Using a microdialysis technique, we continuously infused D-kynurenine (KYN) (0, 50, and 100 microM) into the prefrontal cortices (PFCs) of male Sprague-Dawley rats. We then used column-switching high-performance liquid chromatography to assess the alterations in the concentration of kynurenic acid (KYNA)-an antagonist of N-methyl-D-aspartate and alpha7 nicotinic acetylcholine receptors-in the extracellular fluid in the PFC. Local infusion of D-KYN into the PFC remarkably increased the extracellular KYNA concentration, indicating that D-KYN is metabolized to KYNA in the PFC. The D-KYN-induced increase in KYNA levels was significantly attenuated by the co-administration of 3-methylpyrazole-5-carboxylic acid (AS057278)-a specific inhibitor of D-amino acid oxidase (DAAO). These results suggest that DAAO may be involved in the production of KYNA from D-KYN in the PFC in vivo.
An aqueous solution of enantiomerically pure tryptophan (Trp), namely, D-Trp or L-Trp (100 mg/kg), was administered intraperitoneally to male Sprague-Dawley rats. The time-course profiles of the rat plasma concentrations of D-kynurenine (KYN), L-KYN, and kynurenic acid (KYNA), which are metabolites of D- or L-Trp, were investigated using high-performance liquid chromatography (HPLC) systems that were reported in our previous study. The plasma D-KYN concentration increased after the administration of D-Trp, but this increase was not observed after the administration of L-Trp. The plasma L-KYN concentration increased after the administration of L-Trp, but no significant change was observed after the administration of D-Trp. The plasma KYNA concentration drastically increased in the case of rats administered D-Trp and those administered L-Trp. Additionally, an inhibitor of D-amino acid oxidase (DAAO), 5-methylpyrazole-3-carboxylic acid (MPC) (50 mg/kg), was administrated to the rats 30 min before the administration of D-Trp. The preadministration of MPC remarkably increased the D-KYN concentration and suppressed the production of KYNA. These results suggest that DAAO may contribute to the metabolism of D-KYN to KYNA in vivo.
Radiotherapy for malignant pelvic disease is often followed by acute radiation colitis (ARC). It has been reported that sucralfate treatment has a protective effect against ARC, though the mechanisms of action are unknown. The effects of sucralfate on X-ray radiation-induced apoptosis was studied at 4 Gy in the colonic crypt cells of rats. Sucralfate enemas given prior to radiation resulted in the following: (1) reduction in number of apoptotic colonic crypt cells; (2) reduction in number of caspase-3 positive cells; (3) decreases in p53 accumulation and p21 expression; (4) decreases of Bax/Bcl-2 ratio. The protective effects of sucralfate against ARC may be partially due to the suppression of radiation-induced apoptosis by way of p53 in the colon and the protection of the colonic epithelial stem cell region.
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