Puntel Robson Luiz, Nogueira Cristina Wayne, Rocha João Batista Teixeira
Departamento de Quimica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, RS, Brazil.
Neurochem Res. 2005 Mar;30(3):417-24. doi: 10.1007/s11064-005-2617-0.
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.
氧化应激在多种与N-甲基-D-天冬氨酸（NMDA）受体相互作用的物质的神经毒性中起重要作用。在此，我们以比较的方式研究了喹啉酸（QA）和丙二酸这两种神经毒性物质的促氧化作用，它们通过不同的主要分子机制对脑匀浆中硫代巴比妥酸反应性物质（TBARS）的产生产生影响。事实上，QA被认为直接激活NMDA受体，而丙二酸似乎主要通过抑制氧化代谢起作用。丙二酸诱导的TBARS形成不受氰化物（CN-）或2,4-二硝基苯酚的影响。MK-801在新鲜组织制剂中未降低基础或丙二酸诱导的TBARS产生。然而，在热处理的制剂中，观察到MK-801对基础TBARS产生有显著影响，但对丙二酸诱导的TBARS产生没有影响。在新鲜或热处理的制剂中，MK-801均能显著抑制QA诱导的TBARS产生。随着用于处理S1的温度升高，MK-801对基础和QA诱导的TBARS产生的抗氧化作用增强。琥珀酸脱氢酶（SDH）被丙二酸抑制，但不被QA抑制。丙二酸能够螯合亚铁离子（Fe2+），并且通过其对脱氧核糖降解试验的活性测定，丙二酸-铁复合物具有活性。这些发现表明，丙二酸与NMDA受体的直接相互作用不参与其体外促氧化活性。QA的体外促氧化活性至少部分与其刺激NMDA受体的能力有关。综上所述，这些发现表明丙二酸的体外促氧化活性可归因于其改变Fe2+/Fe3+比例的能力，这对TBARS的产生至关重要。
