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

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PURPOSE: The study aimed to evaluate the effect of roflumilast on modulating TNF-α/Caspase mediated cellular signals in cisplatin-induced nephrotoxicity in rats. METHODS: The rats (Male Wistar) were divided into five groups: normal control, disease control (cisplatin: 7 mg/kg i.p.), and cisplatin + roflumilast (0.25, 0.5, and 1 mg/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. FINDINGS: 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. CONCLUSION: Roflumilast manifested as a potential reno-protective agent against cisplatin-induced nephrotoxicity.