tacrolimus and 3-hydroxykynurenine

Xanthurenic acid (XA), formed from 3-hydroxykynurenine (3-HK) in the kynurenine pathway of tryptophan degradation, may modulate glutamatergic neurotransmission by inhibiting the vesicular glutamate transporter and/or activating Group II metabotropic glutamate receptors. Here we examined the molecular and cellular mechanisms by which 3-HK controls the neosynthesis of XA in rat, mouse and human brain, and compared the physiological actions of 3-HK and XA in the rat brain. In tissue homogenates, XA formation from 3-HK was observed in all three species and traced to a major role of kynurenine aminotransferase II (KAT II). Transamination of 3-HK to XA was also demonstrated using human recombinant KAT II. Neosynthesis of XA was significantly increased in the quinolinate-lesioned rat striatum, indicating a non-neuronal localization of the process. Studies using rat cortical slices revealed that newly produced XA is rapidly released into the extracellular compartment, and that XA biosynthesis can be manipulated experimentally in the same way as the production of kynurenic acid from kynurenine (omission of Na

Topics: Aged; Animals; Brain; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fluoroquinolones; Glucose; Glutamine; Humans; In Vitro Techniques; Kynurenine; Male; Mice; Middle Aged; Piperazines; Postmortem Changes; Pyruvic Acid; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Tacrolimus; Temperature; Tissue Distribution; Transaminases; Veratridine; Xanthurenates