Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice.

ABSTRACT

Background and objective The hypolipidemic statins have been associated with various side effects, and in some cases, adverse reactions in humans and experimental animals, such as myotoxicity, neurobehavioral toxicity, as well as liver and kidney injuries. The purpose of the present study was to examine the possibility of the induction of oxidative stress in the brain and plasma of mice dosed with single or repetitive doses of three statins (atorvastatin, simvastatin, and rosuvastatin). Methods Male Swiss-origin mice were dosed orally with single doses of each of the three statins at 500 or 1000 mg/kg of body weight. Other groups of mice were dosed orally with repeated daily doses of each of the statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days. These doses of statins were chosen to not produce overt toxicity in mice within the time frame allocated for each experiment. Brain and plasma glutathione (GSH) and malondialdehyde (MDA) levels, as well as liver enzymes activities alanine transaminase (ALT) and aspartate transaminase (AST), were determined using commercial kits. Results Single-dose treatments of the mice with the statins at either 500 or 1000 mg/kg significantly and dose-dependently (p < 0.05) reduced the GSH level in the plasma and the whole brain when compared with respective control values. Atorvastatin was the least effective statin, as only the high dose achieved a significant reduction in brain GSH level in comparison with the respective control value. Repetitive administration of the three statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days significantly and time-dependently reduced plasma and brain GSH levels in comparison with respective control values. The oxidative stress biomarker MDA level significantly increased in the plasma and brain of mice following single or repetitive treatments with the three statins, and the most effective one was rosuvastatin. In association with these changes, activities of the liver enzymes ALT and AST were also increased in the plasma with single and repetitive statin treatments, and the most effective one was rosuvastatin. Conclusion The data suggest an association of high doses of three statins (atorvastatin, simvastatin, and rosuvastatin) with the induction of oxidative stress manifested as GSH reduction and MDA elevation as adverse effects in the brain and plasma of mice, which suffered from the additional burden of liver injury. These effects could be the basis of an in-depth exploration of statin adverse effects in experimental animals and to find an animal model, probably the mice, for the induction of adverse effects of statins that target the brain, as well as to shed light on potential statin intolerance outcomes following single-dose treatments in this species.