Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol
Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol
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DOI：
10.1016/j.brainresbull.2018.01.014
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发表时间：
2018-05-01
影响因子：
3.8
通讯作者：
Schroder, Nadja
中科院分区：
文献类型：
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作者：
da Silva, Vanessa Kappel;de Freitas, Betania Souza;Schroder, Nadja
有证据表明，铁在患有神经退行性疾病的患者的特定脑区域中积累，并且这种金属已被认为是神经退行性疾病的促成因素。使用脑铁积累的实验模型，我们已经表明，铁诱导严重的记忆缺陷，伴随着氧化应激，增加凋亡标记物，并减少突触素在大鼠海马区。本研究的目的是表征铁负荷的影响，以及确定大麻二酚（CBD），大麻唾液的主要非精神模拟化合物，对线粒体的分子靶点。大鼠在新生期接受铁，成年期接受CBD 14天。铁诱导线粒体DNA（mtDNA）缺失，减少mtDNA的表观遗传调节，线粒体铁蛋白水平和琥珀酸脱氢酶活性。CBD拯救了线粒体铁蛋白和线粒体DNA的表观遗传调节，并恢复了铁处理大鼠的琥珀酸脱氢酶活性。这些发现为铁神经毒性的分子靶点提供了新的见解，并支持使用CBD作为治疗神经退行性疾病的疾病修饰剂。
Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration. Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippo campus of rats. The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis saliva, on mitochondria. Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity. CBD rescued mitochondria] ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats. These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.