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
Pellagra and Alcoholism: A Biochemical Perspective
TL;DR: Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6, and the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra should be explored.
Journal ArticleDOI
Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid
Zuzana Justinova,Zuzana Justinova,Paola Mascia,Paola Mascia,Hui-Qiu Wu,Maria E Secci,Godfrey H. Redhi,Leigh V. Panlilio,Maria Scherma,Chanel Barnes,Alexandra Parashos,Tamara Zara,Walter Fratta,Marcello Solinas,Marcello Solinas,Marco Pistis,Jack Bergman,Brian D. Kangas,Sergi Ferré,Gianluigi Tanda,Robert Schwarcz,Steven R. Goldberg +21 more
TL;DR: It is reported that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas and offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
Journal ArticleDOI
Quantification of Local De Novo Synthesis Versus Blood Contributions to Quinolinic Acid Concentrations in Brain and Systemic Tissues
Melvyn P. Heyes,Paul F. Morrison +1 more
TL;DR: It is established that the brain normally synthesizes QUIN, that the blood is a significant source of quinolinic acid in controls and during acute systemic immune activation, and that the rate of QUIN formation by brain tissue increases in conditions of brain and systemic immuneactivation.
Journal ArticleDOI
The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. An emerging field.
TL;DR: The role of IDO-mediated tryptophan metabolism and its metabolites in the modulation of ‘classical’ cardiovascular risk factors, such as hypertension, obesity, lipid metabolism, diabetes mellitus, and in the development of atherosclerotic CVD is emphasized.
Journal ArticleDOI
Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with Down syndrome.
TL;DR: The involvement ofKYNA-metabolism in the cellular mechanisms underlying altered cognitive function in patients with DS is demonstrated and the reduction of KAT I may suggest impairment of KYNA metabolism in neuronal and/or nonneuronal compartments.
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.