Baiula Monica, Bedini Andrea, Baldi Jacopo, Cavet Megan E, Govoni Paolo, Spampinato Santi
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Global Pharmaceutical R&D, Bausch & Lomb Inc., Rochester, NY, USA.
Drug Des Devel Ther. 2014 Jun 10;8:745-57. doi: 10.2147/DDDT.S62659. eCollection 2014.
Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6-10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines.
In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α).
Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more effective than dexamethasone in increasing, in conjunctival sections of OVA-treated guinea pigs, apoptotic eosinophils.
Mapracorat displays anti-allergic properties in controlling the late phase of ocular allergic conjunctivitis and is a promising candidate for the topical treatment of allergic eye disorders.
马普拉考特是一种新型非甾体选择性糖皮质激素受体激动剂，因其与人糖皮质激素受体具有高亲和力和选择性结合，并表现出强大的抗炎活性，已被提议用于炎症性疾病的局部治疗，但在激活许多基因方面似乎效果较差，导致副作用可能性较低。与经典糖皮质激素相反，马普拉考特升高眼压以及诱导与眼压升高相关的蛋白质肌纤蛋白的能力降低。过敏性结膜炎是眼部过敏最常见的形式，可分为早期阶段，在接触过敏原后立即发生，主要由肥大细胞脱颗粒驱动，以及晚期阶段，在抗原激发后6 - 10小时出现，其特征是嗜酸性粒细胞和其他免疫细胞浸润结膜以及细胞因子和趋化因子的产生。
在本研究中，在诱导过敏性结膜炎2小时后，将马普拉考特滴入卵清蛋白（OVA）致敏的豚鼠结膜囊内，目的是研究其在减轻晚期眼部反应临床症状方面的活性，并确定其对结膜嗜酸性粒细胞凋亡以及趋化因子C - C基序配体5（CCL5）、C - C基序配体11（CCL11）和白细胞介素 - 8（IL - 8）以及促炎细胞因子白细胞介素 - 1β（IL - 1β）和肿瘤坏死因子 - α（TNF - α）表达的抗过敏作用机制。
在过敏原暴露2小时后，将马普拉考特滴入OVA致敏的豚鼠结膜囊内，可有效减轻豚鼠结膜的临床症状、嗜酸性粒细胞浸润和嗜酸性粒细胞过氧化物酶活性；此外，它降低了结膜中CCL5和CCL11的mRNA水平和蛋白表达。在OVA处理的豚鼠结膜切片中，马普拉考特在增加凋亡嗜酸性粒细胞方面比地塞米松更有效。
马普拉考特在控制眼部过敏性结膜炎晚期表现出抗过敏特性，是局部治疗过敏性眼部疾病的有前景的候选药物。
