A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

Taleb, Omar; Maammar, Mohammed; Klein, Christian; Maître, Michel; Mensah‐Nyagan, Ayikoe Guy

doi:10.3390/ijms22136974

Cited by 22 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These changes indicate an unfavourable upregulation of the KP in all diseased groups independent of disease. Kyn, K/T-ratio, QA and QA/XA are markers of inflammation, QA is neurotoxic and associated with depression and improves glucose control, KA/XA-ratio has been associated with mood disorders, and KA, QA, and XA regulate the carbohydrate metabolism [ 1 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…The raised Trypt level was not expected [ 4 , 5 , 20 ]. XA has a crucial role in the control of the dopaminergic activity in the brain, and hence neuropsychological functions [ 17 ]. Since QA is a marker of depressive and neurodegenerative disease, the significantly raised QA/XA in the COPD group compared with the Healthy and Depressed groups was unexpected [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease

et al. 2023

View full text Add to dashboard Cite

Background: Changes in tryptophan metabolism through the kynurenine pathway (KP) canis observed in several disorders and coupled with pathophysiological deviations. Methods: This study retrospectively compared the KP in serum in healthy subjects (108) with subjects with obesity (141), depression (49), and chronic obstructive pulmonary disease (COPD) (22) participating in four clinical studies and explored predictors of the changes in the KP metabolites. Results: Compared with the healthy group, the KP was upregulated in the disease groups with high kynurenine, quinolinic acid (QA), kynurenine/tryptophan-ratio and QA/xanthurenic acid-ratio and low kynurenic acid/QA-ratio. Tryptophan and xanthurenic acid were upregulated in the depressed group compared with the groups with obesity and COPD. The covariates BMI, smoking, diabetes, and C-reactive protein explained the significant differences between the healthy group and the group with obesity but not between the healthy group and the groups with depression and COPD, indicating that different pathophysiological conditions result in the same changes in the KP. Conclusions: The KP was significantly upregulated in the disease groups compared with the healthy group, and there were significant differences between the disease groups. Different pathophysiological abnormalities seemed to result in the same deviations in the KP.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Notably, attention is not limited to the enzyme’s immediate product 3-HK, though the dual antioxidant and neurotoxic properties of this metabolite are intriguing and may be of considerable biological significance [ 41 ]. KMO also controls the fate of xanthurenic acid (XA), a transamination product of 3-HK [ 42 ] which is gaining attention in neurobiology because of its effect on glutamatergic neurotransmission [ 43 , 44 ] and its ability to modulate extracellular dopamine levels [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma

et al. 2022

View full text Add to dashboard Cite

Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington’s disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions.

show abstract

“…KYN is the central metabolite of the KP and is catabolized to anthranilic acid (AA), 3-hydroxy-L-kynurenine (3-HK), and kynurenic acid (KYNA) by kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), and kynurenine aminotransferase I-IV (KAT I-IV), respectively [ 81 – 83 ]. 3-HK is converted to 3-hydroxyanthranilic acid (3-HANA), the precursor to the neurotoxic metabolite, QA [ 84 , 85 ], and xanthurenic acid (XA) [ 86 ] by KYNU and KAT I-IV, respectively. 3-Hydroxyanthranillate-3,4-dixogygenase (3-HAAO) catalyzes the conversion of 3-HANA to QA [ 87 , 88 ].…”

Section: The Kynurenine Pathwaymentioning

confidence: 99%

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Liang

Xie

et al. 2022

Disease Markers

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

show abstract

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

Cited by 22 publications

References 44 publications

The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease

The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Contact Info

Product

Resources

About