Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
Clin Sci (Lond). 2020 Apr 17;134(7):907-920. doi: 10.1042/CS20191215.
Increased keratinocyte proliferation occurs in the skin of psoriatic patients and is supposed to play a role in the pathogenesis of this disorder. Compounds interfering with keratinocyte proliferation could be useful in the management of psoriatic patients.
To investigate whether albendazole, an anti-helmintic drug that regulates epithelial cell function in various systems, inhibits keratinocyte proliferation in models of psoriasis.
Aldara-treated mice received daily topical application of albendazole. Keratinocyte proliferation and keratin (K) 6 and K16 expression were evaluated by immunohistochemistry and Western blotting and inflammatory cells/mediators were analysed by immunohistochemistry and real-time PCR. In human keratinocytes (HEKa and HaCaT) treated with albendazole, cell cycle and proliferation, keratins and cell cycle-associated factors were evaluated by flow cytometry, colorimetric assay and Western blotting respectively.
Aldara-treated mice given albendazole exhibited reduced epidermal thickness, decreased number of proliferating keratinocytes and K6/K16 expression. Reduction of CD3- and Ly6G-positive cells in the skin of albendazole-treated mice associated with inhibition of IL-6, TNF-α, IL-1β, IL-17A, IL-36, CCL17, CXCL1, CXCL2 and CXCL5 expression. Treatment of keratinocytes with albendazole reduced K6/K16 expression and reversibly inhibited cell growth by promoting accumulation of cells in S-phase. This phenomenon was accompanied by down-regulation of CDC25A, a phosphatase regulating progression of cell cycle through S-phase, and PKR-dependent hyper-phosphorylation of eIF2α, an inhibitor of CDC25 translation. In Aldara-treated mice, albendazole activated PKR, enhanced eIF2α phosphorylation and reduced CDC25A expression.
Data show that albendazole inhibits keratinocyte proliferation and exerts therapeutic effect in a murine model of psoriasis.
银屑病患者的皮肤中角质形成细胞增殖增加，这被认为在该疾病的发病机制中起作用。干扰角质形成细胞增殖的化合物可能对银屑病患者的治疗有用。
研究抗蠕虫药物阿苯达唑（一种调节各种系统上皮细胞功能的药物）是否抑制银屑病模型中的角质形成细胞增殖。
用 Aldara 处理的小鼠接受每日局部应用阿苯达唑。通过免疫组织化学和 Western blot 评估角质形成细胞增殖和角蛋白（K）6 和 K16 的表达，并通过免疫组织化学和实时 PCR 分析炎症细胞/介质。在接受阿苯达唑处理的人角质形成细胞（HEKa 和 HaCaT）中，通过流式细胞术、比色法和 Western blot 分别评估细胞周期和增殖、角蛋白和细胞周期相关因子。
用 Aldara 处理并给予阿苯达唑的小鼠表现出表皮厚度降低、增殖角质形成细胞数量减少和 K6/K16 表达降低。阿苯达唑处理小鼠皮肤中 CD3-和 Ly6G-阳性细胞的减少与 IL-6、TNF-α、IL-1β、IL-17A、IL-36、CCL17、CXCL1、CXCL2 和 CXCL5 表达的抑制相关。用阿苯达唑处理角质形成细胞可降低 K6/K16 表达，并通过促进细胞在 S 期积累而可逆地抑制细胞生长。这种现象伴随着 CDC25A 的下调，CDC25A 是一种通过 S 期调节细胞周期进展的磷酸酶，以及 PKR 依赖性 eIF2α 的过度磷酸化，eIF2α 是 CDC25 翻译的抑制剂。在 Aldara 处理的小鼠中，阿苯达唑激活 PKR，增强 eIF2α 磷酸化并降低 CDC25A 表达。
数据表明阿苯达唑抑制角质形成细胞增殖并在银屑病小鼠模型中发挥治疗作用。
