Quinolinate potentiates the neurotoxicity of excitatory amino acids in hypoxic neuronal tissue in vitro

Abstract

Excitatory amino acids (EAAs) in the central nervous system are involved in both neurotransmission and neurotoxicity. Quinolinate (QUIN) is a neurotoxic endogenous tryptophan metabolite that has been linked to Huntington's disease, Alzheimer's disease, and many inflammatory diseases. We used the rat hippocampal slice preparation and its electrophysiology to study the interaction of QUIN with glutamate receptor agonists such as N-methyl- d-aspartate (NMDA), glutamate, aspartate, kainate, and AMPA ((R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepro pionate). The majority of slices could tolerate an exposure to 10-min hypoxia (86% recovered their neuronal function), but doses of glutamate receptor agonists which were harmless under normoxic conditions, significantly reduced this recovery rate under hypoxic conditions. QUIN, at doses that even under hypoxic conditions were innocuous (20–50 μM), potentiated the neurotoxic effects of all the glutamate receptor agonists tested in hypoxic hippocampal slices. The NMDA antagonist d,l-2-amino-5-phosphonovalerate blocked this potentiation while 7-chlorokynurenate, at a dose sufficient to block the effect of NMDA alone, was ineffective in blocking the potentiation of NMDA toxicity by QUIN. Non-toxic analogues of QUIN (6-methyl-QUIN and 2,3-pyrazine dicar☐ylate) were also able to potentiate NMDA toxicity in hypoxic slices. The results of these experiments provided indirect evidence that QUIN is an endogenous potentiator of the NMDA and the kainate receptor subtypes: therefore, we postulate that QUIN has a specific modulatory binding site on all glutamate receptor subtype complexes. Regardless of its site of interaction, the importance of QUIN as a potentiator of the agonistic activation of these receptors cannot be overemphasized. Thus, the in vivo involvement of QUIN in increasing the neurotoxic efficacy of EAAs in brain disorders such as cerebral ischemia should be considered.