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

Area of Science:

• Pharmacology
• Nephrology
• Toxicology

Background:

• Cisplatin (CP) is a potent chemotherapeutic agent that causes significant nephrotoxicity.
• Organic Cationic Transporter 2 (OCT2) plays a crucial role in the renal accumulation of CP, contributing to its toxicity.
• Clonidine has emerged as a potential inhibitor of OCT2 and modulator of p38 mitogen-activated protein kinase (p38 MAPK), suggesting potential nephroprotective properties.

Purpose of the Study:

• To investigate the nephroprotective effects of clonidine (Clon) against cisplatin (CP)-induced nephrotoxicity.
• To evaluate clonidine's role as an inhibitor of OCT2 and its impact on p38 MAPK signaling.
• To explore the underlying anti-inflammatory, antioxidative, and antiapoptotic mechanisms of clonidine in CP-induced nephrotoxicity.

Main Methods:

• Rats were divided into groups receiving varying doses of clonidine (0.125, 0.25, 0.5 mg/kg/day) or a control, followed by cisplatin injection.
• Clonidine was administered orally for 10 days, with cisplatin administered on day 7.
• Key parameters assessed included renal function, oxidative stress markers, inflammatory status, OCT2 expression, and p38 MAPK phosphorylation.

Main Results:

• Clonidine at a dosage of 0.25 mg/kg demonstrated the most significant nephroprotective effects.
• This optimal dose substantially improved renal function and attenuated oxidative stress and inflammation.
• Furthermore, it effectively modulated OCT2 expression and the phosphorylation of p38 MAPK and p53.

Conclusions:

• Clonidine exhibits promising nephroprotective potential against cisplatin-induced nephrotoxicity.
• Its efficacy is linked to its role as an OCT2 inhibitor, reducing CP accumulation.
• Clonidine proficiently attenuates oxidative stress, inflammation, and apoptosis, supporting its therapeutic utility.