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-β-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.

Fig. 1.

Mean (±SD) urinary excretion of N-acetyl-β-d-glucosaminidase (NAG) in the control, colistin, melatonin, and colistin-melatonin groups. *, Significantly different from control group (P < 0.0001); #, significantly different from baseline for the same group (P < 0.005).

Fig. 2.

Representative photomicrographs of normal renal cortex (A), rat kidney from the colistin group with grade 1 lesions, mild acute tubular damage with tubular dilatation, prominent nuclei, and a few pale tubular casts (B), rat kidney from the colistin group showing grade 2 lesions with severe acute tubular damage with necrosis of the tubular epithelial cells and numerous tubular casts (C), rat kidney from the colistin group showing grade 3 lesions with acute cortical necrosis with necrosis and/or infarction of tubules and glomeruli (D), rat kidney from the colistin-melatonin group in which the renal cortex and medulla appeared normal (E), and rat kidney from the melatonin group without kidney damage (F). G, glomerulus (hematoxylin and eosin stain). Original magnifications: ×200 for panels A, B, C, and D and ×20 for panels E and F.

Fig. 3.

Mean (±SD) plasma colistin concentration versus time profiles after the first intravenous dose of colistin (0.5 mg/kg) either alone (♢) or preceded by melatonin at 5 mg/kg (■) (n = 5 in each group). The plasma colistin concentrations at 360 min in all rats in the colistin group were below the limit of quantification of the assay (0.125 μg/ml).

Fig. 4.

Mean (±SD) amounts of unchanged colistin excreted in the urine on days 3, 5, and 6 after multiple intravenous doses of colistin for 7 days (the cumulative dose was 36.5 mg/kg) or the same regimen of colistin plus melatonin. *, P < 0.0001 compared to the colistin group.