Dual effect ofDL-homocysteine andS-adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acid
| Autor: | Jerzy W. Lazarewicz, R. Paczek, Apolonia Ziembowicz, Tomasz Kocki, Ewa M. Urbańska, Elzbieta Luchowska, Piotr Luchowski, Waldemar A. Turski, Marian Wielosz |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Phenylalanine Down-Regulation Pharmacology Biology Kynurenic Acid Receptors Metabotropic Glutamate Hippocampus Cellular and Molecular Neuroscience chemistry.chemical_compound Organ Culture Techniques Kynurenic acid Leucine Animals Sulfhydryl Compounds Glutamate receptor antagonist Rats Wistar Homocysteine Transaminases Cerebral Cortex Dose-Response Relationship Drug Glutamate receptor Antagonist S-Adenosylhomocysteine Rats Up-Regulation Receptors Glutamate chemistry Biochemistry Metabotropic glutamate receptor NMDA receptor Female Rabbits Excitatory Amino Acid Antagonists Kynurenine Ionotropic effect |
| Zdroj: | Journal of Neuroscience Research. 79:375-382 |
| ISSN: | 1097-4547 0360-4012 |
| DOI: | 10.1002/jnr.20359 |
| Popis: | Increased serum level of homocysteine, a sulfur-containing amino acid, is considered a risk factor in vascular disorders and in dementias. The effect of homocysteine and metabolically related compounds on brain production of kynurenic acid (KYNA), an endogenous antagonist of glutamate ionotropic receptors, was studied. In rat cortical slices, DL-homocysteine enhanced (0.1-0.5 mM) or inhibited (concentration inducing 50% inhibition [IC50]=6.4 [5.5-7.5] mM) KYNA production. In vivo peripheral application of DL-homocysteine (1.3 mmol/kg intraperitoneally) increased KYNA content (pmol/g tissue) from 8.47 +/- 1.57 to 13.04 +/- 2.86 (P0.01; 15 min) and 11.4 +/- 1.72 (P0.01; 60 min) in cortex, and from 4.11 +/- 1.54 to 10.02 +/- 3.08 (P0.01; 15 min) in rat hippocampus. High concentrations of DL-homocysteine (20 mM) applied via microdialysis probe decreased KYNA levels in rabbit hippocampus; this effect was antagonized partially by an antagonist of group I metabotropic glutamate receptors, LY367385. In vitro, S-adenosylhomocysteine acted similar to but more potently than DL-homocysteine, augmenting KYNA production at 0.03-0.08 mM and reducing it ator =0.5 mM. The stimulatory effect of S-adenosylhomocysteine was abolished in the presence of the L-kynurenine uptake inhibitors L-leucine and L-phenyloalanine. Neither the N-methyl-D-aspartate (NMDA) antagonist CGS 19755 nor L-glycine influenced DL-homocysteine- and S-adenosylhomocysteine-induced changes of KYNA synthesis in vitro. DL-Homocysteine inhibited the activity of both KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, whereas S-adenosylhomocysteine reduced only the activity of KAT II. L-Methionine and L-cysteine, thiol-containing compounds metabolically related to homocysteine, acted only as weak inhibitors, reducing KYNA production in vitro and inhibiting the activity of KAT II (L-cysteine) or KAT I (L-methionine). The present data suggest that DL-homocysteine biphasically modulates KYNA synthesis. This seems to result from conversion of compound to S-adenosylhomocysteine, also acting dually on KYNA formation, and in part from the direct interaction of homocysteine with metabotropic glutamate receptors and KYNA biosynthetic enzymes. It seems probable that hyperhomocystemia-associated brain dysfunction is mediated partially by changes in brain KYNA level. |
| Databáze: | OpenAIRE |
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