Roflumilast mitigates cisplatin-induced nephrotoxicity by regulating TNF-α/TNFR1/TNFR2/Fas/Caspase mediated apoptosis and inflammatory signals.

Abstract

The study aimed to evaluate the effect of roflumilast on modulating TNF-α/Caspase mediated cellular signals in cisplatin-induced nephrotoxicity in rats. The rats (Male Wistar) were divided into five groups: normal control, disease control (cisplatin: 7mg/kg i.p.), and cisplatin + roflumilast (0.25, 0.5, and 1mg/kg b.w., p.o.). Cisplatin was administrated to rats on 0 day, and roflumilast treatment was started from the 6th-15th days. Blood and tissue were collected. Tissue was used to measure oxidative stress, such as malondialdehyde, superoxide dismutase, and catalase. Gene expression study involved real-time PCR of key genes linked with inflammation and apoptosis, i.e. Tnf-α, Tnfr1, Tnfr2, Fas, Nfkb, Casp3, Casp8, and Nrf2. Cisplatin showed decreased serum creatinine and urea, high albumin, and total protein. Cisplatin elevated the malondialdehyde and reduced superoxide dismutase and catalase activity. Cisplatin also attributed an overexpression of Tnf-α, Tnfr1, Tnfr2, Nfkb, Fas, Casp3, and Casp8, and a decrease in the Nrf2 gene. Roflumilast decreased creatinine and urea and increased albumin and total protein levels. Roflumilast also downregulated the expression of Tnf-α, Tnfr1, Tnfr2, Nfkb, Fas, Casp3, and Casp8 and upregulated the Nrf2 gene expression. Roflumilast manifested as a potential reno-protective agent against cisplatin-induced nephrotoxicity.