HIGH-LEVELS OF QUINOLINIC ACID IN BRAIN OF EPILEPSY-PRONE E1 MICE

Quinolinic acid (QUIN) may act as an excitotoxin when it is abundant i n the brain. We have shown previously that the activity of 3-hydroxyan thranilate 3,4-dioxygenase, a QUIN-synthesizing enzyme, was abnormally high in the brains of epilepsy-prone E1 mice as compared with that of ddY mice. Here, we estimated the QUIN contents in the brains of these mice. The results showed that the basal QUIN content in the cerebral cortex of E1 mice was twice as high as that of ddY mice. Systemic inje ction of 400 mumol/kg body weight of L-tryptophan (L-Trp) increased th e cortical levels of QUIN in both E1 mice and ddY mice by 189% and 118 %, respectively. Administration of 400 mumol/kg each of L-threonine an d D,L-methionine had no appreciable effect on the L-Trp-caused increas e in the cortical QUIN levels. Co-administration of 5-fluorotryptophan or 5-methyltryptophan, tryptophan analogs, with L-Trp did not reduce but rather enhanced the cortical QUIN levels (by 18% and 92%, respecti vely). No significant change in the cortical QUIN concentrations was o bserved with injection of 2 mg/kg body weight of E. coli lipopolysacch aride (LPS) in E1 mice. However, injection of L-Trp in the LPS-treated E1 mice produced a more marked increase in the cortical QUIN levels t han that injected With L-Trp alone. These results suggest that the bra in QUIN contents of E1 mice are dependent not only on the activity of QUIN-synthesizing enzyme but also on the rate of flux of its substrate , L-Trp or its metabolite(s), in the brain.