The effects of chronic 3-hydroxy-3-methylglutaryl coenzyme a (HMG CoA) reductase inhibitor administration on penicillin induced brain epileptic activity

Epilepsy is a multifactorial neurologic disorder, may result from many different causes altering brain functions that effect worldwide independent from an age range. Statins, also known as 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors, are widely used cholesterol lowering drugs which are prescribed in clinic for hypercholesterolemia and cardio vascular diseases for years. During the past decade, several studies published suggesting statins have neuroprotective effects. However different epilepsy models and statin therapies do not exhibit similar results;hence action mechanism of statins on epileptic activity is unclear. In the present study, three different HMG-CoA reductase inhibitor form, atorvastatin, simvastatin and rosuvastatin were compared regarding antiepileptic activity on penicillin induced focal epilepsy model. Atorvastatin and rosuvastatin decreased spike frequency and amplitude effectively throughout seizure activity comparing vehicle treated group of animals. Nevertheless rosuvastatin treatment showed the most promising results, significantly decreased spike frequency and amplitude, improved blood brain barrier permeability and increased cerebral blood flow. Neuroprotective effects of rosuvastatin treatment supported by upregulated eNOS and iNOS expressions and downregulated pro-apoptotic p53 and Bax, apoptotic Caspase 3 levels. Serum cholesterol levels showed no difference among these three statin forms, which means anticonvulsant effect of rosuvastatin is not related to cholesterol levels. To question if antiepileptic effect of rosuvastatin related with eNOS, activity of eNOS was inhibited via L-NG-Nitroarginine methyl ester (L-NAME). L-NAME reversed antiepileptic activity of rosuvastatin by means of spike frequency and amplitude severity, but did not alter downregulating effect of rosuvastatin on p53, Bax and Caspase 3 expressions. The findings of this study suggest rosuvastatin is the most effective HMG-CoA reductase inhibitor form in terms of inhibiting epileptic activity.