Pioglitazone ameliorates cisplatin-induced testicular toxicity by attenuating oxidative stress and inflammation via TLR4/MyD88/NF-κB signaling pathway

Abstract

Background: Cisplatin (CIS) is a chemotherapeutic agent widely used to cure several cancers. It exerts detrimental cellular effects that restrain its clinical application as an antineoplastic agent, as testicular damage. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is used to treat type-2 diabetes mellitus. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. The present study aimed to investigate the effect of PIO in a rat model of cisplatin-induced testicular toxicity and address the possible role of the Toll-like receptors (TLR4) / myeloid differentiation factor 88 (MyD88) / nuclear factor-kappa B (NF-kB) signal pathway.

Methods: Rats received a single dose of cisplatin (7 mg/kg, IP) on the first day and PIO (10 mg/kg, P.O.) for 7 days. At the end of the treatment period, rats were killed. Testicular weights, histopathological alterations, and serum testosterone levels were determined. Moreover, tissue samples were collected for the estimation of oxidative stress parameters, inflammatory markers, and the determination of TLR4 /MyD88/NF-kB signaling.

Results: Concurrent PIO administration with CIS markedly improved testicular weights, histopathological alteration, and serum testosterone level changes. Moreover, Concurrent PIO administration abrogated oxidative stress status and inflammatory markers caused by CIS administration. Furthermore, PIO inhibited the expression levels of TLR4, MyD88, and NF-κBp65, proteins that are activated by CIS administration.

Conclusion: These findings suggested that PIO can protect against cisplatin-induced testicular toxicity in rats through inhibition of the TLR4 /MyD88/NF-kB signal pathway.

Keywords: Cisplatin; Inflammation; Oxidative stress; Pioglitazone; Testicular toxicity.