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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Time-course correlation of early toxic events in three models of striatal damage: modulation by proteases inhibition.
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Time-course correlation of early toxic events in three models of striatal damage: modulation by proteases inhibition.

机译：纹状体损伤的三种模型中早期毒性事件的时程相关性：蛋白酶抑制调节。

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摘要

Metabolic alterations in the nervous system can be produced at early stages of toxicity and are linked with oxidative stress, energy depletion and death signaling. Proteases activation is responsible for triggering deadly cascades during cell damage in toxic models. In this study we evaluated the early time-course of toxic events (oxidative damage to lipids, mitochondrial dysfunction and LDH leakage, all at 1, 3 and 6h) in rat striatal slices exposed to quinolinic acid (QUIN, 100 microM) as an excitotoxic/pro-oxidant model, 3-nitropropionic acid (3-NP, 1mM) as an inhibitor of mitochondrial succinate dehydrogenase, and a combined model produced by the co-administration of these two toxins at subtoxic concentrations (21 and 166 microM for QUIN and 3-NP, respectively). In order to further characterize a possible causality of caspases or calpains on the toxic mechanisms produced in these models, the broad calpain inhibitor IC1 (50 microM), and the pan-caspase inhibitor Z-VAD (100 microM) were tested. Lipid peroxidation (LP) was increased at all times and in all models evaluated. Both IC1 and Z-VAD exerted significant protection against LP in all models and at all times evaluated. Mitochondrial dysfunction (MD) was consistently affected by all toxic models at 3 and 6h, but was mostly affected by 3-NP and QUIN at 1h. IC1 differentially protected the slices against 3-NP and QUIN at 1h and against QUIN at 3h, while Z-VAD exhibited positive actions against QUIN and 3-NP at all times tested, and against their combination at 3 and 6h. LDH leakage was enhanced at 1 and 3h in all toxic models, but this effect was evident only for 3-NP + QUIN and 3-NP at 6h. IC1 protected against LDH leakage at 1h in 3-NP + QUIN and 3-NP models, at 3h in all toxic models, and at 6h in 3-NP + QUIN and 3-NP models. In turn, Z-VAD protected at 1 and 6h in all models tested, and at 3h in the combined and QUIN models. Our results suggest differential chronologic and mechanistic patterns, depending on the toxic insult. Although LP, MD and membrane cell rupture are shared by the three models, the occurrence of each event seems to obey to a selective recruitment of damaging signals, including a differential activation of proteases in time. Proteases activation is likely to be an up-stream event influencing oxidative stress and mitochondrial dysfunction in these toxic models.
机译：神经系统中的代谢变化可在毒性的早期产生，并与氧化应激，能量消耗和死亡信号有关。蛋白酶激活是在毒性模型中的细胞损伤过程中引发致命级联的原因。在这项研究中，我们评估了暴露于喹啉酸（QUIN，100 microM）作为兴奋性中毒的大鼠纹状体切片中毒性事件的早期过程（在1,3和6h对脂质的氧化损伤，线粒体功能障碍和LDH泄漏） /氧化剂模型，作为线粒体琥珀酸脱氢酶抑制剂的3-硝基丙酸（3-NP，1mM）以及通过共同施用这两种毒素以亚毒性浓度（QUIN和分别为21和166 microM）产生的组合模型3-NP）。为了进一步表征胱天蛋白酶或钙蛋白酶对这些模型产生的毒性机制的可能因果关系，测试了宽泛的钙蛋白酶抑制剂IC1（50 microM）和泛半胱氨酸蛋白酶抑制剂Z-VAD（100 microM）。脂质过氧化（LP）一直都在增加，并且在所有评估的模型中都增加。在所有模型中，IC1和Z-VAD都对LP发挥了重要的保护作用，并且始终进行评估。线粒体功能障碍（MD）始终在3和6h受到所有毒性模型的影响，但在1h受到3-NP和QUIN的影响最大。 IC1分别在1h和3h分别保护切片免受3-NP和QUIN的侵害，而在3h受到QUIN的保护，而Z-VAD在所有测试时间均表现出针对QUIN和3-NP的积极作用，并在3h和6h表现出积极的作用。在所有毒性模型中，LDH的泄漏在1和3h均得到增强，但是这种效果仅在6h时对3-NP + QUIN和3-NP才明显。在3-NP + QUIN和3-NP模型中，IC1防止LDH泄漏，在1h时，在所有毒性模型中，在3h时，在3-NP + QUIN和3-NP模型中，在6h时，LDH泄漏。反过来，在所有测试的型号中，Z-VAD在1h和6h受到保护，在组合和QUIN模型中，在3h受保护。我们的研究结果表明了不同的年代和机理模式，这取决于有毒的侮辱。尽管LP，MD和膜细胞破裂由这三个模型共享，但每个事件的发生似乎服从于选择性募集破坏性信号，包括及时激活蛋白酶。在这些毒性模型中，蛋白酶激活可能是影响氧化应激和线粒体功能障碍的上游事件。

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