Azelastine attenuates Cisplatin-induced renal and testicular injury: Involvement of Nrf2/SLC7A11-GPX4 and NCOA4-mediated ferroptosis.

AIM: Renal and testicular toxicities are side effects of the chemotherapeutic agent cisplatin (Cis). The study aims to assess the potential repurpose of Azelastine (Az), an H1-receptor antagonist to alleviate Cis-induced toxicity.

MATERIALS AND

METHODS

Sprague Dawley rats received Az (4 or 6 mg/kg/orally) for ten days and were challenged by a single i.p. injection of Cis (10 mg/kg) on the fifth day. Renal and testicular tissues were investigated using histopathology, immunohistochemistry, qRT-PCR, and ELISA techniques.

RESULTS

Az (6 mg/kg) attenuated Cis-induced nephrotoxicity by reversing the elevation of serum creatinine, BUN, and urinary total protein [38.5 %, 32.3 % and 60 % (p < 0.0001)], and the decline of urinary creatinine and CrCl by 2.15- and 2.8-fold (p < 0.0001 and p < 0.01, respectively). Az (6 mg/kg) induced a significant decrease in both renal and testicular levels of MDA, tissue iron (70.9 %, 51 %, 44.5 % and 33.6 %, respectively, p < 0.0001) and TFR (27.6 %, p < 0.05 and 39 %, p < 0.0001, respectively). Moreover, Az up-regulated renal and testicular Nrf2 and GPX4 (6.9-, 15.6-, 3.9- and 4.8-fold, respectively, p < 0.0001). Both renal and testicular GSH and SLC7A11 were enhanced by Az (2.7-, 2.1-, 4.5-fold, p < 0.0001, and 3.4-fold, p < 0.01, respectively). Finally, Az induced a decrease of renal and testicular NCOA4 and FTH1 gene expressions (53.4 %, 48.6 %, 51.5 % and 41.3 %, respectively, p < 0.0001). Interestingly, Az enhanced the protein levels of NCOA4, but reduced FTH1 (44.5 %, p < 0.0001, 41 %, p < 0.001 and 1.29- and 1.33-fold p < 0.01, respectively)

CONCLUSION

Az mitigates Cis-induced nephrotoxicity and testicular injury by inhibiting ferroptosis.