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.
Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Germany. ravati@mailer.uni-marburg.de
A
A
Ravati
V
V
Junker
M
M
Kouklei
B
B
Ahlemeyer
C
C
Culmsee
J
J
Krieglstein
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D002273:Carcinogens / Q000009:adverse effects; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D005290:Ferric Compounds / Q000009:adverse effects; D005296:Ferrous Compounds / Q000009:adverse effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000009:adverse effects; D018698:Glutamic Acid / Q000009:adverse effects; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D019311:Staurosporine / Q000009:adverse effects; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D002273:Carcinogens; D005290:Ferric Compounds; D005296:Ferrous Compounds; D016166:Free Radical Scavengers; D005609:Free Radicals; D007546:Isoquinolines; D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D018698:Glutamic Acid; D004656:Enalapril; D019311:Staurosporine; C058302:moexipril