Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism

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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 × 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 × 10−4μmol/s/g and 0.16 μmol/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 × 10−3 ml/s/g), and at far lower rates (PA, 2–7 × 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.