Objectives

The fact that methotrexate (MTX) is hepatotoxic is an important reason to limit its clinical use. Rebamipide (REB) has antioxidant and anti-inflammatory properties and is useful for the treatment of gastro-duodenal ulcers. This study investigated the impact and protective mechanisms of REB against MTX-induced hepatotoxicity in rats.

Materials and Methods

Animals were divided into four groups of six rats each: a control group, REB group (REB 100 mg/kg/day, orally), MTX control group (20 mg/kg, single i.p.), and MTX + REB group.

Results

The administration of MTX induced marked hepatic injury in the form of hepatocyte inflammatory swelling, degeneration, apoptosis, and focal necrosis. In parallel, our biochemical investigations revealed a marked hepatic dysfunction associated with the disturbance of the oxidant/antioxidant balance in the group treated with only MTX. Moreover, MTX led to the down-regulation of the hepatic Nrf2 and Bcl-2 expressions along with a marked elevation in the hepatic NF-κβ-p65, GSK-3β, JAK1, STAT3, PUMA, and Bax expressions. On the other hand, co-treatment with REB significantly ameliorated the aforementioned histopathological, biochemical, and molecular defects caused by MTX treatment.

Conclusion

the outcomes of the present study showed REB’s ability to protect from hepatic injury induced by MTX, possibly through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These effects could be attributed to REB’s ability to modulate, at least in part, the Nrf2/GSK-3β,NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2signaling pathways.

中文翻译：

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瑞巴派特对甲氨蝶呤引起的肝中毒的肝保护作用：Nrf2 /GSK-3β，NF-κβ-p65/ JAK1 / STAT3和PUMA / Bax / Bcl-2信号通路的作用。

目标

甲氨蝶呤（MTX）具有肝毒性这一事实是限制其临床用途的重要原因。瑞巴派特（REB）具有抗氧化和抗炎特性，可用于治疗胃十二指肠溃疡。这项研究调查了REB对MTX诱导的大鼠肝毒性的影响和保护机制。

材料和方法

将动物分为四组，每组六只大鼠：对照组，REB组（REB 100 mg / kg /天，口服），MTX对照组（20 mg / kg，单次ip）和MTX + REB组。

结果

MTX的给药以肝细胞炎性肿胀，变性，凋亡和局灶性坏死的形式引起明显的肝损伤。同时，我们的生化研究显示，在仅使用MTX治疗的组中，肝功能异常与氧化剂/抗氧化剂平衡紊乱有关。此外，MTX导致肝Nrf2和Bcl-2表达下调，同时肝NF-κβ-p65，GSK-3β，JAK1，STAT3，PUMA和Bax表达明显升高。另一方面，与REB共同治疗可显着改善由MTX治疗引起的上述组织病理学，生化和分子缺陷。

结论

本研究的结果表明，REB可能具有抗氧化，抗炎和抗凋亡特性，能够抵抗MTX引起的肝损伤。这些影响可以归因于REB至少部分地调节Nrf2 /GSK-3β，NF-κβ-p65/ JAK1 / STAT3和PUMA / Bax / Bcl-2信号通路的能力。