crocin and Chemical-and-Drug-Induced-Liver-Injury--Chronic

Leflunomide-induced liver injury has been an important problem since its approval. Although, severe cases of leflunomide-induced liver injury leading to hospitalization are rare, the risk is higher with concurrent liver disease or use of other hepatotoxic drugs. The current study was conducted to investigate the potential protective effects of carvedilol and crocin alone and in combination against leflunomide-induced hepatic injury and to clarify the possible mechanism(s) through which carvedilol and crocin may elicit their effects. Fifty male albino mice were allocated into five groups: normal control group, leflunomide group, carvedilol group, crocin group, and combination group. These groups were given vehicle, leflunomide, leflunomide plus carvedilol, leflunomide plus crocin, and leflunomide plus combination of carvedilol and crocin, respectively. The study was conducted for 8 weeks, and different parameters were assessed. The results demonstrated that leflunomide significantly increased the serum levels of AST, ALT, ALP, hepatic MDA, nitrite, mTOR gene, PI3K gene, TGF-β, and the pathological changes alongside with the significant decrease of serum albumin, total protein, hepatic catalase, and GSH. While the coadministration of carvedilol, crocin and their combination with leflunomide significantly decreased the serum levels of AST, ALT, ALP, hepatic MDA, mTOR gene, PI3K gene, TGF-β, and the pathological changes alongside with the significant elevation of serum albumin, total protein, hepatic catalase, and GSH. This study is suggesting several solutions for Leflunomide-induced hepatotoxicity demonstrated by the protective effect of the antihypertensive drug carvedilol, the natural product crocin, and their combination which was demonstrated to be superior to each drug alone.

Topics: Animals; Carvedilol; Catalase; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Leflunomide; Liver; Male; Mice; Oxidative Stress; Phosphatidylinositol 3-Kinases; Serum Albumin; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity.. For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats.. MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1β, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity.. CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Biomarkers; Carotenoids; Chemical and Drug Induced Liver Injury, Chronic; Dose-Response Relationship, Drug; Inflammation; Male; Methotrexate; Oxidative Stress; Rats, Wistar