L-arginine mitigates against cisplatin-induced defective cardiac metabolic flexibility by activating Nrf2/HO-1 and upregulating glutathione in male Wistar rat.

BACKGROUND

Cisplatin-induced cardiotoxicity is a major global health challenge among patients on platinum-based chemotherapy and it has limited the clinical use of this drug despite its effectiveness Cisplatin. It exerts its cardiotoxicity via the downregulation of Nrf2/HO-1 and glutathione system, while L-arginine, a semi-essential amino acid and an anti-oxidant, activates Nrf2/HO-1 and enhances glutathione antioxidants. However, data on the effect of L-arginine on cisplatin-induced cardiotoxicity is scarce.

AIM: Therefore, this study examined the effect of L-arginine on cisplatin-induced cardiotoxicity. Also, the involvement of the Nrf2/HO-1 pathway and glutathione system was explored.

MATERIALS AND

METHODS

Twenty-four male Wistar rats were randomly allotted into 4 groups after a 2-week acclimatization period; control, arginine-treated, cisplatin-treated, and cisplatin+arginine-treated.

RESULTS

L-arginine blunted cisplatin-induced decrease in body and cardiac weight, and cardiac/tibial length ratio. Also, L-arginine attenuated cisplatin-induced rise in cardiac lactate dehydrogenase and creatinine kinase activities and lactate and troponin levels. More so, L-arginine attenuated cisplatin-induced rise in the circulating levels of glucose, total cholesterol, and triglyceride, as well as atherogenic indices and insulin resistance. Furthermore, L-arginine improved cisplatin-induced alteration in cardiac histoarchitecture. These findings were associated with L-arginine-led suppression of cisplatin-induced rise in cardiac MDA, IL-1β, TNF-α, NF-kB, and myeloperoxidase activity, and cisplatin-induced reductions in cardiac GPx, GST, SOD, catalase, and HO-1 activities, and Nrf2 expression.

CONCLUSION

L-arginine attenuated cisplatin-induced cardiotoxicity and defective cardiac metabolic flexibility by activating Nrf2/HO-1 signaling and upregulating glutathione.