Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration
Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration
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DOI：
10.1186/s40035-019-0148-x
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发表时间：
2019-03-08
影响因子：
12.6
通讯作者：
Galve-Roperh, Ismael
中科院分区：
文献类型：
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作者：
Aguareles, Jose;Paraiso-Luna, Juan;Galve-Roperh, Ismael
背景：在神经退行性疾病模型中，某些大麻素的应用通过不同的细胞和分子机制提供神经保护。神经系统中的许多大麻素活动是通过CB1受体介导的，CB1受体可以引起精神效应，但其他缺乏精神活性的靶点，包括CB2和核内PPAR伽马受体，也可以成为特定大麻素的靶点。方法：通过体内突变型亨廷顿素腺相关病毒表达和体外小鼠胚胎干细胞分化，研究合成的大麻酚衍生物VCE-003.2在纹状体神经变性中的前神经发生潜能。结果：口服VCE-003.2对突变型亨廷丁诱导的纹状体中棘神经元具有保护作用，减轻神经炎症，改善运动能力。对VCE-003.2的生物利用度进行了表征，并通过分析慢性治疗后的肝脏毒性来评估其潜在的不良副作用。VCE-003.2可促进脑室下区神经前体细胞的动员，增加双皮质激素阳性的神经母细胞向损伤区域的迁移，并促进有效的神经再生。此外，我们还证实了VCE-003.2在胚胎干细胞中的成神经活性。VCE-003.2可促进神经母细胞的形成和纹状体样CTIP2介导的神经发生。结论：大麻酚衍生物VCE-003.2可促进突变型亨廷丁诱导的脑室下区神经发生，具有一定的神经保护作用。
Background: The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPAR gamma receptors, can also be the target of specific cannabinoids.Methods: We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.Results: Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.Conclusions: The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.