Kynurenines, neurodegeneration and Alzheimer's disease.
Bottom Line: The kynurenine (KYN) pathway is the major route for the metabolism of the essential amino acid tryptophan.Some of the metabolites of this pathway, such as 3-hydroxykynurenine and quinolinic acid, are known to have neurotoxic properties, whereas others, such as kynurenic acid, are putative neuroprotectants.Intervention at these key steps may serve as the aim of potential therapy.
Affiliation: Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Hungary.Show MeSH
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Mentions: The kynurenine (KYN) pathway is the major route for the metabolism of the essential amino acid tryptophan (TRP) , the final product of which is nicotinamide adenosine dinucleotide (NAD) (Fig. 3). The first stable metabolite of the pathway is KYN, which is transformed either by KYN aminotransferase (KAT) to kynurenic acid (KYNA) or by KYN hydroxylase to 3-hydroxykynurenine (3-OH-KYN), which is further metabolized to quinolinic acid (QUINA), the precursor of NAD (Fig. 3). These metabolites are usually referred to as neuroactive KYNs [27, 28]. KYNA is an antagonist of the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor [29, 30], a weak antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainite receptors  and also an inhibitor of the α7 nicotinic receptor , which is involved in the pre-synaptic regulation of glutamate (L-Glu) release. Conversely, the neuroinhibitory effect of KYNA is concentration dependent: in nanomolar concentrations, it facilitates field excitatory postsynaptic potentials (EPSPs) . QUINA is neurotoxic , and has been shown to be a direct activator of NMDA receptors , to modulate the release or reuptake inhibition of L-Glu  and to be involved in lipid peroxidation [37, 38] and the production of reactive oxygen species (ROS) [38, 39]. 3-OH-KYN also leads to cell death involving apoptotic features by generating ROS [39–42].
Affiliation: Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Hungary.