Journal ArticleDOI
Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
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TLDR
The results demonstrate the saturable transfer of L‐KYN across the blood–brain barrier and suggest that circulating L‐ KYN, 3‐HKYN, and ANA may each contribute significantly to respective cerebral pools under normal conditions.Abstract:
To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.read more
Citations
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Journal ArticleDOI
Addiction and the kynurenine pathway: A new dancing couple?
Nuria Morales-Puerto,Pablo Giménez-Gómez,Mercedes Pérez-Hernández,Cristina Abuin-Martínez,Leticia Gil de Biedma-Elduayen,Rebeca Vidal,María Dolores Gutiérrez-López,Esther O'Shea,María Isabel Colado +8 more
TL;DR: In this paper, the authors present an up-to-date summary of evidences of a relationship between drug use and the kynurenine pathway, both the alterations of the pathway due to drug use as well as modulation of pathway as a potential approach to treat drug addiction.
Journal ArticleDOI
Abnormalities in Functional Connectivity in Collegiate Football Athletes with and without a Concussion History: Implications and Role of Neuroactive Kynurenine Pathway Metabolites
Timothy B. Meier,Timothy B. Meier,Melissa A. Lancaster,Andrew R. Mayer,Andrew R. Mayer,T. Kent Teague,T. Kent Teague,Jonathan Savitz,Jonathan Savitz +8 more
TL;DR: The results suggest that football exposure with and without concussion history can have a significant effect on intrinsic brain connectivity and implicate the kynurenine metabolic pathway as one potential moderator of functional connectivity dependent on football exposure and concussion history.
Journal ArticleDOI
Urinary metabolomics reveals kynurenine pathway perturbation in newborns with transposition of great arteries after surgical repair
Manuela Simonato,Igor Fochi,Luca Vedovelli,Sonia Giambelluca,C. Carollo,Massimo A. Padalino,Virgilio P. Carnielli,Paola Cogo +7 more
TL;DR: This is the first report on metabolic response to cardiac surgery in TGA newborns, and an experimental design was developed that allowed the identification of perturbed metabolic pathways and potential biomarkers of brain damage, limiting drugs interference in the analysis.
Journal ArticleDOI
Chronic fatigue and depression due to multiple sclerosis: Immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways.
Heidi Ormstad,Cecilia Smith Simonsen,Line Broch,Michael Maes,George M. Anderson,Elisabeth Gulowsen Celius +5 more
TL;DR: It seems likely that proinflammatory cytokines, tryptophan catabolites and the KYN pathway and the gut-brain axis are involved in the mechanisms causing chronic fatigue and MDD-like symptoms in MS, but the evidence base is weak, and more research is needed.
Journal ArticleDOI
Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid.
TL;DR: Whether AC has the ability to reduce Fe(2+)-induced lipid peroxidation, O(2)(-) generation and QA-induced superoxide anion generation, and to bind free Fe is determined.
References
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Journal ArticleDOI
Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain
TL;DR: Intracerebral injection of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical and neuropathological consequences reminiscent of those of exogenous excitotoxins, such as kainic and ibotenic acids.
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Distinct mediating systems for the transport of neutral amino acids by the ehrlich cell
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Amino acid assignment to one of three blood-brain barrier amino acid carriers
William H. Oldendorf,John Szabo +1 more
TL;DR: Affinity for a basic amino acid carrier system was demonstrated for arginine, ornithine, and lysine and a third, low-capacity independent carrier system transporting aspartic and glutamic acids was demonstrated.
Journal ArticleDOI
An in situ brain perfusion technique to study cerebrovascular transport in the rat
TL;DR: The in situ brain perfusion technique is a sensitive new method to study cerebrovascular transfer in the rat and permits absolute control of perfusate composition.