Xanthurenic acid distribution, transport, accumulation and release in the rat brain.
Tryptophan metabolism through the kynurenine pathway leads to several neuroactive compounds, including kynurenic and picolinic acids. Xanthurenic acid (Xa) has been generally considered as a substance with no physiological role but possessing toxic and apoptotic properties. In the present work, we present several findings which support a physiological role for endogenous Xa in synaptic signalling in brain. This substance is present in micromolar amounts in most regions of the rat brain with a heterogeneous distribution. An active vesicular synaptic process inhibited by bafilomycin and nigericin accumulates xanthurenate into pre-synaptic terminals. A neuronal transport, partially dependant on adenosine 5'-triphosphate (ATP), sodium and chloride ions exists in NCB-20 neurons which could participate in the clearance of extracellular xanthurenate. Both transports (neuronal and vesicular) are greatly enhanced by the presence of micromolar amounts of zinc ions. Finally, electrical in vivo stimulation of A10-induced Xa release in the extracellular spaces of the rat prefrontal cortex. This phenomenon is reproduced by veratrine, K+ ions and blocked by EGTA and tetrodotoxin. These results strongly argue for a role for Xa in neurotransmission/neuromodulation in the rat brain, thus providing the existence of specific Xa receptors.
Gobaille
Serge
S
INSERM U-575 and Department of Biochemistry, Faculty of Medicine, Strasbourg, France.
Kemmel
Véronique
V
Brumaru
Daniel
D
Dugave
Christophe
C
Aunis
Dominique
D
Maitre
Michel
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D004558:Electric Stimulation; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D014977:Xanthurenates / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
D002712:Chlorides; D018377:Neurotransmitter Agents; D011500:Protein Synthesis Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014977:Xanthurenates; C028330:xanthurenic acid; D000255:Adenosine Triphosphate; D012964:Sodium; D015032:Zinc