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.