Antioxidant-statin combination for the management of intraperitoneal sepsis in rats

ABSTRACT

There is a good evidence that endotoxemia, sepsis, and septic shock are associated with the generation and release of reactive oxygen species [ROS], indicating that oxygen-derived free radicals play an important role in the pathogenesis of septic shock. Inhibitors of HMG-CoA reductase in addition to lowering serum cholesterol levels, exert many pleiotropic effects as antioxidant and anti-inflammatory action. The present study was designed to investigate the possible modulatory effect, if any, of atorvastatin alone or in combination with N-acetylcysteine in cecal ligaiton and perforation [CLP] model of sepsis in rats. Sixty four male albino rats weighing 150-200 g were used in the present study. Rats were randomly divided into eight groups, each of eight rats. Group I, sham operated group. Group II, non treated CLP control group. Group HI, vehicle-treated CLP control group, received saline SC and 2% gum acacia orally. Group IV, CLP group, treated by ceftriaxone plus gentamicin IM every six hours immediately after resuscitation. Group V, CLP group, treated by atorvastatin orally suspended in 2% gum acacia after resuscitation. Group VI, CLP group, treated by N-acetylcysteine [NAC] SC every 6 hours starting after resuscitation. Group VII, CLP group, treated by both atorvastatin and NAC in the same doses and routes of groups V and VI respectively. Group VIII, CLP group, treated by ceftriaxone-gentamicin combination as in group IV in addition to atorvastatin-NAC combination as in group VII. Twelve hours after CLP, malondialdehyde [MDA] levels, my eloperoxidase [MPO], superoxide dismutase [SOD], and catalase activities in heart, liver, and kidney were significantly elevated. Early treatment of CLP rats with ceftriaxone-gentamicin combination, atorvastatin and/or NAC caused a significant reduction in the aforementioned parameters. The concomitant administration of atorvastatin-NAC combination with ceftriaxone -gentamicin combined therapy nearly normalized the studied parameters. The results of the present work demonstrated that ROS plays an important role in CLP model of sepsis in rats. Furthermore, atorvastatin proved to have a protective effect in CLP rats which could be due to an antioxidant effect in addition to a possible anti-inflammatory action. These beneficial effects are augmented by the co-administration of NAC. Nevertheless, it is not advisable to use antioxidants alone for the management of sepsis, so it is recommended to use atorvastatin-NAC combination with optimum chemotherapeutic agents. Future human studies are indicated to assess the clinical relevance of the results of the present work in patients with septic shock