The prominent protective effects in diverse neuron injury paradigms exerted by cannabinoids and in particular their endogenously produced species render the endocannabinoid system a promising molecular target in the treatment of neurodegenerative diseases.

However, the effects of individual endocannabinoids in human cells remain poorly investigated.

Neural derivatives of human induced pluripotent stem cells (iPSC) offer unique opportunities for studying the neuroprotective compounds and development of patient-specific treatment. For the first time the cytotoxic and neuroprotective effects endocannabinoids N-arachidonoyl dopamine (N-ADA) and N-docosahexaenoyl dopamine (N-DDA) were assessed in human neural progenitors and dopamine neurons derived from iPSCs of healthy donors and patients with Parkinson’s disease. While the short-term treatment with the investigated compounds in 0.1–10 μM concentration range exerted no toxicity in these cell types, the long-term exposure to 0.1–5 μM N-ADA or N-DDA reduced the survival of human neural progenitors. At the same time, both N-ADA and N-DDA protected neural progenitors and terminally differentiated neurons both from healthy donors and patients with Parkinson’s disease against oxidative stress induced by hydrogen peroxide. The observed dramatic difference in the mode of action of N-acyl dopamines points on the possible existence of novel pathogenic mechanism of neurodegeneration induced by prolonged uncompensated production of these substances within neuronal tissue and should also be considered as a precaution in the future development of N-acyl dopamine-based therapeutic drugs.

大麻素在不同神经元损伤范式中的显着保护作用，特别是其内源性产生的物种，使内源性大麻素系统成为治疗神经退行性疾病的有希望的分子靶点。

然而，个体内源性大麻素对人体细胞的影响仍然缺乏研究。

人类诱导多能干细胞 (iPSC) 的神经衍生物为研究神经保护化合物和开发患者特异性治疗提供了独特的机会。首次在来自健康供体和帕金森病患者的 iPSC 的人类神经祖细胞和多巴胺神经元中评估了内源性大麻素 N-花生四烯酰多巴胺 (N-ADA) 和 N-二十二碳六烯酰多巴胺 (N-DDA) 的细胞毒性和神经保护作用。虽然用 0.1-10 μM 浓度范围的研究化合物短期处理这些细胞类型没有毒性，但长期暴露于 0.1-5 μM N-ADA 或 N-DDA 会降低人类神经祖细胞的存活率。同时，N-ADA 和 N-DDA 都保护来自健康供体和帕金森病患者的神经祖细胞和终末分化神经元，以抵抗过氧化氢诱导的氧化应激。观察到的 N-酰基多巴胺作用方式的巨大差异表明，神经元组织内这些物质的长期未代偿产生引起的神经变性的新致病机制可能存在，也应考虑作为 N-酰基多巴胺未来发展的预防措施。 -基于酰基多巴胺的治疗药物。