Alleviation of Simvastatin-Induced Myopathy in Rats by the Standardized Extract of Ginkgo Biloba (EGb761): Insights into the Mechanisms of Action

Abstract

Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q₁₀ (CoQ₁₀), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ₁₀, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ₁₀, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ₁₀, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ₁₀ levels, and antagonizing mitochondrial damage.