Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats

Abstract

Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n ‫؍‬ 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-␤-D-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P ‫؍‬ 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ؎ 0.26 ml/min/kg) was lower than in the colistin group (4.28 ؎ 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.

Major Pathways of Polymyxin-Induced Apoptosis in Rat Kidney Proximal Tubular Cells

“…Furthermore, we observed the generation of reactive oxygen species (ROS) in polymyxin-treated kidney tubular cells, a phenomenon that has been associated with apoptotic mitochondrial morphology changes (46). These findings are in line with our previous studies which showed that antioxidants can act to attenuate polymyxin-induced nephrotoxicity in rats (30,31,47). The present results support the notion of a need for evaluation of the possible role of antioxidants to ameliorate polymyxin-induced nephrotoxicity in patients.…”

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

“…*, P Ͻ 0.05; **, P Ͻ 0.01 (compared to the control group); #, P Ͻ 0.05; ##, P Ͻ 0.01 (compared to the colistin group). [16][17][18]55). Increased production of ROS is an important mechanism in colistin-induced nephrotoxicity and neurotoxicity (17,(56)(57)(58).…”

“…[16][17][18]55). Increased production of ROS is an important mechanism in colistin-induced nephrotoxicity and neurotoxicity (17,(56)(57)(58). Excessive ROS levels cause damage to DNA, lipids, and proteins, eventually leading to apoptosis (14,59).…”

“…Caspase-3 is a key biomarker of apoptosis (18), which can be activated by both intrinsic and extrinsic apoptotic pathways and consequently lead to DNA breakdown (14,57,62). Several studies showed that activated caspase-3 played a key role in colistin-induced apoptosis in rat kidney tissue (12,17,18). The mitochondrion is a major producer of ROS and plays a central role in the process of oxidative stress (58,63).…”

“…Reactive oxygen species (ROS) molecules are mainly generated by mitochondria and are among the major mediators of oxidative stress; they initiate renal cell apoptosis, which finally leads to renal dysfunction (14,15). ROSmediated oxidative stress plays a key role in colistin-induced nephrotoxicity (12,(16)(17)(18).…”