Colle Dirleise, Santos Danúbia Bonfanti, Hartwig Juliana Montagna, Godoi Marcelo, Engel Daiane Fátima, de Bem Andreza Fabro, Braga Antonio L, Farina Marcelo
Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Trindade, Bloco C, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
Escola de Química e Alimentos, Universidade Federal do Rio Grande, Campus Santo Antônio da Patrulha, Rio Grande, RS, Brazil.
Mol Neurobiol. 2016 Mar;53(2):1280-1295. doi: 10.1007/s12035-014-9086-x. Epub 2015 Jan 27.
Succinobucol (succinyl ester of probucol) is a lipid-lowering compound with anti-inflammatory and antioxidant properties. Recent experimental evidence has highlighted the potential neuroprotective effects of succinobucol. In the present study, cultured neuroblastoma (SH-SY5Y) cells were used to investigate mechanisms mediating the potential protective effect of succinobucol against mitochondrial metabolic impairment and oxidative stress induced by 3-nitropropionic acid (3-NP), a succinate dehydrogenase inhibitor that has been used in experimental models of the Huntington disease (HD). 3-NP decreased cellular viability after 24 h of incubation. This decline in cellular viability was preceded by (i) reduced mitochondrial complex II activity, (ii) increased reactive species generation, (iii) decreased mitochondrial membrane potential (ΔΨm), and (iv) diminished glutathione (GSH) levels. Succinobucol pretreatment (6 days) significantly prevented 3-NP-induced loss of cellular viability, generation of reactive oxygen species, and decrease of ΔΨm. However, succinobucol pretreatment did not protect against 3-NP-induced inhibition of mitochondrial complex II activity, pointing to the mitigation of secondary events resultant from mitochondrial complex II inhibition. Succinobucol pretreatment (6 days) significantly increased (50 %) the levels of GSH in SH-SY5Y cells, and this event was paralleled by significant increases in glutamate cysteine ligase messenger RNA (mRNA) expression and activity (GCL; the first enzyme in the GSH biosynthesis). The present findings are the first to show that succinobucol increases GSH levels via upregulation of GCL activity (possibly through the activation of the nuclear (erythroid-derived 2)-related factor (Nrf2)/antioxidant response element (ARE) pathway), displaying protective effects against mitochondrial dysfunction-derived oxidative stress.
丁二酸布可洛尔（丙丁酚的琥珀酸酯）是一种具有抗炎和抗氧化特性的降脂化合物。最近的实验证据凸显了丁二酸布可洛尔潜在的神经保护作用。在本研究中，培养的神经母细胞瘤（SH-SY5Y）细胞被用于探究介导丁二酸布可洛尔对线粒体代谢损伤和由3-硝基丙酸（3-NP）诱导的氧化应激的潜在保护作用的机制，3-NP是一种琥珀酸脱氢酶抑制剂，已被用于亨廷顿病（HD）的实验模型中。孵育24小时后，3-NP降低了细胞活力。细胞活力的这种下降之前伴随着：（i）线粒体复合物II活性降低；（ii）活性物质生成增加；（iii）线粒体膜电位（ΔΨm）降低；（iv）谷胱甘肽（GSH）水平降低。丁二酸布可洛尔预处理（6天）显著预防了3-NP诱导的细胞活力丧失、活性氧生成以及ΔΨm降低。然而，丁二酸布可洛尔预处理并未预防3-NP诱导的线粒体复合物II活性抑制，表明减轻了线粒体复合物II抑制导致的继发事件。丁二酸布可洛尔预处理（6天）显著增加了（50%）SH-SY5Y细胞中的GSH水平，并且这一事件伴随着谷氨酸半胱氨酸连接酶信使核糖核酸（mRNA）表达和活性（GCL；GSH生物合成中的第一种酶）的显著增加。本研究结果首次表明，丁二酸布可洛尔通过上调GCL活性（可能通过激活核（红细胞衍生2）相关因子（Nrf2）/抗氧化反应元件（ARE）途径）来增加GSH水平，对线粒体功能障碍衍生的氧化应激具有保护作用。
