Do Statins Influence the Activity of c-fos Gene Following Transient Forebrain Ischaemia in the Adult Rat Hippocampus?

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been associated with stroke prevention. This stroke prevention appears to occur apart from cholesterol lowering effects. A number of mechanisms have been postulated for this prevention. The aim of our study was to investigate the effect of simvastatin on the c-fos gene activity and its relation to delayed neuronal death in CA1 region of hippocampus following transient forebrain ischemia in the adult rat hippocampus. A total of 17 male Wistar albino rats were used in this study. The animals were divided into three groups: 5 sham-operated animals; 6 ischemised rats without statin pre-treatment and 6 ischemised rats with statin pre-treatment. We used simvastatin at the dose of 20 mg/kg during 14 days prior to the ischemic attack. Fifteen min long transient forebrain ischemia was induced by the four-vessel occlusion. Two and a half h reperfusion was used for the c-Fos activity detection using immunostaining and 72 h reperfusion was used for the determination of neurons surviving using haematoxylin/eosin staining. The average neuronal density in the CA1 region of hippocampus in the sham-operated rats, in ischemised rats without pre-treatment and in ischemised rats with statin pre-treatment was 47.03 ± 3.09/0,025 mm2, 9.05 ± 2.46/0,025 mm2 and 16.45 ± 2.78/025 mm2, respectively. A significant neuroprotective effect was observed in the pre-treated ischemic group (P < 0.001) in comparison to the ischemic group without pre-treatment. The average of c-Fos positive nuclei density in the CA1 region of hippocampus in the sham-operated rats, in ischemised rats without pre-treatment and in ischemised rats with statin pre-treatment was 0.266 ± 0.074/025 mm2, 28.2 ± 2.053/025 mm2, 30.3 ± 4.816/025 mm2, respectively. A highly significant difference in c-Fos positivity (P < 0.001) was found between the sham operated group and both ischemic groups (with and without pre-treatment). No significant difference in c-Fos positivity was observed between untreated ischemic and pre-treated ischemic groups (P > 0.05). These findings indicate that simvastatin provides protection against CA1 hypoxic neuronal injury, which is independent of c-fos activation. We can conclude that simvastatin neuroprotection may be mediated by multiple mechanisms as can be expected based on its pleiotropic effects.