Kynurenines in the Central Nervous System: Recent Developments

The intermediates of the kynurenine pathway, called kynurenines, are derived directly or indirectly from the tryptophan metabolism. This metabolic pathway is responsible for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, which participate in basic cellular processes. It was discovered some thirty years ago that kynurenines have neuroactive properties. Kynurenine, the central compound of this pathway, can be converted to two other important agents: the neuroprotective kynurenic acid and the neurotoxic quinolinic acid. Kynurenic acid is an endogenous broad-spectrum antagonist of excitatory amino acid receptors, including the N-methyl- D-aspartate receptors. It can inhibit the overexcitation of these receptors and reduce the cell damage induced by excitotoxins. Moreover, kynurenic acid non-competitively blocks the α7-nicotinic acetylcholine receptors, thereby permitting modulation of the cholinergic and glutamatergic neurotransmission. Quinolinic acid is a selective N-methyl-D-aspartate receptor agonist which can cause lipid peroxidation, the generation of free radicals and apoptosis via the overexcitation of these receptors. Changes in the relative or absolute concentrations of the kynurenines have been found in several neurodegenerative disorders, such as Huntington's disease and Parkinson's disease, stroke and epilepsy, in which the hyperactivation of amino acid receptors could be involved. Increase of the brain level of kynurenic acid seems to be a good therapeutic strategy; however, kynurenic acid can cross the blood-brain barrier only poorly. The latest findings provide promising opportunities involving the development of the analogues 4-chloro-kynurenine and glucoseamine-kynurenic acid, which can enter the brain and exert neuroprotective effects. Another recent possibility is the use of different enzyme inhibitors which can reduce the production of the neurotoxic quinolinic acid.