Enalapril and moexipril protect from free radical-induced neuronal damage in vitro and reduce ischemic brain injury in mice and rats

Angiotensin-converting enzyme inhibitors have been demonstrated to protect spontaneously hypertensive rats from cerebral ischemia. The present study investigated the protective effect of enalapril and moexipril in models of permanent focal cerebral ischemia in normotensive mice and rats. To elucidate the mechanism of neuroprotection the influence of these angiotensin-converting enzyme inhibitors on glutamate-, staurosporine- or Fe2+/3+-induced generation of reactive oxygen species and neuronal cell death in primary cultures from chick embryo telencephalons was studied. Treatment with moexipril or enalapril dose-dependently reduced the percentage of damaged neurons, as well as mitochondrial reactive oxygen species generation induced by glutamate, staurosporine or Fe2+/3+. Furthermore, moexipril and enalapril attenuated staurosporine-induced neuronal apoptosis as determined by nuclear staining with Hoechst 33258. In mice, 1 h pretreatment with enalapril (0.03 mg/kg) or moexipril (0.3 mg/kg) significantly reduced brain damage after focal ischemia as compared to control animals. Additionally, moexipril (0.01 mg/kg) was able to reduce the infarct volume in the rat model after focal cerebral ischemia. The results of the present study indicate that the angiotensin-converting enzyme inhibitors enalapril and moexipril promote neuronal survival due to radical scavenging properties. (C) 1999 Elsevier Science B.V. All rights reserved.