Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats.
In the present study we investigated the effect of intrastriatal administration of 150 nmol quinolinic acid to young rats on critical enzyme activities of energy production and transfer, as well as on 14CO2 production from [1-14C]acetate at distinct periods after quinolinic acid injection. We observed that quinolinic acid injection significantly inhibited complexes II (50%), III (46%) and II-III (35%), as well as creatine kinase (27%), but not the activities of complexes I and IV and citrate synthase in striatum prepared 12 h after treatment. In contrast, no alterations of these enzyme activities were observed 3 or 6 h after quinolinic acid administration. 14CO2 production from [1-14C]acetate was also significantly inhibited (27%) by quinolinic acid in rat striatum prepared 12 h after injection. However, no alterations of these activities were observed in striatum homogenates incubated in the presence of 100 microm quinolinic acid . Pretreatment with the NMDA receptor antagonist MK-801 and with creatine totally prevented all inhibitory effects elicited by quinolinic acid administration. In addition, alpha-tocopherol plus ascorbate and the nitric oxide synthase inhibitor l-NAME completely abolished the inhibitions provoked by quinolinic acid on creatine kinase and complex III. Furthermore, pyruvate pretreatment totally blocked the inhibitory effects of quinolinic acid injection on complex II activity and partially prevented quinolinic acid-induced creatine kinase inhibition. These observations strongly indicate that oxidative phosphorylation, the citric acid cycle and cellular energy transfer are compromised by high concentrations of quinolinic acid in the striatum of young rats and that these inhibitory effects were probably mediated by NMDA stimulation.
Ribeiro
César A J
CA
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Grando
Vanessa
V
Dutra Filho
Carlos S
CS
Wannmacher
Clóvis M D
CM
Wajner
Moacir
M
D000818:Animals; D000831:Animals, Newborn; D002245:Carbon Dioxide / Q000378:metabolism; D002247:Carbon Isotopes / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000254:growth & development; D003402:Creatine Kinase / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors
D002247:Carbon Isotopes; D045222:Electron Transport Chain Complex Proteins; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D002245:Carbon Dioxide; D016291:Dizocilpine Maleate; D003402:Creatine Kinase; D017378:Quinolinic Acid