Uptake of Kynurenine into Rat Brain Slices

Abstract

The transport of [3H]kynurenine ([3H]KYN) into slices from rat tissue was examined in vitro. Brain accumulated KYN seven to eight times more effectively than any of several peripheral organs. Of all the organs tested, only the brain exhibited a sodium-dependent component of the uptake process. After an incubation period of 1 h, sodium-dependent transport amounted to 60% of total uptake. Both processes were abolished by prior sonication of the tissue and significantly inhibited by inclusion of metabolic blockers in the incubation medium. Time resolution showed that the sodium-independent uptake occurred rapidly and reached saturation within 30 min. In contrast, sodium-dependent transport was linear for at least 2 h of incubation. Brain regional analysis revealed a sevenfold difference between the areas of highest (cortex) and lowest (cerebellum) uptake. With the exception of cerebellar tissue, the ratio between sodium-dependent and sodium-independent processes was consistent among brain regions. Kinetic analyses were performed on striatal slices and revealed a Km of 927 microM and a Vmax of 18 nmol/h/mg of protein for the sodium-dependent process, and a Km of 3.8 mM and a Vmax of 38 nmol/10 min/mg of protein for the sodium-independent transport. The transporters were equally amenable to inhibition by KYN and tryptophan, indicating that KYN entry into the cell may be mediated by neutral amino acid uptake sites. No strict stereoselectivity existed, but L enantiomers were clearly more active than the D forms.(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid

“…The poor bioavailability of this compound, and of its more potent congeners, such as 5,7-Cl 2 -KYNA, however has stimulated attempts to identify new agents with greater CNS access and therapeutic action. 3 The potential for a prodrug approach to address this problem is based on the knowledge that, first, L-KYN, the precursor of KYNA, can gain ready access to brain via the large neutral amino acid transporter of the blood-brain barrier 6 and brain cell membranes 13 and, second, that the brain has the metabolic machinery to convert L-KYN as well as its halogenated analogs to KYNA derivatives via the enzyme kynurenine aminotransferase. 9 The L system transporter is fairly loose in its requirements for substrate binding and transfer, 5,7 and it is not surprising that both 4-Cl-KYN and 4,6-Cl 2 -KYN show some affinity for the transport carrier.…”

Murine Glial Cells Regenerate NAD, After Peroxide‐Induced Depletion, Using Either Nicotinic Acid, Nicotinamide, or Quinolinic Acid as Substrates

“…This does not rule out a significant role for de novo synthesis for acute regeneration of NAD. Further investigations are required to established whether extracellular supplies of kynurenine, which is actively taken up by glial cells (Speciale and Schwarcz, 1990), or other tryptophan metabolites can be converted efficiently to the pyridine nucleotide under conditions of acute NAD depletion.…”

Kynurenic Acid Influences the Respiratory Parameters of Rat Heart Mitochondria

“…In in vitro studies using a human heart extract, an increase of L-KYN Baran/Staniek/Kepplinger/Gille/Stolze/ Nohl concentration from 2 Ìmol/l to 3 mmol/l in the incubation medium at pHs between 7.4 and 9.6 induced an elevation of KYNA formation up to approximately 800-fold [10]. At least in the brain L-KYN is actively accumulated by both astrocytes and neurons [11]. Although a major part of KYNA, the transamination product of L-KYN, is rapidly released from the cell [12], it has been suggested that KYNA is to some extent stored in the cell [13].…”