Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
TL;DR: 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.
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TL;DR: With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions on the basis of the kynurenine pathway.
Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
1,097 citations
TL;DR: Results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.
Abstract: Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.
1,069 citations
TL;DR: The results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β,IL-12 and IL-18 and higher CSF concentrations of T GF-β.
866 citations
TL;DR: This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression and potential therapeutic strategies that target inflammatory cytokine signaling.
771 citations
TL;DR: It is concluded that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease.
Abstract: Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.
642 citations
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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.
Abstract: A current hypothesis links the neuroexcitatory properties of certain acidic amino acids to their ability to cause selective neuronal lesions. 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. Its qualities as a neurotoxic agent suggest that quinolinic acid should be considered as a possible pathogenic factor in neurodegenerative disorders.
1,251 citations
"Blood–Brain Barrier Transport of Ky..." refers background in this paper
...Direct infusion of QUIN into brain produces region-selective, axon-sparing lesions that resemble both neurochemically and neuropathologically those observed in Huntington’s disease and temporal lobe epilepsy (Schwarcz et al., 1983)....
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801 citations
749 citations
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.
Abstract: The percentages of 22 14C-labeled amino acids remaining in rat brain 15 s after carotid injection were measured relative to a simultaneously injected diffusible internal standard, 3HOH. The injected solution also contained a nondiffusible internal standard, [113mIn]EDTA to correct for incomplete brain blood compartment washout. Self-inhibition and cross-inhibition was demonstrated by inclusion of unlabeled amino acids and carboxylic acids. All amino acids tested, excluding proline, alanine, and glycine, could be assigned to one, and only one, blood-brain barrier carrier system. The neutral carrier system transported phenylalanine, leucine, tyrosine, isoleucine, methionine, tryptophane, valine, DOPA, cysteine, histidine, threonine, glutamine, asparagine, and serine. Affinity for a basic amino acid carrier system was demonstrated for arginine, ornithine, and lysine. A third, low-capacity independent carrier system transporting aspartic and glutamic acids was demonstrated.
585 citations
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.
Abstract: The right cerebral hemisphere of the rat was perfused in situ by retrograde infusion of HCO3 saline or blood into the right external carotid artery. Infusion rate was adjusted to minimize the contribution of systemic blood to flow in the hemisphere. During perfusion with whole or artificial blood, regional cerebral blood flow and blood volume were comparable to respective values in the conscious rat, whereas perfusion with HCO3 saline increased regional flow three- to fourfold due to the low viscosity of the saline perfusate. Perfusion with whole blood for 300 S or with HCO3 saline for 60 S did not alter the permeability of the blood-brain barrier. Cerebrovascular permeability coefficients of eight nonelectrolytes ranged from 10(-8) to 10(-4) cm X S-1 and were directly proportional to the octanol-water partition coefficient of the solute. Thus 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.
544 citations
"Blood–Brain Barrier Transport of Ky..." refers background or methods in this paper
...This procedure has been shown previously to allow accurate quantitation of solute uptake into brain over a 104-fold range in cerebrovascular permeability and does not disrupt the integrity of the blood-brain barrier (Takasato et al., 1984; Smith, 1989)....
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...F during saline perfusion was measured using 13H]diazepam (Takasato et al., 1984) and ranged from 4....
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...region (dpm/g); V, is the regional intravascular volume (ml/ g); C;f is the tracer concentration in perfusion fluid (dpm/ ml); and Tis the net perfusion time ( s ) (Takasato et al., 1984)....
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...4) and the empirical relation between blood-brain barrier permeability and solute lipid solubility (Takasato et al., 1984)....
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...The measured PA for L-[~H]KYN, at tracer concentrations, exceeded by 50- to 600-fold that of more slowly penetrating compounds, such as urea, mannitol, and sucrose, and was within 20% of that of the rapidly penetrating compound antipyrine (Takasato et al., 1984)....
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