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 i nvestigated the protective effect of enalapril and moexipril in models of p ermanent focal cerebral ischemia in normotensive mice and rats. To elucidat e the mechanism of neuroprotection the influence of these angiotensin-conve rting enzyme inhibitors on glutamate-, staurosporine- or Fe2+/3+-induced ge neration of reactive oxygen species and neuronal cell death in primary cult ures from chick embryo telencephalons was studied. Treatment with moexipril or enalapril dose-dependently reduced the percentage of damaged neurons, a s well as mitochondrial reactive oxygen species generation induced by gluta mate, staurosporine or Fe2+/3+. Furthermore, moexipril and enalapril attenu ated staurosporine-induced neuronal apoptosis as determined by nuclear stai ning 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 cere bral ischemia. The results of the present study indicate that the angiotens in-converting enzyme inhibitors enalapril and moexipril promote neuronal su rvival due to radical scavenging properties. (C) 1999 Elsevier Science B.V. All rights reserved.