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
A mechanism for increased quinolinic acid formation following acute systemic immune stimulation.
TL;DR: Increased activities of kynurenine pathway enzymes in various tissues following systemic immune stimulation, in conjunction with macrophage infiltration of the affected tissue, provide a mechanism to account for increased concentrations of quinolinic acid.
Journal ArticleDOI
Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse
TL;DR: It is concluded that acute and chronic increases in quinolinic acid and neuroactive kynurenines follow immune stimulation in mice, and result from indoleamine-2,3-dioxygenase induction.
Journal ArticleDOI
3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Generate Hydrogen Peroxide and Promote α-Crystallin Cross-Linking by Metal Ion Reduction†
Lee E. Goldstein,Michael C. Leopold,Xudong Huang,Craig S. Atwood,Aleister J. Saunders,Mariana A. Hartshorn,James Lim,Kyle Y. Fagét,Julien Muffat,Richard C. Scarpa,Leo T. Chylack,Edmond F. Bowden,Rudolph E. Tanzi,Ashley I. Bush +13 more
TL;DR: The reaction of kynurenine pathway catabolites with copper and iron, as well as interactions with the major lenticular structural proteins, the alpha-crystallins, support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins through interactions with redox-active metals and especially copper.
Journal ArticleDOI
Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides.
TL;DR: The results suggest that the permeability of peptides through the BBB is governed by the same physicochemical parameter (hydrogen bonding potential) as their permeability through the intestinal mucosa.
Journal ArticleDOI
Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: A role for IFN-γ?
TL;DR: These data are the first to demonstrate that a systemic inflammatory challenge stimulates KMO expression in brain; a situation that is likely to favour kynurenine metabolism in a neurotoxic direction, however, the observation that expression of KAT II is much higher than KMO in rat brain islikely to counteract potential neurotoxicity that could arise from KMO induction following an acute inflammation.
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.
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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.