China
Africa
Explore chapters and articles related to this topic
Pathogenesis of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
Among the products of the kynurenine pathway, kynurenic acid has a putative neuroprotective role by acting as an antagonist of NMDA receptors, while it also decreases glutamate levels via inhibition of α7 nicotinic receptors. 3-hydroxykynurenine is a free radical generator, and QA is an NMDA receptor agonist that also exerts neurotoxic effects via lipid peroxidation and disruption of the blood–brain barrier. The neurotoxic activity of QA has been known for more than 30 years and this metabolite should a priori be a therapeutic target by blocking its formation or antagonizing its excitotoxic effect on NMDA glutamatergic receptors. However, in the context of an inflamed brain the microglia are activated which release large quantities of glutamate, a process facilitated by the uptake of extracellular glutamine that is converted to glutamate by the enzyme glutaminase. Moreover, oxidative stress generated by 3-hydroxykynurenine and 3-hydroxyanthranilic acid further contributes to microglia priming. In the normal brain the clearance of glutamate is efficient as astrocytes uptake this substance and convert it to glutamine via glutamine synthetase which is recycled back to neurons for the continued formation of glutamate. However, in conditions of excitotoxicity the extracellular concentration of glutamate can increase up to 100 fold, overwhelming this mechanism of glutamate reprocessing. Such pathologically increased levels of glutamate result in atrophic changes in key mood regulating areas like the hippocampus and amygdala.30
Clinical Studies in Humans
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Hansson181 studied the excretion of 3-hydroxykynurenine and 3-hydroxyanthranilic acid after a tryptophan load in four healthy volunteers treated with 200 to 400 mg deoxypyridoxine plus a normal diet for 3 to 19 days. Excretion of 3-hydroxyanthranilic acid during the 24 hr after tryptophan load was increased about 3- to 5-fold during deoxypyridoxine treatment. Excretion of 3-hydroxyanthranilic acid after a load was also increased in eight out of ten trials. Treatment with pyridoxine restored the values to normal. In controls, the ratio of 3-hydroxyanthranilic acid to 3-hydroxykynurenine in the urine exceeded 1.0 at least once during the 4 hr following a tryptophan load. However, the ratios fell in three subjects after deoxypyridoxine treatment for 13 days or more. In one case in which deoxypyridoxine treatment was terminated 24 hours before the load test, the ratios remained normal. Similar treatment in a second subject failed to indicate that the normal ratio was due to a rapid turn to normal. However, we feel that conflicting data from only two subjects is not adequate to establish that point, particularly in view of our recent demonstration of the rapid excretion of deoxypyridoxine.
Serum metabolomics of end-stage renal disease patients with depression: potential biomarkers for diagnosis
Published in Renal Failure, 2021
Dezhi Yuan, Tian Kuan, Hu Ling, Hongkai Wang, Liping Feng, Qiuye Zhao, Jinfang Li, Jianhua Ran
Phenylalanine, tyrosine, and tryptophan belong to aromatic amino acids, in which phenylalanine is catalyzed by phenylalanine hydroxylase to form tyrosine, and tyrosine is further metabolized to produce catecholamine (dopamine, norepinephrine, and epinephrine) [35]. Compared with the healthy controls, the tyrosine content of the ESRD patients without depression was significantly decreased, which was consistent with previous studies [36], and the significantly decreased tyrosine level was also observed in patients and animal models with CKD [37–39]. In addition, patients with ESRD had a significantly decreased kynurenine level and a significantly increased 3-hydroxyanthranilic acid (3-HANA) level than healthy controls [40]. Tryptophan is mainly metabolized by the kynurenine pathway and the serotonin metabolic pathway, the former being more than 95% in mammals [41]; kynurenine can inhibit antigen presentation, suppress the immune response, and ultimately reduce inflammation [42]. However, 3-HANA is neurotoxic and induces the formation of free radicals such as hydroxyl radicals and hydrogen peroxide, and raises the level of oxidative stress [43]. It is concluded that ESRD may be in a state of a high inflammatory response and oxidative stress [44,45].
Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease
Published in Expert Opinion on Therapeutic Targets, 2019
Fanni A. Boros, Péter Klivényi, József Toldi, László Vécsei
The product of the first enzymatic conversion of the KP, N-formyl-L-kynurenine is converted by formamidase into L-kynurenine (L-KYN). L-KYN represents an important branch point of the pathway as it can be metabolized alternatively into kynurenic acid (KYNA), or anthranilic acid (AA), or 3-hydroxykynurenine (3-HK). KYNA is synthesized from L-KYN by kynurenine aminotransferases (KATs). There are four subtypes of KATs (KATI-IV) [40] that can catalyze the conversion. The principal enzyme from these in the human CNS is KATII [40,41]. Besides KATs, L-KYN can also be metabolized by the kynureninase enzyme (KYNU) and kynurenine 3-monooxygenase (KMO) forming AA or 3-HK, respectively. 3-HK can be metabolized into xanthurenic acid (XA) by KATs, and both AA and 3-HK can be converted into 3-hydroxyanthranilic acid (3-HAA), a metabolite which is a free radical generator (like other compounds of the pathway, see below) [20]. 3-HAA transforms into the unstable 2-amino-3-carboxymuconate-semialdehyde (ACMS) by 3–hydroxyanthranilate oxidase (3-HAO). ACMS can give rise to either picolinic acid (PIC) by conversion via aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) or to QUIN, a NAD+ and NADP+ precursor metabolite, via a non-enzymatic conversion.
Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Sharma, Karan Razdan, Yashika Bansal, Anurag Kuhad
Formation of QUIN can be prevented by inhibiting 3-hydroxyanthranilic acid 3, 4-dioxygenase (3-HAO) [253,254]. Significant inhibition is produced by a series of 4-halo-3-hydroxyanthranilic acids, which lead to corresponding reduction in the formation of QUIN. Todd, Carpenter [255] synthesized 4-fluoro-, 4-chloro-, and 4-bromo-3-hydroxyanthranilic acids and demonstrated their potential to inhibit 3-HAO obtained from rodent and human brain homogenates. All three halo-compounds were found to be potent inhibitors of QUIN production with IC50 values in the range of 2–24 nM and 4–17 nM in case of rat and human brain homogenates, respectively. Linderberg, Hellberg [256] synthesized 4,5-, 4,6-, and 4,5,6- substituted 3-hydroxyanthranilic acid analogues and evaluated the potential to inhibit 3-HAO in rat brain tissue homogenate and also in vivo. The compounds showed good correlation between in vitro and in vivo inhibition.