Sutovska Martina, Kocmalova Michaela, Franova Sona, Vakkalanka Swaroop, Viswanadha Srikant
Department of Pharmacology, Jessenius Faculty of Medicine, Comenius University, Martin's Biomedical Center (BioMed) Malá Hora, 11161 4D Martin, Slovakia.
Rhizen Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland.
Eur J Pharmacol. 2016 Feb 5;772:62-70. doi: 10.1016/j.ejphar.2015.12.047. Epub 2015 Dec 25.
The increase in intracellular Ca(2+) levels through the activation of Ca(2+) release-activated Ca(2+) (CRAC) channels is essential for mediating a wide scale of immune cell responses. Emerging evidence indicates an involvement of abnormal CRAC channel activity in human diseases such as certain types of immunodeficiency, autoimmunity and allergic disorders. This objective of this study was to evaluate the therapeutic potency of a novel CRAC channel inhibitor, RP3128, in experimental models of allergic asthma using guinea pigs. Ovalbumin-induced allergic airway inflammation was determined upon acute and long-term (14 days) oral administration of RP3128. In vivo changes in specific airways resistance (sRaw) and amplitude of isometric contraction (mN) of ASM (in vitro) were estimated to evaluate bronchodilatory effect upon acute and long-term administration of RP3128 or salbutamol. Exhaled nitric oxide (eNO), immunohistochemical and histological analysis of cellular infiltration in airways tissue, and levels of cytokines in plasma as well as bronchoalveolar lavage fluid (BALF), were determined using Bio-Plex® 200 System (BIO-RAD, USA). Ciliary beat frequency (CBF, in Hz) was estimated using a high-speed video camera and LabVIEW™ Software. Additionally, the impact of RP3128 and budesonide on mucociliary clearance was determined. Acute and long-term administration of RP3128 resulted in significant bronchodilation. Long-term administration of RP3128 exceeded the bronchodilatory effect of salbutamol and significantly decreased eNO and cytokine levels in plasma and BALF, which together with histological and immunohistochemical analysis validated its anti-inflammatory effect compared to budesonide. Data demonstrate the therapeutic potential of RP3128 in respiratory diseases causally associated with allergic inflammation.
通过激活钙释放激活钙（CRAC）通道来提高细胞内钙离子（Ca(2+)）水平，对于介导广泛的免疫细胞反应至关重要。新出现的证据表明，CRAC通道活性异常与某些类型的免疫缺陷、自身免疫和过敏性疾病等人类疾病有关。本研究的目的是评估新型CRAC通道抑制剂RP3128在豚鼠过敏性哮喘实验模型中的治疗效果。在急性和长期（14天）口服RP3128后，测定卵清蛋白诱导的过敏性气道炎症。估计急性和长期给予RP3128或沙丁胺醇后体内特定气道阻力（sRaw）和气道平滑肌（体外）等长收缩幅度（mN）的变化，以评估支气管扩张作用。使用Bio-Plex® 200系统（美国伯乐公司）测定呼出一氧化氮（eNO）、气道组织中细胞浸润的免疫组织化学和组织学分析以及血浆和支气管肺泡灌洗液（BALF）中的细胞因子水平。使用高速摄像机和LabVIEW™软件估计纤毛摆动频率（CBF，单位为Hz）。此外，还确定了RP3128和布地奈德对黏液纤毛清除的影响。急性和长期给予RP3128均导致显著的支气管扩张。长期给予RP3128的支气管扩张作用超过了沙丁胺醇，并且显著降低了血浆和BALF中的eNO和细胞因子水平，与组织学和免疫组织化学分析一起证实了其与布地奈德相比的抗炎作用。数据证明了RP3128在与过敏性炎症因果相关的呼吸系统疾病中的治疗潜力。
