2-Oxoacids Regulate Kynurenic Acid Production in the Rat Brain
| Autor: | H. R. Zielke, Hui-Qiu Wu, Paul S. Hodgkins, Robert Schwarcz |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Microdialysis Transamination Neurotoxins Excitotoxicity Biology Kynurenic Acid Kynurenate medicine.disease_cause Hippocampus Biochemistry Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Organ Culture Techniques Kynurenic acid Pyruvic Acid Excitatory Amino Acid Agonists medicine Animals Kynurenine Transaminases Brain Chemistry Cerebral Cortex chemistry.chemical_classification Veratridine Glutamate receptor Quisqualic Acid Corpus Striatum Hypoglycemia Rats Glucose chemistry NMDA receptor 2-Aminoadipic Acid |
| Zdroj: | Journal of Neurochemistry. 72:643-651 |
| ISSN: | 0022-3042 |
| DOI: | 10.1046/j.1471-4159.1999.0720643.x |
| Popis: | This study was designed to examine the role of 2-oxoacids in the enzymatic transamination of L-kynurenine to the excitatory amino acid receptor antagonist, kynurenate, in the rat brain. In brain tissue slices incubated in Krebs-Ringer buffer with a physiological concentration of L-kynurenine, pyruvate, and several other straight- and branched-chain 2-oxoacids, substantially restored basal kynurenate production in a dose-dependent manner without increasing the intracellular concentration of L-kynurenine. All 2-oxoacids tested also reversed or attenuated the hypoglycemia-induced decrease in kynurenate synthesis, but only pyruvate and oxaloacetate also substantially restored intracellular L-kynurenine accumulation. Thus, 2-oxoacids increase kynurenate formation in the brain primarily by functioning as co-substrates of the transamination reaction. This was supported further by the fact that the nonspecific kynurenine aminotransferase inhibitors (aminooxy)acetic acid and dichlorovinylcysteine prevented the effect of pyruvate on kynurenate production in a dose-dependent manner. Moreover, all 2-oxoacids tested attenuated or prevented the effects of veratridine, quisqualate, or L-alpha-aminoadipate, which reduce the transamination of L-kynurenine to kynurenate. Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or alpha-ketoisocaproate were demonstrated by in vivo microdialysis. Taken together, these data show that 2-oxoacids can directly augment the de novo production of kynurenate in several areas of the rat brain. 2-Oxoacids may therefore provide a novel pharmacological approach for the manipulation of excitatory amino acid receptor function and dysfunction. |
| Databáze: | OpenAIRE |
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