Clonidine ameliorates cisplatin-induced nephrotoxicity: impact on OCT2 and p38 MAPK pathway

Abstract

Objectives: To explore clonidine (Clon) nephroprotective effects as an inhibitor of organic cationic transporter 2 (OCT2) and p38 mitogen-activated protein kinase (p38 MAPK) against cisplatin (CP)-induced nephrotoxicity. OCT2 is mainly responsible for renal accumulation of CP. Clon has been recently recognized as an OCT2 inhibitor and exerts beneficial effects on renal function and p38 MAPK. This study further investigates its underlying anti-inflammatory, antioxidative and antiapoptotic effects.

Methods: Rats were randomly assigned into five groups: (I) CON, (II) CP, (III) CP + Clon 0.125, (IV) CP + Clon 0.25, (V) CP + Clon 0.5, and (VI) Clon 0.5 alone. Clon was administered orally at 0.125, 0.25 and 0.5 mg/kg/day dosages for 10 days. On day 7, rats in groups from (II) to (V) received a single intraperitoneal injection of CP (10 mg/kg).

Key findings: Clon 0.25 mg/kg displayed the best nephroprotective outcomes, justified by the significant amelioration of parameters like renal function, oxidative stress, and inflammatory status, as well as modulated the OCT2 expression, phosphorylation of p38 and p53, compared with Clon 0.125 and 0.5 mg/kg.

Conclusion: This study suggests the promising nephroprotective impact of Clon as an OCT2 inhibitor against CP nephrotoxicity and its proficient role in attenuating oxidative stress, inflammatory status and apoptotic status.

Keywords: OCT2; cisplatin; clonidine; nephrotoxicity; p38; p53.