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.
Subject(s)
2-Amino-5-phosphonovalerate/analogs & derivatives , Brain Ischemia/diagnosis , Brain/drug effects , Magnetic Resonance Imaging , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Binding, Competitive , Brain/pathology , Brain Edema/pathology , Brain Edema/prevention & control , Cats , Rats , Time FactorsABSTRACT
Focal cerebral ischaemia was induced in rats by occlusion of the left middle cerebral artery. Two days later, infarct volume was determined by magnetic resonance imaging and the concentrations of the polyamines putrescine (PU), spermine and spermidine by HPLC. In control (occluded) animals, PU levels were elevated in infarcted and non-infarcted areas of the left hemisphere. Treatment with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine, prevented the ischaemia-induced increase in tissue PU without affecting infarct volume. Conversely, administration of the N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116 decreased cortical infarction without changing the tissue content of PU. We conclude that there is no direct link between NMDA receptor activation and brain PU, or PU and post-ischaemic tissue damage, and that inhibitors of ODC are not cerebroprotective in this animal model of stroke.
Subject(s)
2-Amino-5-phosphonovalerate/analogs & derivatives , Brain Ischemia/pathology , Cerebral Infarction/pathology , Eflornithine/pharmacology , Polyamines/metabolism , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Brain/metabolism , Brain Ischemia/diagnosis , Cerebral Infarction/diagnosis , Magnetic Resonance Imaging , Male , Ornithine Decarboxylase Inhibitors , Putrescine/pharmacology , Rats , Rats, Inbred F344 , Spermidine/pharmacology , Spermine/pharmacologyABSTRACT
Excitotoxic neurodegeneration in the rat striatum was induced by direct injection of quinolinic acid. The degree of damage was evaluated in vivo 1 day later by quantitative magnetic resonance imaging (MRI) and 7 days later in the same animals by measuring the activities of the neuronal marker enzymes choline acetyltransferase and glutamic acid decarboxylase. Striatal damage assessed using the two approaches was highly correlated. Moreover the cerebroprotective efficacy of the N-methyl-D-aspartate receptor antagonist CGP 40116 was indistinguishable based on all analytical parameters. MRI, however, was more reproducible than the enzymatic methods and was faster and simpler for routine analyses of excitotoxic damage and cerebroprotection in vivo.
Subject(s)
Corpus Striatum/pathology , Nerve Degeneration/drug effects , Quinolinic Acid/toxicity , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Brain/enzymology , Brain Edema/pathology , Choline O-Acetyltransferase/metabolism , Glutamate Decarboxylase/analysis , Glutamate Decarboxylase/metabolism , Magnetic Resonance Imaging , Male , Naloxone/pharmacology , Rats , Rats, Inbred Strains , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitorsABSTRACT
The complex formed between the anticancer drug 4-[p-[p-(4-quinolylamino)benzamido]anilino]pyridine (SN 6999) and the decadeoxyribonucleoside nonaphosphate d-(GCATTAATGC)2 was investigated using two-dimensional nuclear Overhauser enhancement spectroscopy (NOESY) with a 13C(omega 1)-half-filter. The two quaternary methyl groups in SN 6999 had been labeled with 13C for these experiments. The simplified subspectra of [1H,1H]-NOESY obtained with this procedure greatly facilitate the identification and assignment of intermolecular NOEs. Quite generally, the combined use of isotope labeling and heteronuclear filters in [1H,1H]-NOESY provides an improved experimental basis for structural studies of drug/DNA complexes.
