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 PPARγ receptors, can also be the target of specific cannabinoids. 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. 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. The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.

中文翻译：

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口服大麻酚衍生物 VCE-003.2 可促进室下区神经发生并防止突变亨廷顿蛋白诱导的神经变性

某些大麻素的施用通过各种细胞和分子机制发挥作用，在神经退行性疾病模型中提供神经保护。神经系统中的许多大麻素作用是由 CB1 受体介导的，可引起精神作用，但缺乏精神活性的其他靶点，包括 CB2 和核 PPARγ 受体，也可以是特定大麻素的靶点。我们通过体内突变亨廷顿蛋白的腺相关病毒表达和体外小鼠胚胎干细胞分化研究了合成大麻酚衍生物 VCE-003.2 在纹状体神经变性中的促神经发生潜力。口服VCE-003.2可保护纹状体中型多棘神经元免受突变亨廷顿蛋白诱导的损伤，减轻神经炎症并改善运动表现。通过分析长期治疗后的肝毒性，对 VCE-003.2 的生物利用度进行了表征，并评估了潜在的不良副作用。VCE-003.2促进室下区祖细胞动员，增加双皮质素阳性神经母细胞向损伤区域的迁移，并增强有效的神经发生。此外，我们还证明了 VCE-003.2 在胚胎干细胞中的促神经生成活性。VCE-003.2能够增加神经母细胞的形成和纹状体样CTIP2介导的神经发生。大麻酚衍生物 VCE-003.2 可改善室下区衍生的神经发生，以响应突变型亨廷顿蛋白诱导的神经变性，并且通过口服给药具有神经保护作用。