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

Abstract

Recently, we reported that ciprofloxacin, an antimicrobial agent with ␥-aminobutyric acid (GABA A ) 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 SpragueDawley 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 mol/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 mol/kg). In these rats, hepatic regenerative activity was documented at 12, 24, and 60 hours post-D-gal by 3 H-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 F .05). Survival figures in the norfloxacin-and putrescinetreated 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 ؋ 10 3 dpm/mg DNA respectively; P F .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 ؎ Fulminant hepatic failure (FHF) is a multisystem disorder associated with high mortality rates, particularly in patients with stage IV disease. 1 While survival rates for FHF have improved in recent years, those improvements largely reflect advances in intensive care management, rather than the identification or development of specific effective therapies. 2 Liver transplantation likely improves survival, but this has yet to be demonstrated in prospective, controlled, clinical trials. 3 Moreover, liver transplants for FHF require an emergent donor and commits the recipient to long-term immunosuppressive therapy.Because many FHF deaths result from absent or impaired hepatic regenerative activity, 4 an appropriate treatment strategy would consist of medical interventions that either directly promote hepatic regeneration or negate the effects of circulating growth inhibitors. Although encouraging results have recently been reported with exogenous putrescine, a polyamine that is ...

Expression of gamma‐aminobutyric acid and glutamic acid decarboxylases in rat descending colon and their relation to epithelial differentiation

“…Their results showed the appearance of GABA in the developing pancreas and duodenum just prior to the termination of rapid growth and maturation of these tissues. Recently, Kaita et al 15 reported that the GABA-A receptor antagonist ciprofloxacin significantly increased hepatic regenerative activity in animal models of alcohol-induced liver disease and cirrhosis. On the basis of these results, the authors postulated that GABA could be a potent amino-acid inhibitor of hepatic cell growth.…”

Decreased hepatocyte membrane potential differences and GABAa-β3 expression in human hepatocellular carcinoma

“…6,7 Conversely, when GABA A receptors were down-regulated, hepatocyte PDs were depolarized, and proliferative activity was increased. 8,9 Another electrogenic system that may play an important role in regulating hepatocyte PDs is the Na/K adenosine triphosphatase (ATPase) system. Like the GABAergic system, increased Na/K-ATPase activity results in hyperpolarization and inactivation/depolarization of hepatocyte PDs.…”

Non Antimicrobial Effects of Antibacterial Agents

“…Kanada'da D-galaktozamin tarafından karaciğer hasarı meydana getirilen 119 fare üzerinde yapılan bir çalışmada 100 mg/kg siprofloksasin dozunun yaşam süresini ve hepatik rejenerasyonu arttırdığı gösterilmiştir [93] . Karaciğer nakli bekleyen ileri karaciğer yetmezlikli hastalarda günlük siprofloksasin kullanımı hastaneye yatış sıklığını anlamlı olarak azaltmaktadır [94] .…”