In vitro effect of quinolinic acid on energy metabolism in brain of young rats

Quinolinic acid (QA) is found at increased concentrations in brain of patients affected by various common neurodegenerative disorders, including Huntington's and Alzheimer's diseases. Considering that the neuropathology of these disorders has been recently attributed at least in part to energy deficit, in the present study we investigated the in vitro effect of QA (0.1-100 mu M) on various parameters of energy metabolism, such as glucose uptake, (CO2)-C-14 production and lactate production, as well as on the activities of the respiratory chain complexes I-V, the citric acid cycle (CAC) enzymes, creatine kinase (CK), lactate dehydrogenase (LDH) and Na+,K+-ATPase and finally the rate of oxygen consumption in brain of 30-day-old rats. We initially observed that QA significantly increased glucose uptake (55%), whereas (CO2)-C-14 generation from glucose, acetate and citrate was inhibited (up to 60%). Furthermore, QA-induced increase of brain glucose uptake was prevented by the NMDA receptor antagonist MK801. Complex II activity was also inhibited (up to 35%) by QA, whereas the other activities of the respiratory chain complexes, CAC enzymes, CK and Na+,K+-ATPase were not affected by the acid. Furthermore, inhibition of complex 11 activity was fully prevented by pre-incubating cortical homogenates with catalase plus superoxide dismutase, indicating that this effect was probably mediated by reactive oxygen species. In addition, lactate production was also not altered by QA, in contrast to the conversion of pyruvate to lactate catalyzed by LDH, which was significantly decreased (17%) by this neurotoxin. We also observed that QA did not change state III, state IV and the respiratory control ratio in the presence of glutamate/malate or succinate, suggesting that its effect on cellular respiration was rather weak. The data provide evidence that QA provokes a mild impairment of brain energy metabolism in vitro and does not support the view that the brain energy deficiency associated to certain neurodegenerative disorders could be solely endorsed to QA accumulation. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.