Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites.
The synthesis of NAD (or NADP) from tryptophan involves a series of enzymes and the formation of a number of intermediates which are collectively called 'kynurenines.' In the late 1970s and early 1980s, it became clear that intraventricular administration of several 'kynurenines' could cause convulsions and that one of the 'kynurenines,' quinolinic acid, was an agonist of a sub-population of NMDA receptors and caused excitotoxic neuronal death. A related metabolite, kynurenic acid, could, on the other hand, reduce excitotoxin-induced neuronal death by antagonising ionotropic glutamate receptors. Since then, modifications in quinolinic and kynurenic acid synthesis have been proposed as a pathogenetic mechanism in Huntington's chorea and epilepsy. It was subsequently shown that a robust activation of the kynurenine pathway and a large accumulation of quinolinic acid in the central nervous system occurred in several inflammatory neurological disorders. More recently, it has been shown that 3OH-kynurenine or 3OH-anthranilic acid, two other kynurenine metabolites, may cause either apoptotic or necrotic neuronal death in cultures and that inhibitors of kynurenine hydroxylase may reduce neuronal death in in vitro and in vivo models of brain ischaemia or excitotoxicity. Finally, it has been reported that indole metabolites, indirectly linked to the kynurenine pathway, are able to modify neuronal function and animal behaviour by interacting with voltage-dependent Na+ channels. Oxindole, one of these metabolites, has sedative and anticonvulsant properties and accumulates in the blood and brain when liver function is impaired. In conclusion, a number of metabolites affecting brain function originate from tryptophan metabolism. Selective inhibitors of their forming enzymes may be useful to understand their role in physiology or as therapeutic agents in pathology.
Moroni
F
F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy. moronif@ds.unifi.it
D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology*; D002545:Brain Ischemia / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D014364:Tryptophan; D006867:Hydrolases; C021480:kynureninase