PDF(Pubmed)
Abstract：
Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
摘要：
斑秃是一种慢性脱发疾病，涉及CD8T细胞对毛囊的自身免疫破坏。大多数患者表现为头皮上的斑片状脱发，自发改善或局部和病灶内类固醇，局部米诺地尔,或局部免疫疗法。然而,脱发复发是常见的，广泛疾病的患者可能需要口服皮质类固醇或口服Janus激酶（JAK）抑制剂治疗，两者都可能导致长期使用的全身毒性。衣糖酸是在巨噬细胞中合成的内源性分子,其发挥抗炎作用。为了研究衣康酸酯衍生物在治疗斑秃中的应用，我们设计了4-甲基衣康酸（4-MI）的前药，称为SCD-153，与4-MI相比，亲脂性增加(CLogP1.159vs.0.1442）增强皮肤和细胞渗透。在C57BL/6小鼠中,局部SCD-153在穿透角质层时形成4-MI,并显示低全身吸收。当添加到用聚肌苷酸-聚胞嘧啶酸（聚I：C）或干扰素（IFN）γ刺激的人表皮角质形成细胞中时，SCD-153显着减弱polyI：C诱导的白介素（IL）-6，Toll样受体3，IL-1β，和IFNβ表达，以及IFNγ诱导的IL-6表达。在毛发周期的静息期（静止期）对C57BL/6小鼠局部施用SCD-153诱导了显着的毛发生长，在统计学上优于媒介物（二甲基亚砜），细胞渗透性较低的衣康酸类似物4-MI和衣康酸二甲酯，和JAK抑制剂托法替尼。我们的结果表明，SCD-153是治疗斑秃的有希望的局部候选药物。
