefPubMed Steinman RM (2007) Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med 13(10):1155–1159CrossRefPubMed
20.
go back to reference van de Wetering CI, Coleman MC, Spitz DR, Smith BJ, Knudson CM (2008) Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma. Free Radic Biol Med 44(8):1677–1686CrossRefPubMedPubMedCentral van de Wetering CI, Coleman MC, Spitz DR, Smith BJ, Knudson CM (2008) Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma. Free Radic Biol Med 44(8):1677–1686CrossRefPubMedPubMedCentral
21.
go back to reference Wang YH, Xu XJ, Li HL (2014) Hepatoprotective effects of mimic of manganese superoxide dismutase against carbon tetrachloride-induced hepatic injury. Int Immunopharmacol 22(1):126–132CrossRefPubMed Wang YH, Xu XJ, Li HL (2014) Hepatoprotective effects of mimic of manganese superoxide dismutase against carbon tetrachloride-induced hepatic injury. Int Immunopharmacol 22(1):126–132CrossRefPubMed
22.
go back to reference Werfel T (2009) The role of leukocytes, keratinocytes, and allergen-specific IgE in the development of atopic dermatitis. J Invest Dermatol 129(8):1878–1891CrossRefPubMed Werfel T (2009) The role of leukocytes, keratinocytes, and allergen-specific IgE in the development of atopic dermatitis. J Invest Dermatol 129(8):1878–1891CrossRefPubMed
23.
go back to reference Wilson SR, The L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155(2):285–295CrossRefPubMedPubMedCentral Wilson SR, The L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155(2):285–295CrossRefPubMedPubMedCentral
Metadata
Title
Topically applied manganese-porphyrins BMX-001 and BMX-010 display a significant anti-inflammatory response in a mouse model of allergic dermatitis
Authors
Kelsey Stover
Tomoki Fukuyama
Ashlyn T. Young
Michael A. Daniele
Rebecca Oberley
James D. Crapo
Wolfgang Bäumer
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
Archives of Dermatological Research / Issue 10/2016
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-016-1693-0

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