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
Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens.
Pablo Giménez-Gómez,Mercedes Pérez-Hernández,María Dolores Gutiérrez-López,Rebeca Vidal,Cristina Abuin-Martínez,Esther O'Shea,Esther O'Shea,María Isabel Colado,María Isabel Colado +8 more
TL;DR: The results highlight the usefulness of manipulating the KYN pathway as a pharmacological tool for modifying EtOH consumption and point to a possible modulator of alcohol drinking behaviour.
Peripheral Tryptophan - Kynurenine Metabolism Associated with Metabolic Syndrome is Different in Parkinson's and Alzheimer's Diseases.
TL;DR: The data suggest different patterns of KP dysregulation in PD and AD: systemic chronic subclinical inflammation activating central and peripheral KP in PD, and central, rather than peripheral, activation of KP in AD triggered by Aβ1-42.
Journal ArticleDOI
Female Flinders Sensitive Line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism.
Amanda Eskelund,Amanda Eskelund,David P. Budac,Connie Sanchez,Betina Elfving,Gregers Wegener +5 more
TL;DR: The female FSL rat is an interesting preclinical model of depression with altered TRP metabolism, independent of the estrous cycle, which may indicate that an inherent local, cerebral regulation of TRP metabolite levels occurs.
Journal ArticleDOI
Kynurenines and other novel therapeutic strategies in the treatment of dementia.
TL;DR: The kynurenine pathway has been associated with various neurodegenerative disorders and cerebrovascular diseases, and this pathway is also closely related to neuroinflammatory processes and it has been implicated in the pathomechanisms of certain kinds of dementia.
Book ChapterDOI
Chapter 25 – Astrocytes as Pharmacological Targets in the Treatment of Schizophrenia: Focus on Kynurenic Acid
TL;DR: Support for the “KYNA hypothesis” comes from studies in experimental animals in which even relatively moderate increases in brain KYNA result in a spectrum of biochemical and cognitive abnormalities reminiscent of schizophrenia, and interventions leading to a reduction of cerebral KYNA formation may have therapeutic benefits.
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.
Journal ArticleDOI
Distinct mediating systems for the transport of neutral amino acids by the ehrlich cell
Journal ArticleDOI
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.