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
Enzyme-catalyzed production of the neuroprotective NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo.
TL;DR: In situ produced 7-Cl-KYNA offers a novel neuroprotective strategy for targeting the glycine/NMDA site while avoiding excessive receptor blockade and reducing the clinical risks associated with conventional NMDA receptor antagonism.
Journal ArticleDOI
The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia.
María Isabel Cuartero,Juan de la Parra,Alicia García-Culebras,Iván Ballesteros,Ignacio Lizasoain,María A. Moro +5 more
TL;DR: The KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs are detailed.
Journal ArticleDOI
Anti-scarring properties of different tryptophan derivatives.
TL;DR: Evidence is provided for the first time that KynA is promising candidate antifibrogenic agent to improve healing outcome in patients at risk of hypertrophic scarring by investigating the antiscarring properties of kynurenic acid (KynA).
Journal ArticleDOI
Regulation of kynurenic acid synthesis studied by microdialysis in the dorsal hippocampus of unanesthetized rats.
TL;DR: The data demonstrate that hippocampal kynurenic acid can be regulated by direct interference with its biosynthetic enzyme and by a distinct process involving neuron-glia interactions.
Book ChapterDOI
Kynurenines in neurodegenerative disorders: therapeutic consideration.
TL;DR: The kynurenine pathway is a major route for the conversion of tryptophane to NAD and NADP, leading to the production of biologically active molecules with neuroactive properties as discussed by the authors.
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.