Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

Abstract

BackgroundTryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide adenosine dinucleotide (NAD+), and metabolites of this pathway may have protective or degenerative effects on the nervous system. Thus, the KP may be involved in neurodegenerative diseases.ObjectivesThe purpose of this systematic review and meta-analysis is to assess the changes in KP metabolites such as TRP, kynurenine (KYN), kynurenic acid (KYNA), Anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 5-Hydroxyindoleacetic acid (5-HIAA), and 3-Hydroxyanthranilic acid (3-HANA) in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) patients compared to the control group.MethodsWe conducted a literature search using PubMed/Medline, Scopus, Google Scholar, Web of Science, and EMBASE electronic databases to find articles published up to 2022. Studies measuring TRP, KYN, KYNA, AA, 3-HK, 5-HIAA, 3-HANA in AD, PD, or HD patients and controls were identified. Standardized mean differences (SMDs) were used to determine the differences in the levels of the KP metabolites between the two groups.ResultsA total of 30 studies compromising 689 patients and 774 controls were included in our meta-analysis. Our results showed that the blood levels of TRP was significantly lower in the AD (SMD=-0.68, 95% CI=-0.97 to -0.40, p=0.000, I2 = 41.8%, k=8, n=382), PD (SMD=-0.77, 95% CI=-1.24 to -0.30, p=0.001, I2 = 74.9%, k=4, n=352), and HD (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) patients compared to the controls. Moreover, the CSF levels of 3-HK in AD patients (p=0.020) and the blood levels of KYN in HD patients (p=0.020) were lower compared with controls.ConclusionOverall, the findings of this meta-analysis support the hypothesis that the alterations in the KP may be involved in the pathogenesis of AD, PD, and HD. However, additional research is needed to show whether other KP metabolites also vary in AD, PD, and HD patients. So, the metabolites of KP can be used for better diagnosing these diseases.

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease

“…Past studies investigating concentrations of KA among patients with AD compared to controls have shown increased concentrations in the CSF but lower concentrations of KA in plasma. 22,23,31 Meanwhile, other research has shown reduced concentrations of KA in CSF. Unlike QA, KA in CSF is seldom reported to be increased in neurodegenerative diseases other than AD.…”

Study on the mechanism of acute liver injury protection in Rhubarb anthraquinone by metabolomics based on UPLC-Q-TOF-MS

“…With the increase of TC content in serum, the content of LDL, which is the main carrier to promote the absorption and utilization of cholesterol in peripheral tissues, obviously increased, while the content of HDL involved in the reverse transport of total cholesterol decreased due to cholestasis ( Hou et al, 2019 ; Berköz et al, 2021 ). 5-hydroxyindoleacetic acid is produced through the metabolic pathway of 5-HT, which is mainly concentrated in the brain tissue, and has an influence on the toxicity of nerve cells and the transmission of neurotransmitters at the nerve terminals ( Han et al, 2019 ; Zhang et al, 2021 ; Fathi et al, 2022 ). The results showed that, the administration of rhubarb anthraquinone could repair damaged hepatocytes, improve the mitochondrial dysfunction and cholestasis, and enhance the metabolic function of the liver, thus playing a role in protecting the liver.…”

Transition metal ions and neurotransmitters: coordination chemistry and implications for neurodegeneration

“…114,115 KYN then follows a metabolic pathway, also known as the KYN pathway to generate NAD + . 108–113 Such KYN pathways have been reported to modulate dopaminergic, nicotinergic, and glutaminergic neurotransmission, which may be related to numerous psychiatric and neurodegenerative symptoms. 108–113,116…”

“…114,115 KYN then follows a metabolic pathway, also known as the KYN pathway to generate NAD + . [108][109][110][111][112][113] Such KYN pathways have been reported to modulate dopaminergic, nicotinergic, and glutaminergic neurotransmission, which may be related to numerous psychiatric and neurodegenerative symptoms. [108][109][110][111][112][113]116 In neurodegeneration, however, the oxidation process of Trp to KYN can be facilitated in the presence of redox-active transition metal ions producing ROS.…”