Inhibition of Large Neutral Amino Acid Transporters Suppresses Kynurenic Acid Production Via Inhibition of Kynurenine Uptake in Rodent Brain

Abstract

The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor and N-methyl-D-aspartic acid receptor at endogenous brain concentrations. Recent studies have suggested that increases of brain KYNA levels are involved in psychiatric disorders such as schizophrenia and depression, and regulation of KYNA production has become a new target for treatment of these diseases. Kynurenine (KYN), the immediate precursor of KYNA, is transported into astrocytes via large neutral amino acid transporters (LATs). In the present study, the effect of LATs regulation on KYN uptake and KYNA production was investigated in vitro and in vivo using an LATs inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). In the in vitro study, cortical slices of rat brain were incubated with a physiological concentration of KYN and 3 µmol/L-3 mmol/L BCH. BCH inhibited KYNA production and KYN uptake in a dose-dependent manner, and their IC50 values were 90.7 and 97.4 µmol/L, respectively. In the in vivo study, mice were administered KYN (50 mg/kg BW) orally and BCH (200 mg/kg BW) intravenously. Administration of KYN increased brain KYN and KYNA levels compared with the mice treated with vehicle, whereas additional administration of BCH suppressed KYN-induced elevations in KYN and KYNA levels to 50 and 70 % in the brain. These results suggest that inhibition of LATs prevented the increase of KYNA production via blockade of KYN uptake in the brain in vitro and in vivo. LATs can be a target to modulate brain function by regulation of KYNA production in the brain.

Changes in kynurenine pathway metabolism in Parkinson patients with L‐DOPA‐induced dyskinesia

“…In agreement with a higher daily L-DOPA intake in PD-LID patients (Table 1), we observed slightly higher L-DOPA and 3-OMD levels in PD-LID, although not significantly different from PD-L. 3-OMD levels are much higher than L-DOPA, because it has a much longer half-life than L-DOPA (Tohgi et al 1995). L-DOPA and 3-OMD are, like KYN, transported into the brain via the large neutral amino acid transporter and may inhibit the transport of KYN over the blood-brain barrier and into astrocytes (Asanuma and Miyazaki 2016;Sekine et al 2016). A lower availability of KYN in astrocytes in PD-LID, may reduce central KYNA production.…”

“…L‐DOPA and 3‐OMD are, like KYN, transported into the brain via the large neutral amino acid transporter and may inhibit the transport of KYN over the blood‐brain barrier and into astrocytes (Asanuma and Miyazaki ; Sekine et al . ). A lower availability of KYN in astrocytes in PD‐LID, may reduce central KYNA production.…”

Oral administration of a specific kynurenic acid synthesis (KAT II) inhibitor attenuates evoked glutamate release in rat prefrontal cortex

“…If elevations in KYNA levels indeed contribute to the cognitive deficits in SZ, pharmacological interventions leading either to reduced uptake of kynurenine into the brain (Sekine et al, 2016) or to a reduction in KYNA neosynthesis within the brain may result in cognitive enhancement. Using the latter approach, pro-cognitive effects were indeed demonstrated with intracerebral application of the KAT II inhibitor S -ESBA (Pocivavsek et al, 2011), which does not cross the blood-brain barrier.…”

Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

“…By investigating peripheral metabolism, we found that the level of circulating kynurenine is increased after chronic stress, in a manner dependent on Lactobacillus levels. Kynurenine can readily cross the blood-brain barrier to drive depressive behavior, supposedly by disrupting neurotransmitter balance and driving neuroinflammation, within the CNS 84,167,174,[184][185][186] . A recent study by Agudelo et al 84 identified this pathway as also being disrupted in stressed mice using the same model of UCMS.…”

“…In the absence of inflammation, IDO1 expression in the brain is very low and kynurenine is absorbed from peripheral circulation 167,184 . Evidence shows that kynurenine is trafficked through the large neutral amino acid transporter (LAT1), the same transporter used for its precursor, tryptophan 185,189 . LAT1 may be expressed by all the cell types in the brain, but highest expression has been reported on endothelial cells, as well as astrocytes and microglia 190,191 .…”