Protective effect of baicalein alone and losartan?baicalein combination therapy on doxorubicin-induced hepatotoxicity in rats

Abstract
Objective
Doxorubicin (DOX) is a widely used antineoplastic drug with several toxic effects. We investigated the protective effect of co-administration of baicalein (BL; a flavonoid) and losartan (LT; angiotensin receptor blocker) on DOX-induced hepatotoxicity.

Methods
Male Wistar albino rats were divided into these seven groups (n = 6): (1) Control group; (2) DOX group; (3) DOX + LT group (LT, 7 mg/kg/day orally); (4) DOX + BL low-dose group (BL, 5 mg/kg/day orally); (5) DOX + BL high-dose group (BL, 10 mg/kg/day orally); (6) DOX + LT + BL(5) low-dose group; and (7) DOX + LT + BL(10) high-dose group. After 2 weeks of LT and BL treatment, a dose of DOX (15 mg/kg, intraperitoneal) was administered to the rats in groups 2 to 6 and continued for seven more days.

Results
The use of serum levels of liver enzymes, tumor necrosis factor-α, interleukin (IL)-6, and IL1β and estimated the activity of thiobarbituric acid-reactive substances, glutathione, superoxide dismutase, catalase, and glutathione peroxidase in liver homogenates. In addition, we measured the activity of caspase-3, nitric oxide, inducible nitric oxide synthase, endothelial nitric oxide synthase, and nuclear factor kappa-B (NF-κB) p65 in hepatic cells and subjected the liver sections to histological examination. While the DOX-induced increase in serum liver enzymes, pro-inflammatory cytokines, and biomarkers was alleviated by BL and/or LT treatment, the BL + LT groups showed the most potent protective effects.

Conclusions
Our study demonstrates remarkable anti-oxidative and anti-inflammatory effects of BL and LT in rodents challenged with DOX. Concurrent administration of BL and LT showed a marked synergistic effect in restoration of histological features and alleviation of hepatic oxidative injury via inhibition of reactive oxygen species and anti-inflammatory mechanisms.