Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases
Background: The melanocortin α-melanocyte stimulating hormone (α-MSH), an endogenous peptide with high affinity for the melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular inflammation in animal models. Preclinical studies were performed to determine whe...
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01535/full |
| _version_ | 1819096729711017984 |
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| author | Carl Spana Andrew W. Taylor David G. Yee Marie Makhlina Wei Yang John Dodd |
| author_facet | Carl Spana Andrew W. Taylor David G. Yee Marie Makhlina Wei Yang John Dodd |
| author_sort | Carl Spana |
| collection | DOAJ |
| description | Background: The melanocortin α-melanocyte stimulating hormone (α-MSH), an endogenous peptide with high affinity for the melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular inflammation in animal models. Preclinical studies were performed to determine whether two MC1r receptor agonists, PL-8177 and PL-8331, exhibit actions and efficacy similar to α-MSH in preventing and reversing intestinal and ocular inflammation.Methods: Both PL-8177 and PL-8331 were assessed in a Eurofins LeadProfilingScreen selectivity panel including 72 in vitro assays. PL-8177 and PL-8331 were evaluated in an in vitro assay using human whole blood stimulated by lipopolysaccharide to determine inhibition of tumor necrosis factor alpha (TNF-α); for comparison, adrenocorticotropic hormone (ACTH) and α-MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 μg, was assessed in a cannulated rat model of dinitrobenzene sulfonic acid (DNBS)-induced bowel inflammation versus vehicle and oral sulfasalazine. PL-8177 was also dosed at 0.3 mg/kg/mouse injected intraperitoneally versus untreated controls and α-MSH treatment in mice with experimental autoimmune uveitis (EAU). PL-8331 at 3 doses, 3 times daily, was evaluated in a murine model of scopolamine-induced dry eye disease (SiccaSystemTM model), versus twice-daily Restasis® and Xiidra®.Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 μm concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited lipopolysaccharide-induced TNF-α to a similar degree as ACTH and α-MSH. In the DNBS rat model of bowel inflammation, PL-8177 was significantly superior to untreated controls at all 3 doses (P < 0.05) in reducing bowel inflammation parameters, with effects similar to sulfasalazine. In the murine EAU model, PL-8177 significantly reduced retinal inflammation scores versus untreated controls (P = 0.0001) over 3–5 weeks, and to a similar degree as α-MSH. In the murine scopolamine-induced model of dry eye disease, PL-8331 reduced corneal fluorescein staining scores at all doses, significantly (P = 0.02) for the highest dose (1 × 10-5 mg⋅mL-1), and similarly to Restasis®; Xiidra® demonstrated no effect.Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of α-MSH in preventing and reversing intestinal and ocular inflammation in preclinical disease models. |
| first_indexed | 2024-12-22T00:03:50Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T00:03:50Z |
| publishDate | 2019-01-01 |
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| spelling | doaj.art-963d6da34ea948598e8565ed64415d112022-12-21T18:45:37ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-01-01910.3389/fphar.2018.01535427048Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological DiseasesCarl Spana0Andrew W. Taylor1David G. Yee2Marie Makhlina3Wei Yang4John Dodd5Palatin Technologies, Inc., Cranbury, NJ, United StatesDepartment of Ophthalmology, Boston University School of Medicine, Boston, MA, United StatesDepartment of Ophthalmology, Boston University School of Medicine, Boston, MA, United StatesPalatin Technologies, Inc., Cranbury, NJ, United StatesPalatin Technologies, Inc., Cranbury, NJ, United StatesPalatin Technologies, Inc., Cranbury, NJ, United StatesBackground: The melanocortin α-melanocyte stimulating hormone (α-MSH), an endogenous peptide with high affinity for the melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular inflammation in animal models. Preclinical studies were performed to determine whether two MC1r receptor agonists, PL-8177 and PL-8331, exhibit actions and efficacy similar to α-MSH in preventing and reversing intestinal and ocular inflammation.Methods: Both PL-8177 and PL-8331 were assessed in a Eurofins LeadProfilingScreen selectivity panel including 72 in vitro assays. PL-8177 and PL-8331 were evaluated in an in vitro assay using human whole blood stimulated by lipopolysaccharide to determine inhibition of tumor necrosis factor alpha (TNF-α); for comparison, adrenocorticotropic hormone (ACTH) and α-MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 μg, was assessed in a cannulated rat model of dinitrobenzene sulfonic acid (DNBS)-induced bowel inflammation versus vehicle and oral sulfasalazine. PL-8177 was also dosed at 0.3 mg/kg/mouse injected intraperitoneally versus untreated controls and α-MSH treatment in mice with experimental autoimmune uveitis (EAU). PL-8331 at 3 doses, 3 times daily, was evaluated in a murine model of scopolamine-induced dry eye disease (SiccaSystemTM model), versus twice-daily Restasis® and Xiidra®.Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 μm concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited lipopolysaccharide-induced TNF-α to a similar degree as ACTH and α-MSH. In the DNBS rat model of bowel inflammation, PL-8177 was significantly superior to untreated controls at all 3 doses (P < 0.05) in reducing bowel inflammation parameters, with effects similar to sulfasalazine. In the murine EAU model, PL-8177 significantly reduced retinal inflammation scores versus untreated controls (P = 0.0001) over 3–5 weeks, and to a similar degree as α-MSH. In the murine scopolamine-induced model of dry eye disease, PL-8331 reduced corneal fluorescein staining scores at all doses, significantly (P = 0.02) for the highest dose (1 × 10-5 mg⋅mL-1), and similarly to Restasis®; Xiidra® demonstrated no effect.Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of α-MSH in preventing and reversing intestinal and ocular inflammation in preclinical disease models.https://www.frontiersin.org/article/10.3389/fphar.2018.01535/fullmelanocortinmelanocortin 1 receptoralpha-melanocyte stimulating hormonePL-8177PL-8331inflammatory bowel disease |
| spellingShingle | Carl Spana Andrew W. Taylor David G. Yee Marie Makhlina Wei Yang John Dodd Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases Frontiers in Pharmacology melanocortin melanocortin 1 receptor alpha-melanocyte stimulating hormone PL-8177 PL-8331 inflammatory bowel disease |
| title | Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases |
| title_full | Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases |
| title_fullStr | Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases |
| title_full_unstemmed | Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases |
| title_short | Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases |
| title_sort | probing the role of melanocortin type 1 receptor agonists in diverse immunological diseases |
| topic | melanocortin melanocortin 1 receptor alpha-melanocyte stimulating hormone PL-8177 PL-8331 inflammatory bowel disease |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01535/full |
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