Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases
Probing the Role of Melanocortin Type 1 Receptor Agonists in Diverse Immunological Diseases
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DOI：
10.3389/fphar.2018.01535
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发表时间：
2019-01-14
影响因子：
5.6
通讯作者：
Dodd, John
中科院分区：
文献类型：
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作者：
Spana, Carl;Taylor, Andrew W.;Dodd, John
背景：黑素皮质素α-黑素细胞刺激素(α-MSH)是一种与黑素皮质素1受体(MC1R)具有高亲和力的内源性多肽，已在动物模型中显示出预防和逆转肠道和眼部炎症的作用。进行临床前研究，以确定两种MC1R受体激动剂PL-8177和PL-8331在预防和逆转肠道和眼部炎症方面是否表现出与α-MSH相似的作用和疗效。方法：在Eurofins LeadProfilingScreen选择性小组中对PL-8177和PL-8331进行评估，该小组包括72项体外分析。用脂多糖刺激的人全血体外测定对肿瘤坏死因子α(TNF-α)的抑制作用，并以促肾上腺皮质激素(ACTH)和α-MSH作为阳性对照。在二硝基苯磺酸(DNBS)诱导的肠炎大鼠模型中，比较了剂量为0.5、1.5和5.0 mg的PL-8177与赋形剂和口服柳氮磺吡啶的疗效。在实验性自身免疫性葡萄膜炎(EAU)小鼠中，PL-8177也以0.3 mg/kg/只的小鼠腹腔注射，与未治疗的对照组和α-MSH治疗组相比。结果：在72种体外实验中，PL-8177和PL-8331在1 mM浓度下均无显著活性。PL-8177和PL-8331对脂多糖诱导的肿瘤坏死因子-α的抑制作用与ACTH和α-MSH相似。在DNBS大鼠肠炎症模型中，PL-8177在降低肠道炎症参数方面均显著优于未治疗对照组(P<；0.05)，其效果与柳氮磺胺吡啶相似。在小鼠EAU模型中，与未经治疗的对照组相比，PL-8177在3-5周内显著降低了视网膜炎症评分(P=0.0001)，其程度与α-MSH相似。结论：MC1R受体激动剂PL-8177和PL-8331在预防和逆转临床前疾病模型中的肠道和眼部炎症方面表现出与α-MSH相似的作用，在最大剂量(1×10(-5)mg·mL(-1))时显著降低角膜荧光素染色分数(P=0.02)，与Restasis(R)相似。
Background: The melanocortin alpha-melanocyte stimulating hormone (alpha-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 alpha-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-alpha); for comparison, adrenocorticotropic hormone (ACTH) and alpha-MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 mu g, 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 alpha-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 (SiccaSystem (TM) model), versus twice-daily Restasis (R) and Xiidra (R).Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 mu m concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited lipopolysaccharide-induced TNF-alpha to a similar degree as ACTH and alpha-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 alpha-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 x 10(-5) mg.mL(-1)), and similarly to Restasis (R); Xiidra (R) demonstrated no effect.Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of alpha-MSH in preventing and reversing intestinal and ocular inflammation in preclinical disease models.