Aggravation of focal cerebral ischemia by tissue-plasminogen activator is reversed by rosuvastatin – role of endothelial NO synthase

Background: It has been proposed that the thrombolytic tissue-plasminogen activator (t-PA) may aggravate ischemic injury after stroke via secondary hemodynamic disturbances. The underlying mechanisms, however, are unclear. To elucidate this issue, we examined the effects of t-PA, administered either alone or in combination with rosuvastatin, on focal ischemic brain injury, intracellular signaling and endothelial NO synthase (eNOS) expression.

Methods and Results: Mice were subjected to transient (90 minutes) intraluminal middle cerebral artery (MCA) occlusions. t-PA treatment initiated immediately after ischemia significantly increased infarct size 24 hours after reperfusion. Co-administration of rosuvastatin completely reversed the t-PA-induced increase of injury. Western blots of ischemic brain lysates showed that t-PA markedly diminished eNOS levels, increased Erk-2 and decreased MAP kinase/p38 activity. Co-treatment with rosuvastatin prevented the decrease in eNOS, reduced Erk-1/-2 and normalized p38 levels.

Conclusions: In a mouse model of focal cerebral ischemia, aggravation of brain injury following t-PA treatment is associated with inhibition of eNOS, which is reversed by rosuvastatin. Thus, statins may be beneficial as add-on treatment in thrombolysis.