Journal ArticleDOI
Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
Reads0
Chats0
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
More filters
Journal ArticleDOI
Novel Kynurenic Acid Analogues in the Treatment of Migraine and Neurodegenerative Disorders: Preclinical Studies and Pharmaceutical Design
TL;DR: The kynurenine pathway of the tryptophan metabolism produces the only known endogenous Nmethyl-D-aspartate receptor antagonist, kynurenic acid, which has been proven in different preclinical studies to exert a neuroprotective effect as mentioned in this paper.
Journal ArticleDOI
The 'Yin' and the 'Yang' of the kynurenine pathway: excitotoxicity and neuroprotection imbalance in stress-induced disorders.
TL;DR: It will be proposed that modulation of the excitotoxicity/neuroprotection balance is a valuable strategy for new and more effective treatments of mood disorders.
Journal ArticleDOI
Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects.
Josef Isung,Mathias Granqvist,Ada Trepci,Jesse Huang,Lilly Schwieler,Marie Kierkegaard,Sophie Erhardt,Jussi Jokinen,Jussi Jokinen,Fredrik Piehl +9 more
TL;DR: In this article, the authors report that acute aerobic physical exercise affects immune markers and kynurenine pathway metabolites systemically and in the cerebrospinal fluid (CSF) respectively.
Journal ArticleDOI
Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia.
Stein Erik Hafstad Solvang,Stein Erik Hafstad Solvang,Jan Erik Nordrehaug,Jan Erik Nordrehaug,Dag Aarsland,Johannes Lange,Johannes Lange,Per Magne Ueland,Adrian McCann,Øivind Midttun,Grethe S. Tell,Grethe S. Tell,Lasse Melvaer Giil,Lasse Melvaer Giil +13 more
TL;DR: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance and a higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.
Journal ArticleDOI
Endogenous antagonists of N-methyl-d-aspartate receptor in schizophrenia.
TL;DR: A systematic review of the neurobiology and the role of endogenous NMDA receptor antagonists in animal models of schizophrenia, and in patients, and highlights the pressing need to restore the NMda receptor functions for therapeutic benefits.
References
More filters
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.