Oleamide Reduces Mitochondrial Dysfunction and Toxicity in Rat Cortical Slices Through the Combined Action of Cannabinoid Receptors Activation and Induction of Antioxidant Activity.
Oleamide Reduces Mitochondrial Dysfunction and Toxicity in Rat Cortical Slices Through the Combined Action of Cannabinoid Receptors Activation and Induction of Antioxidant Activity.
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油酰胺通过大麻素受体激活和抗氧化活性诱导的联合作用，减少大鼠皮质切片的线粒体功能障碍和毒性。
DOI：
10.1007/s12640-022-00575-7
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发表时间：
2022
影响因子：
3.7
通讯作者：
Santamaría,Ab
中科院分区：
文献类型：
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作者：
Reyes-Soto,CarolinaY;Villaseca-Flores,Mariana;Ovalle-Noguez,EnidA;Nava-Osorio,Jade;Galván-Arzate,Sonia;Rangel-López,Edgar;Maya-López,Marisol;Retana-Márquez,Socorro;Túnez,Isaac;Tinkov,AlexeyA;Ke,Tao;Aschner,Michael;Santamaría,Ab
神经退行性疾病的潜在治疗需要在实验水平上开发新的药理策略，例如基于内源性大麻素的治疗。油酰胺(OEA)是一种对大麻素受体具有活性的脂肪酸伯胺，它对电子传递链复合体II抑制剂3-硝基丙酸(3-NP)诱导的大鼠大脑皮层脑片线粒体毒性有拮抗作用。OEA在5-NM-25µM的浓度范围内可阻止3-NP诱导的线粒体功能/细胞活力的丧失，这种保护作用仅在酰胺作为预处理时观察到，而不作为后处理观察到。用大麻素受体1(CB1R)选择性抑制剂AM281或大麻素受体2(CB2R)选择性抑制剂JTE-907预先孵育脑片，3-NP中毒模型中OEA诱导的线粒体功能/细胞活力的保护作用消失。2 5nM OEA可恢复3-NP对琥珀酸脱氢酶(线粒体复合体II)活性的抑制作用。对3-NP所致的脂质过氧化和还原型/氧化型谷胱甘肽(GSH/GSSG)比值的变化也有保护作用。OEA可减轻3-NP诱导的细胞损伤，评估为细胞内碘化丙啶的掺入。我们的新发现表明，在皮质细胞损伤的早期阶段，OEA表现出的神经保护特性包括CB1R和CB2R的聚合激活和抗氧化活性的增加，这两者结合在一起可能出现在保护线粒体功能完整性的基础上。
The potential treatment of neurodegenerative disorders requires the development of novel pharmacological strategies at the experimental level, such as the endocannabinoid-based therapies. The effects of oleamide (OEA), a fatty acid primary amide with activity on cannabinoid receptors, was tested against mitochondrial toxicity induced by the electron transport chain complex II inhibitor, 3-nitropropionic acid (3-NP), in rat cortical slices. OEA prevented the 3-NP-induced loss of mitochondrial function/cell viability at a concentration range of 5 nM–25 µM, and this protective effect was observed only when the amide was administered as pretreatment, but not as post-treatment. The preservation of mitochondrial function/cell viability induced by OEA in the toxic model induced by 3-NP was lost when the slices were pre-incubated with the cannabinoid receptor 1 (CB1R) selective inhibitor, AM281, or the cannabinoid receptor 2 (CB2R) selective inhibitor, JTE-907. The 3-NP-induced inhibition of succinate dehydrogenase (mitochondrial Complex II) activity was recovered by 25 nM OEA. The amide also prevented the increased lipid peroxidation and the changes in reduced/oxidized glutathione (GSH/GSSG) ratio induced by 3-NP. The cell damage induced by 3-NP, assessed as incorporation of cellular propidium iodide, was mitigated by OEA. Our novel findings suggest that the neuroprotective properties displayed by OEA during the early stages of damage to cortical cells involve the converging activation of CB1R and CB2R and the increase in antioxidant activity, which combined may emerge from the preservation of the functional integrity of mitochondria.