Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madina Al-Munawwarah, 30001, Saudi Arabia. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
Toxicol Appl Pharmacol. 2020 Apr 15;393:114931. doi: 10.1016/j.taap.2020.114931. Epub 2020 Feb 25.
Concanavalin A (ConA) is a well-established model to induce autoimmune hepatitis (AIH) in mice which mimics pathological alterations that occur in human. The pathogenesis of ConA-induced AIH involves many signaling pathways. Montelukast is a leukotriene receptor antagonist that is mainly used in the management of asthma. The antioxidant, anti-inflammatory and anti-apoptotic effects of montelukast have been reported in previous studies. Lately, montelukast has been documented to confer protection against various inflammatory diseases. Up to date, no study has explored the effect of montelukast on AIH induced by ConA.
This study aims to detect the protective effects of montelukast (10 mg/kg) on ConA (20 mg/kg)- induced AIH in mice and to demonstrate its hepatoprotective mechanisms. Hepatic function, histological changes, oxidative stress, inflammation, autophagy, and apoptotic markers were investigated.
Hepatic function and histological data revealed that treatment with montelukast significantly attenuated ConA-induced hepatic damage. Montelukast significantly reduced JNK level and NFκB p65 expression, and inhibited proinflammatory cytokines (TNF-α and IL-6) as well as oxidative stress (MDA, NO, and GSH). Moreover, inflammatory cells (CD4+ infiltration and the levels of apoptotic markers (Bax and caspase-3) besides autophagy biomarkers (Beclin1 and LC3) were reduced.
Our results suggest that montelukast could be a potential therapeutic drug against the ConA-induced AIH through its anti-oxidant, anti-inflammatory, anti- autophagy as well as anti-apoptotic properties.
刀豆蛋白 A（ConA）是诱导小鼠自身免疫性肝炎（AIH）的经典模型，其病理改变与人 AIH 相似。ConA 诱导的 AIH 发病机制涉及多种信号通路。孟鲁司特是一种白三烯受体拮抗剂，主要用于哮喘的治疗。孟鲁司特具有抗氧化、抗炎和抗凋亡作用，这在之前的研究中已有报道。最近，有研究报道孟鲁司特可预防多种炎症性疾病。迄今为止，尚无研究探讨孟鲁司特对 ConA 诱导的 AIH 的作用。
本研究旨在检测孟鲁司特（10mg/kg）对 ConA（20mg/kg）诱导的 AIH 小鼠的保护作用，并阐明其肝保护机制。检测了肝功能、组织学变化、氧化应激、炎症、自噬和凋亡标志物。
肝功能和组织学数据显示，孟鲁司特治疗可显著减轻 ConA 诱导的肝损伤。孟鲁司特可显著降低 JNK 水平和 NFκB p65 表达，抑制促炎细胞因子（TNF-α和 IL-6）和氧化应激（MDA、NO 和 GSH）。此外，还降低了炎症细胞（CD4+浸润）和凋亡标志物（Bax 和 caspase-3）以及自噬标志物（Beclin1 和 LC3）的水平。
我们的结果表明，孟鲁司特可能通过抗氧化、抗炎、抗自噬和抗凋亡作用成为治疗 ConA 诱导的 AIH 的潜在药物。
