Celastrol protects against cisplatin-induced ovarian toxicity via modulation of PPAR-γ and AMPK

Abstract

Celastrol (CELA) is a naturally occurring pentacyclic nortriterpenoid quinone found in Tripterygium wilfordii with diverse pharmacological activities. A major and constrictive adverse effect of cisplatin (CIS) is ovarian insufficiency, which affects both the reproductive and non-reproductive health. Current study investigated the ability of CELA to protect against CIS-induced ovarian toxicity in rats. Animals received CELA (0.5 and 1 mg/kg; orally) for 17 consecutive days and CIS (6.0 mg/kg; i.p.) on the 7th and 14th day of the study. CIS induced overt ovarian toxicity as indicated biochemically and histopathologically. CELA protected against CIS-induced reduction in the relative ovarian weight and serum levels of estradiol and anti-mullerian hormones. Co-treatment with CELA prevented the histopathological alterations in ovarian tissues and enhanced the fraction of healthy follicles. Further, it significantly ameliorated CIS-induced lipid peroxidation & antioxidant enzyme exhaustion and inhibited the rise in the expression of the inflammatory markers; tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor kappa B. This was associated with modulation of Bax and Bcl-2 mRNA expression in favor of inhibition of apoptosis. Notably, co-treatment with CELA prevented CIS-induced reduction in both peroxisome proliferators-activated receptor-γ (PPAR-γ) and phospho-AMP-activated protein kinase (p-AMPK) content. In conclusion, CELA protects against CIS-induced ovarian toxicity in rats. This may be attributed, at least partly, to its antioxidant, anti-inflammatory, and anti-apoptotic activities in addition to enhancement of PPAR-γ and p-AMPK expression in ovarian tissues.

Keywords: Celastrol; Cisplatin; Ovarian toxicity; PPAR-γ; p-AMPK.