Evaluation of < sup > D < /sup > -amino acid oxidase activity in rat kidney using a < sup > D < /sup > -kynurenine derivative, 6-methylthio- < sup > D < /sup > -kynurenine: An in vivo microdialysis study

Drug Discov Ther. 2023 Dec 3. doi: 10.5582/ddt.2023.01083. Online ahead of print.ABSTRACTD-Amino acid oxidase (DAO), a D-amino acid metabolizing enzyme, is reportedly associated with the psychiatric disease schizophrenia, suggesting a role for DAO inhibitors in its treatment. We have previously reported that DAO catalyzes the conversion of nonfluorescent 6-methylthio-D-kynurenine (MeS-D-KYN) to fluorescent 5-methylthiokynurenic acid (MeS-KYNA) in vitro. The present study aimed to determine the potential of MeS-D-KYN in evaluating DAO activity in vivo using renal microdialysis technique in rats. Male Sprague-Dawley rats were subjected to linear microdialysis probe implantation in the left kidney. Continuous perfusion of MeS-D-KYN was maintained, and DAO activity in the kidney cortex was evaluated by measuring the MeS-KYNA content in the microdialysate. The microdialysate was collected every 30 min and analyzed by high-performance liquid chromatography with fluorescence detection, monitored at 450 nm with an excitation wavelength of 364 nm. A significant production of MeS-KYNA was observed during, but not before, infusion of MeS-D-KYN, indicating that this compound is not endogenous. MeS-KYNA production was suppressed by the co-infusion of DAO inhibitor, 5-chlorobenzo[d]isoxazol-3-ol (CBIO), suggesting that MeS-D-KYN was converted to MeS-KYNA by renal DAO. Moreover, oral administration of CBIO effectively suppressed DAO activity in a dose-dependent manner. DAO converted MeS-D-K...
Source: Drug Discoveries and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research