The beneficial effects of ciprofloxacin on survival and hepatic regenerative activity in a rat model of fulminant hepatic failure

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Abstract
Recently, we reported that ciprofloxacin, an antimicrobial agent with γ-aminobutyric acid (GABAA) receptor antagonist properties, significantly increases hepatic regenerative activity in animal models of alcohol-induced liver disease and cirrhosis. In the present study, we documented the effects of ciprofloxacin on survival and hepatic regeneration in a d -galactosamine (d -gal)-induced model of acute hepatic injury in rats. One hundred nineteen adult, male Sprague-Dawley rats (n = 19-20/group) were treated with intraperitoneal d -gal (total dose: 2.5 g/kg), followed by gastric gavage with either saline, ciprofloxacin (10, 50, or 100 mg/kg), norfloxacin (250 mg/kg), or intraperitoneal putrescine (300 μmol/kg), a potent hepatic growth promoter. Mortality rates were then documented over a 4-day period. An additional 45 rats (n = 15/group) received a sublethal dose of d -gal (1.0 g/kg), followed by gastric gavage with either saline or ciprofloxacin (100 mg/kg), or intraperitoneal putrescine (300 μmol/kg). In these rats, hepatic regenerative activity was documented at 12, 24, and 60 hours post-d -gal by 3H-thymidine incorporation into hepatic DNA and proliferating cell nuclear antigen (PCNA) staining. In the survival study, a dose-response effect of ciprofloxacin on survival was observed (ciprofloxacin: 10 mg/kg, 10%; 50 mg/kg, 26%; and 100 mg/kg, 35%) with the results in the 100-mg/kg-treated group being significant when compared with the 5% survival rate in saline-treated controls (P < .05). Survival figures in the norfloxacin- and putrescine-treated groups were not significantly improved (15% and 25%, respectively). In the regeneration study, compared with the d -gal + saline-treated control group, DNA synthesis rates at 60 hours were increased in the d -gal + ciprofloxacin and d -gal + putrescine groups (10.2 ± 3.3 vs. 18.2 ± 5.1 and 18.8 ± 6.8 × 103 dpm/mg DNA respectively; P < .05). The results of PCNA staining also supported enhanced hepatic regeneration in the ciprofloxacin-treated group at 60 hours (saline, 13.4 ± 3.7; ciprofloxacin, 47.4 ± 7.3; and putrescine, 8.4% ± 2.8% hepatocytes staining positive). Ciprofloxacin at a dose of 100 mg/kg significantly improves survival and hepatic regenerative activity in this animal model of acute hepatic injury.