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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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Prevention of epidermal hyperplasia by transdermal application of selective PPAR β/δ antagonists.Both the PPAR β/δ agonist GW501516 (GW) and the antagonists GSK0660 (GSK) or compound 3 h were applied topically to the skin, as described in the text. Left: representative H&E-stained paraffin-sections of dorsal skin from PPAR β/δ transgenic mice after treatment with ointments containing the indicated drugs for twenty days, as detailed in Methods. Horizontal bar represents 5 µm. Right: quantification of H&E-based epidermal thickness observed in n = 4 mice per group, performed as detailed in Methods. * p<0.05 in a two-sided independent t-test.
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pone-0037097-g005: Prevention of epidermal hyperplasia by transdermal application of selective PPAR β/δ antagonists.Both the PPAR β/δ agonist GW501516 (GW) and the antagonists GSK0660 (GSK) or compound 3 h were applied topically to the skin, as described in the text. Left: representative H&E-stained paraffin-sections of dorsal skin from PPAR β/δ transgenic mice after treatment with ointments containing the indicated drugs for twenty days, as detailed in Methods. Horizontal bar represents 5 µm. Right: quantification of H&E-based epidermal thickness observed in n = 4 mice per group, performed as detailed in Methods. * p<0.05 in a two-sided independent t-test.

Mentions: We next sought to determine whether skin-targeted administration of PPAR β/δ antagonists would be sufficient to inhibit PPAR β/δ agonist-driven development of skin disease. In a first set of experiments we applied both the agonist (GW501516), as well as either antagonist (GSK0660 or compound 3 h) directly to the skin in order to minimise pharmacokinetic differences associated with alternative routes of drug administration (i.e. oral verus transdermal) between the competing chemicals. GW501516 was formulated as an 0.1% ointment and applied five times per week to shaved dorsal skin of PPAR β/δ transgenic mice. This agonist concentration was chosen because (a) lower agonist concentrations had resulted in significantly prolonged time-to-onset of the phenotype in pilot experiments and (b) higher concentrations would not achieve a molar excess of the antagonist (using 1% ointments for the antagonists), which was important since the available in vitro data suggested that competitive antagonism at the receptor might not be achieved at equimolar concentrations of both agonist and antagonist. Antagonist-containing ointments were applied once per day six hours apart from the agonist in order to minimise any influence of penetration of both chemicals. Mice receiving GW501516 ointment and vehicle-only served as positive control, while mice receiving only vehicle ointments for both the antagonist as well as the agonist served as negative control. After 20 days of treatment, mice were sacrificed and skin samples processed for H&E histology. As shown in figure 5, both GSK0660 and compound 3 h, respectively, significantly attenuated the psoriasis – like epidermal hyperplasia induced by GW501516-mediated activation of PPAR β/δ. These data suggest that bioavailability of both antagonists is sufficient upon transdermal delivery to compete for agonist-binding to the receptor in vivo. MS-based quantification of GSK0660 in PPAR β/δ mice 12 h after the last cream application showed a concentration of 48 ± 18 ng/g of tissue while no GSK was detectable in blood (threshold of detection: 25 nmol/l), showing that penetration through inflamed skin with altered permeability properties does not lead to increased local or systemic accumulation of GSK0660 after prolonged administration.


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)

Prevention of epidermal hyperplasia by transdermal application of selective PPAR β/δ antagonists.Both the PPAR β/δ agonist GW501516 (GW) and the antagonists GSK0660 (GSK) or compound 3 h were applied topically to the skin, as described in the text. Left: representative H&E-stained paraffin-sections of dorsal skin from PPAR β/δ transgenic mice after treatment with ointments containing the indicated drugs for twenty days, as detailed in Methods. Horizontal bar represents 5 µm. Right: quantification of H&E-based epidermal thickness observed in n = 4 mice per group, performed as detailed in Methods. * p<0.05 in a two-sided independent t-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351437&req=5

pone-0037097-g005: Prevention of epidermal hyperplasia by transdermal application of selective PPAR β/δ antagonists.Both the PPAR β/δ agonist GW501516 (GW) and the antagonists GSK0660 (GSK) or compound 3 h were applied topically to the skin, as described in the text. Left: representative H&E-stained paraffin-sections of dorsal skin from PPAR β/δ transgenic mice after treatment with ointments containing the indicated drugs for twenty days, as detailed in Methods. Horizontal bar represents 5 µm. Right: quantification of H&E-based epidermal thickness observed in n = 4 mice per group, performed as detailed in Methods. * p<0.05 in a two-sided independent t-test.
Mentions: We next sought to determine whether skin-targeted administration of PPAR β/δ antagonists would be sufficient to inhibit PPAR β/δ agonist-driven development of skin disease. In a first set of experiments we applied both the agonist (GW501516), as well as either antagonist (GSK0660 or compound 3 h) directly to the skin in order to minimise pharmacokinetic differences associated with alternative routes of drug administration (i.e. oral verus transdermal) between the competing chemicals. GW501516 was formulated as an 0.1% ointment and applied five times per week to shaved dorsal skin of PPAR β/δ transgenic mice. This agonist concentration was chosen because (a) lower agonist concentrations had resulted in significantly prolonged time-to-onset of the phenotype in pilot experiments and (b) higher concentrations would not achieve a molar excess of the antagonist (using 1% ointments for the antagonists), which was important since the available in vitro data suggested that competitive antagonism at the receptor might not be achieved at equimolar concentrations of both agonist and antagonist. Antagonist-containing ointments were applied once per day six hours apart from the agonist in order to minimise any influence of penetration of both chemicals. Mice receiving GW501516 ointment and vehicle-only served as positive control, while mice receiving only vehicle ointments for both the antagonist as well as the agonist served as negative control. After 20 days of treatment, mice were sacrificed and skin samples processed for H&E histology. As shown in figure 5, both GSK0660 and compound 3 h, respectively, significantly attenuated the psoriasis – like epidermal hyperplasia induced by GW501516-mediated activation of PPAR β/δ. These data suggest that bioavailability of both antagonists is sufficient upon transdermal delivery to compete for agonist-binding to the receptor in vivo. MS-based quantification of GSK0660 in PPAR β/δ mice 12 h after the last cream application showed a concentration of 48 ± 18 ng/g of tissue while no GSK was detectable in blood (threshold of detection: 25 nmol/l), showing that penetration through inflamed skin with altered permeability properties does not lead to increased local or systemic accumulation of GSK0660 after prolonged administration.

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