Evaluation of possible pro- or antioxidative properties and of the interaction capacity with the microsomal cytochrome P450 system of different NMDA-receptor ligands and of taurine in vitro.
In the first part of the study possible additional antioxidative effects of various N-methyl-D-aspartate (NMDA)-receptor antagonists, some of which are used in the treatment of Parkinson's or Alzheimer's disease or as narcotic (dizocilpine, ketamine, budipine, memantine, amantadine, AP-5) were investigated in vitro in comparison to the respective agonists (NMDA, glutamate, aspartate, glycine) and the putative antioxidative amino acid taurine. For this purpose, effects on cytochrome P450 (P450) mediated oxidase functions in rat liver and brain microsomes were examined by measuring the influence on stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin and luminol amplified chemiluminescence. Additionally, effects on rat whole blood chemiluminescence (WB-CL) were assessed. In the second part of the study the influence of the substances on P450 mediated monooxygenase functions in rat liver 9000 g supernatants, as assessed by the model reactions ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD), and ethylmorphine N-demethylation (EMND), was investigated in order to evaluate possible interactions with the biotransformation of other foreign or endogenous substances. The non-competitive antagonists dizocilpine, ketamine, budipine and memantine concentration-dependently diminished all oxidase model reactions in both rat liver and brain microsomes. Amantadine was only slightly effective in brain microsomes and on LPO in liver microsomes. No noticeable effect was seen with the competitive antagonist AP-5, with all agonists and with taurine. WB-CL was diminished by all antagonists and by glutamate but not affected by the other agonists and taurine. Dizocilpine, ketamine, budipine and memantine concentration dependently inhibited EROD, ECOD and EMND, amantadine only EROD and ECOD activity. The other substances were without any effect. These results demonstrate that only the non-competitive NMDA-receptor antagonists seem to have antioxidative properties. On the other hand, only with the non-competitive antagonists interactions with the P450 system and thus with the biotransformation of other substances are to be expected.
Lupp
Amelie
A
Institute of Pharmacology and Toxicology, Friedrich Schiller University of Jena, Jena, Germany. Amelie.Lupp@mti.uni-jena.de
Kerst
Steffen
S
Karge
Elke
E
D000818:Animals; D021461:Animals, Outbred Strains; D000975:Antioxidants / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007527:Isoenzymes; D007649:Ketamine / Q000494:pharmacology; D008024:Ligands; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology*
D000975:Antioxidants; D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D007649:Ketamine; D003577:Cytochrome P-450 Enzyme System