Quantification of local de novo synthesis versus blood contributions to quinolinic acid concentrations in brain and...

The source of the neurotoxin quinolinic acid (QUIN) in brain and systemic tissues under normal and pathologic circumstances reflects either de novo synthesis from L-tryptophan and other precursors, or entry of QUIN itself from the blood. To quantify the relative contributions of blood- versus tissue-derived QUIN, [13C7]-QUIN was infused subcutaneously via osmotic pumps (0.55 microliter/h, 30 mM) in gerbils, and the fraction of QUIN in tissue (Tl; measured in tissue homogenates) derived from blood (Bl; measured in serum) was calculated by the formula ([13C7]QUINTi/QUINTi)/([13C7]QUINBl/ QUINBl). In controls, blood QUIN contributed 38-49% of QUIN in brain, 70% in CSF, between 40 and 70% in kidney, heart, and skeletal muscle, but < 5% in spleen, lung, liver, and intestine. Systemic endotoxin (450 micrograms/kg) increased blood, brain, CSF, and systemic tissue QUIN levels. Notably, the relative proportion of QUIN derived from blood in brain, spleen, lung, and intestine was unchanged by endotoxin, but increased in kidney, heart, and skeletal muscle. In contrast, cerebral ischemic injury (10 min of bilateral carotid artery occlusion) increased regional brain QUIN concentrations at 4 days post ischemia, with a proportional increase in the amount of QUIN derived from de novo synthesis by brain tissue. In the blood and systemic tissues of postischemic gerbils, there were no changes in systemic tissue or blood QUIN levels, or changes in the relative proportions of blood- versus systemic tissue-derived QUIN. These results establish that the brain normally synthesizes QUIN, that the blood is a significant source of QUIN in controls and during acute systemic immune activation, and that the rate of QUIN formation by brain tissue increases in conditions of brain and systemic immune activation.