title: Characterization of the cerebroprotective efficacy of the competitive NMDA receptor antagonist CGP40116 in a rat model of focal cerebral ischemia: an in vivo magnetic resonance imaging study.
abstract: The cerebroprotective properties of the competitive NMDA antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) were evaluated in a rat model of focal cerebral ischemia. CGP 40116 (5-40 mg/kg i.v.) was injected immediately following permanent occlusion of the left middle cerebral artery (MCA). MK 801 (1 or 3 mg/kg i.v.), D-CPPene (20 mg/kg i.v.), and CGS 19755 (40 mg/kg i.v.) were used for comparison. Lesion volume was assessed using in vivo magnetic resonance imaging, which in initial experiments with parallel histological determinations proved to be an accurate method for the measurement of brain infarction and the determination of a cerebroprotective drug effect. CGP 40116 dose-dependently reduced the volume of cortical infarction, with an ED50 of 11 mg/kg i.v. and a maximal effect equivalent to a 62% reduction in cortical edema volume. Its cerebroprotective efficacy was thus comparable to that of MK 801. The rank order of potency for the NMDA antagonists was MK 801 > CGP 40116 approximately D-CPPene > CGS 19755. Neuroprotection by CGP 40116 was still apparent when treatment was started 30 min after MCA occlusion. It is concluded that CGP 40116 is an effective cerebroprotectant with potential clinical utility for amelioration of focal cerebral ischemic damage.
authors.affiliation: Biology Research Laboratory, Ciba-Geigy Ltd., Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Sauer
authors.forename: P R
authors.initials: PR
authors.lastname: Allegrini
authors.forename: A
authors.initials: A
authors.lastname: Cosenti
authors.forename: A
authors.initials: A
authors.lastname: Pataki
authors.forename: H
authors.initials: H
authors.lastname: Amacker
authors.forename: G E
authors.initials: GE
authors.lastname: Fagg
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000175:diagnosis*; D002415:Cats; D008279:Magnetic Resonance Imaging; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D015763:2-Amino-5-phosphonovalerate