N-methyl-D-aspartate receptors are involved in the quinolinic acid, but not in the malonate pro-oxidative activity in vitro.
Oxidative stress plays a significant role in the neurotoxicity of a variety of agents that interact with the N-methyl-D-aspartate (NMDA) receptors. Here we investigated in a comparative way the pro-oxidative effects of quinolinic acid (QA) and malonate, two neurotoxic substances that act through distinct primary molecular mechanisms on the production of thiobarbituric acid reactive species (TBARS) by brain homogenates. In fact, QA is thought to activate directly the NMDA receptor, whereas malonate seems to act primarily by inhibiting oxidative metabolism. The malonate-induced TBARS formation was not modified by cyanide (CN-) or 2,4-dinitrophenol. MK-801 did not reduce basal or malonate induced-TBARS production in fresh tissues preparations. However, in heat-treated preparations a significant effect of MK-801 against basal TBARS production was observed, but not on the malonate induced-TBARS production. QA induced-TBARS production was significantly prevented by MK-801 either in fresh or heat-treated preparations. The antioxidant effect of MK-801 on basal and QA-induced TBARS production increased as the temperatures used to treat S1 were increased. Succinate dehydrogenase (SDH) was inhibited by malonate but not by QA. Malonate was able to chelate iron(II) and the malonate-iron complex(es) is(are) active as measured by its(their) activity on deoxyribose degradation assay. These findings indicate that direct interactions of malonate with NMDA receptors are not involved in malonate pro-oxidative activity in vitro. QA pro-oxidative activity in vitro was related, at least in part, to its capability in stimulate NMDA receptors. Taken together, these findings indicated that malonate pro-oxidative activity in vitro could be attributed to its capability of changing the ratio Fe2+/Fe3+, which is essential to TBARS production.
Puntel
Robson Luiz
RL
Departamento de Quimica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, RS, Brazil.
Nogueira
Cristina Wayne
CW
Rocha
João Batista Teixeira
JB
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003855:Deoxyribose / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008314:Malonates / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002614:Chelating Agents; D008314:Malonates; D016194:Receptors, N-Methyl-D-Aspartate; D017392:Thiobarbituric Acid Reactive Substances; D003855:Deoxyribose; D016291:Dizocilpine Maleate; D013385:Succinate Dehydrogenase; D017378:Quinolinic Acid