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Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

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Control of PPAR β/δ – mediated skin disease using reduced-frequency application of ointment containing an irreversible PPAR β/δ antagonist.Skin disease in PPAR β/δ transgenic mice was induced by i.p. injection of the agonist GW501516. Additionally, mice were shaved on their abdomen and were treated with vehicle-ointment or ointment containing either GSK0660 (twice daily) or GSK3787 at the indicated frequencies. Red arrow denotes apoptotic cells noted in the GW-only treatment group. A. Top: Representative H&E stains from 3 different mice in each treatment group. Horizontal bar represents 5 µm. Bottom: Quantification of epidermal thickness (p<0.01 in all treatment groups vs. GW-only). B. Quantification of dermal infiltrate. Data shown represent average ± s.d. of five mice per group.
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pone-0037097-g007: Control of PPAR β/δ – mediated skin disease using reduced-frequency application of ointment containing an irreversible PPAR β/δ antagonist.Skin disease in PPAR β/δ transgenic mice was induced by i.p. injection of the agonist GW501516. Additionally, mice were shaved on their abdomen and were treated with vehicle-ointment or ointment containing either GSK0660 (twice daily) or GSK3787 at the indicated frequencies. Red arrow denotes apoptotic cells noted in the GW-only treatment group. A. Top: Representative H&E stains from 3 different mice in each treatment group. Horizontal bar represents 5 µm. Bottom: Quantification of epidermal thickness (p<0.01 in all treatment groups vs. GW-only). B. Quantification of dermal infiltrate. Data shown represent average ± s.d. of five mice per group.

Mentions: The half-life of GSK0660 suggested that the frequency of cream application might be limiting for treatment efficacy. Indeed, we found that twice-daily ointment application was required for full efficacy (fig. S1). The PPAR β/δ antagonist GSK3787 has been shown to covalently bind to its target, causing permanent inactivation. Since this property may be extremely useful clinically by offering the potential of less frequent cream application, we explored the effect of GSK3787 in the present system. As shown in figure 7, treatment using GSK3787-containing ointment proved to be as effective as GSK0660 in preventing epidermal hyperplasia (fig. 7a), as well as reducing the amount of dermal infiltrate (fig. 7b), even when applied only 3× per week. The tissue level of unmodified GSK3787 in lesional skin (GSK3787 covalently attached to PPAR β/δ could not be quantified) did not differ significantly between the three treatment groups 16 h after the final application and was found overall slightly higher than that found for GSK0660 (240 ± 116 nmol/g of tissue vs. 91 ± 21 nmol/g for GSK0660), indicating that slightly better tissue penetration may contribute to treatment efficacy. Efficacy of GSK3787 at reduced frequency application was further confirmed in an additional experiment testing the effect of twice-daily versus three times weekly application of GSK3787 (figure 8). This experiment also verified suppression of the PPAR β/δ target genes LCE3f, IL1-beta, and HBEGF (fig. 8b). Quantification of GSK3787 in blood of at the end of the experiment (16 h after last cream application) yielded a concentration of 445 ± 429 nmol/l, suggesting higher systemic resorption than GSK0660. Systemic resorption appears to be facilitated through inflamed skin since GSK3787 blood concentration in healthy mice after 20 days of twice-daily treatment was only 50.2 ± 25.7 nmol/l (n = 3 mice). Nonetheless, the therapeutic activity is mediated locally, since efficacy was limited to the area of cream application (figure S2). Taken together, the data show that irreversible covalent modification of PPAR β/δ may harbour the potential of less frequent ointment application.


Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Control of PPAR β/δ – mediated skin disease using reduced-frequency application of ointment containing an irreversible PPAR β/δ antagonist.Skin disease in PPAR β/δ transgenic mice was induced by i.p. injection of the agonist GW501516. Additionally, mice were shaved on their abdomen and were treated with vehicle-ointment or ointment containing either GSK0660 (twice daily) or GSK3787 at the indicated frequencies. Red arrow denotes apoptotic cells noted in the GW-only treatment group. A. Top: Representative H&E stains from 3 different mice in each treatment group. Horizontal bar represents 5 µm. Bottom: Quantification of epidermal thickness (p<0.01 in all treatment groups vs. GW-only). B. Quantification of dermal infiltrate. Data shown represent average ± s.d. of five mice per group.
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Related In: Results  -  Collection

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pone-0037097-g007: Control of PPAR β/δ – mediated skin disease using reduced-frequency application of ointment containing an irreversible PPAR β/δ antagonist.Skin disease in PPAR β/δ transgenic mice was induced by i.p. injection of the agonist GW501516. Additionally, mice were shaved on their abdomen and were treated with vehicle-ointment or ointment containing either GSK0660 (twice daily) or GSK3787 at the indicated frequencies. Red arrow denotes apoptotic cells noted in the GW-only treatment group. A. Top: Representative H&E stains from 3 different mice in each treatment group. Horizontal bar represents 5 µm. Bottom: Quantification of epidermal thickness (p<0.01 in all treatment groups vs. GW-only). B. Quantification of dermal infiltrate. Data shown represent average ± s.d. of five mice per group.
Mentions: The half-life of GSK0660 suggested that the frequency of cream application might be limiting for treatment efficacy. Indeed, we found that twice-daily ointment application was required for full efficacy (fig. S1). The PPAR β/δ antagonist GSK3787 has been shown to covalently bind to its target, causing permanent inactivation. Since this property may be extremely useful clinically by offering the potential of less frequent cream application, we explored the effect of GSK3787 in the present system. As shown in figure 7, treatment using GSK3787-containing ointment proved to be as effective as GSK0660 in preventing epidermal hyperplasia (fig. 7a), as well as reducing the amount of dermal infiltrate (fig. 7b), even when applied only 3× per week. The tissue level of unmodified GSK3787 in lesional skin (GSK3787 covalently attached to PPAR β/δ could not be quantified) did not differ significantly between the three treatment groups 16 h after the final application and was found overall slightly higher than that found for GSK0660 (240 ± 116 nmol/g of tissue vs. 91 ± 21 nmol/g for GSK0660), indicating that slightly better tissue penetration may contribute to treatment efficacy. Efficacy of GSK3787 at reduced frequency application was further confirmed in an additional experiment testing the effect of twice-daily versus three times weekly application of GSK3787 (figure 8). This experiment also verified suppression of the PPAR β/δ target genes LCE3f, IL1-beta, and HBEGF (fig. 8b). Quantification of GSK3787 in blood of at the end of the experiment (16 h after last cream application) yielded a concentration of 445 ± 429 nmol/l, suggesting higher systemic resorption than GSK0660. Systemic resorption appears to be facilitated through inflamed skin since GSK3787 blood concentration in healthy mice after 20 days of twice-daily treatment was only 50.2 ± 25.7 nmol/l (n = 3 mice). Nonetheless, the therapeutic activity is mediated locally, since efficacy was limited to the area of cream application (figure S2). Taken together, the data show that irreversible covalent modification of PPAR β/δ may harbour the potential of less frequent ointment application.

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Show MeSH
Related in: MedlinePlus