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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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Absence of inflammatory changes induced by PPAR β/δ antagonists in skin after topical application.(a) C57Bl/6j wild type mice were treated with ointments containing GSK0660 or compound 3 h applied twice daily to shaved dorsal skin for one week. Mice were sacrificed 1 h after the last ointment application and skin tissue processed for H&E based histology and mass spectrometry, as described in Methods. Data shown represent average ± s.d. of n = 3 mice per data point (left) treated with GSK (blue columns) or compound 3 h (red). Representative histology sections of all treated mice are shown on right. The inset in the middle panel shows a section of GSK0660-treated epidermis showing apoptotic looking cells (marked by red arrow head). Horizontal bar represents 5 µm. (b) Representative H&E sections of C57Bl/6j wild type mice treated for one week with either GSK0660 (top) or GSK3787 (bottom). Red arrow-heads denoting apoptotic looking cells.
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pone-0037097-g004: Absence of inflammatory changes induced by PPAR β/δ antagonists in skin after topical application.(a) C57Bl/6j wild type mice were treated with ointments containing GSK0660 or compound 3 h applied twice daily to shaved dorsal skin for one week. Mice were sacrificed 1 h after the last ointment application and skin tissue processed for H&E based histology and mass spectrometry, as described in Methods. Data shown represent average ± s.d. of n = 3 mice per data point (left) treated with GSK (blue columns) or compound 3 h (red). Representative histology sections of all treated mice are shown on right. The inset in the middle panel shows a section of GSK0660-treated epidermis showing apoptotic looking cells (marked by red arrow head). Horizontal bar represents 5 µm. (b) Representative H&E sections of C57Bl/6j wild type mice treated for one week with either GSK0660 (top) or GSK3787 (bottom). Red arrow-heads denoting apoptotic looking cells.

Mentions: We next determined the local concentrations in skin at steady state after prolonged topical application. GSK0660 or compound 3 h were administered to shaven dorsal skin twice daily for seven days. Skin samples were then extracted and analysed by mass spectrometry for concentration determination as well as processed for histology. As shown in figure 4a, both compounds achieved high local concentrations even for the lower dose used (0.2%), suggesting active concentrations are present locally for prolonged time periods at the twice-daily dosing regimen, assuming a half life of approximately. 90 min (cf. fig. 2b). Under these conditions, neither antagonist produced notable epidermal hyperplasia (fig. 4, panels on right). The number of dermal nuclei counted per high power field was also unchanged as compared to vehicle-only treated skin (not shown). This was also found for the alternative PPAR β/δ antagonist GSK3787 (figure 4b). Infrequently, we noted apoptotic epidermal keratinocytes (inset, middle row of H&E sections). Since these cells were also found in transgenic PPAR β/δ mice treated with the agonist only (figure S1), the exact underlying cause is unclear but unlikely to underlie the treatment effect of the antagonist creams.


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)

Absence of inflammatory changes induced by PPAR β/δ antagonists in skin after topical application.(a) C57Bl/6j wild type mice were treated with ointments containing GSK0660 or compound 3 h applied twice daily to shaved dorsal skin for one week. Mice were sacrificed 1 h after the last ointment application and skin tissue processed for H&E based histology and mass spectrometry, as described in Methods. Data shown represent average ± s.d. of n = 3 mice per data point (left) treated with GSK (blue columns) or compound 3 h (red). Representative histology sections of all treated mice are shown on right. The inset in the middle panel shows a section of GSK0660-treated epidermis showing apoptotic looking cells (marked by red arrow head). Horizontal bar represents 5 µm. (b) Representative H&E sections of C57Bl/6j wild type mice treated for one week with either GSK0660 (top) or GSK3787 (bottom). Red arrow-heads denoting apoptotic looking cells.
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getmorefigures.php?uid=PMC3351437&req=5

pone-0037097-g004: Absence of inflammatory changes induced by PPAR β/δ antagonists in skin after topical application.(a) C57Bl/6j wild type mice were treated with ointments containing GSK0660 or compound 3 h applied twice daily to shaved dorsal skin for one week. Mice were sacrificed 1 h after the last ointment application and skin tissue processed for H&E based histology and mass spectrometry, as described in Methods. Data shown represent average ± s.d. of n = 3 mice per data point (left) treated with GSK (blue columns) or compound 3 h (red). Representative histology sections of all treated mice are shown on right. The inset in the middle panel shows a section of GSK0660-treated epidermis showing apoptotic looking cells (marked by red arrow head). Horizontal bar represents 5 µm. (b) Representative H&E sections of C57Bl/6j wild type mice treated for one week with either GSK0660 (top) or GSK3787 (bottom). Red arrow-heads denoting apoptotic looking cells.
Mentions: We next determined the local concentrations in skin at steady state after prolonged topical application. GSK0660 or compound 3 h were administered to shaven dorsal skin twice daily for seven days. Skin samples were then extracted and analysed by mass spectrometry for concentration determination as well as processed for histology. As shown in figure 4a, both compounds achieved high local concentrations even for the lower dose used (0.2%), suggesting active concentrations are present locally for prolonged time periods at the twice-daily dosing regimen, assuming a half life of approximately. 90 min (cf. fig. 2b). Under these conditions, neither antagonist produced notable epidermal hyperplasia (fig. 4, panels on right). The number of dermal nuclei counted per high power field was also unchanged as compared to vehicle-only treated skin (not shown). This was also found for the alternative PPAR β/δ antagonist GSK3787 (figure 4b). Infrequently, we noted apoptotic epidermal keratinocytes (inset, middle row of H&E sections). Since these cells were also found in transgenic PPAR β/δ mice treated with the agonist only (figure S1), the exact underlying cause is unclear but unlikely to underlie the treatment effect of the antagonist creams.

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