Kynurenine pathway abnormalities in Parkinson's disease

Abstract

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.

Unconventional ligands and modulators of nicotinic receptors

“…Numerous reports have indicated that cerebral KYNA levels are moderately increased in patients with AD (Baran et al, 1999), DS (Baran et al, 1996), and schizophrenia (Ravikumar et al, 2000;Erhardt et al, 2001;Schwarcz et al, 2001), and slightly, albeit significantly decreased in patients with end-stage Parkinson's disease (PD) (Ogawa et al, 1992) and Huntington's disease (HD, Beal et al, 1990). The physiopathologic consequences of relatively modest variations in brain levels of KYNA raised the possibility of the existence of a high-affinity target for this tryptophan metabolite in neurons.…”

“…It can be hypothesized that inhibition of ␣7 nAChRs by increased levels of KYNA contributes to the cognitive deficits in patients with AD and DS (see Court et al, 1999). It is also conceivable that reduced levels of KYNA in the brain of patients with PD (Ogawa et al, 1992) contribute to decreased ␣4␤2 nAChR expression, which correlates well with the severity of motor dysfunctions in this disease (Banerjee et al, 2000;Perry et al, 2000). Moreover, the lower incidence of PD among cigarette smokers compared to nonsmokers (Fratiglioni and Wang, 2000) could be explained at least in part by nicotine-induced increased levels of KYNA leading to higher expression of ␣4␤2 nAChRs.…”

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

“…Within the central nervous system (CNS), it is involved in several important catabolic pathways including those of serotonin and kynurenine [1,2]. The overview of tryptophan catabolism with relationships with CNS diseases [3][4][5][6][7][8][9][10][11] is illustrated in Figure 1.…”

Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

“…Subsequent studies revealed that the levels of 3-HK in the brain are also significantly elevated in other pathological conditions such as dementia associated with human immunodeficiency virus (HIV) infection (6), hepatic encephalopathy (7), and Parkinson disease (8). All the above syndromes are characterized by severe neurological dysfunctions.…”