Estrada-Valencia Rubén, Túnez Isaac, Tinkov Alexey A, Aschner Michael, López-Goerne Tessy, Pedraza-Chaverrí José, Santamaría Abel
Programa de Posgrado (Maestría) en Ciencias Biológicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
Mol Neurobiol. 2025 Jun 4. doi: 10.1007/s12035-025-05104-z.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons. Drugs modulating the endocannabinoid system (ECS) emerge as promising tools for reducing symptomatology and/or progression of this disease. Here, the protective potential of ECS regulation against 6-hydroxydopamine (6-OHDA)-induced neuronal damage was evaluated in the nematode, Caenorhabditis elegans. First, the effect of the endocannabinoid anandamide (AEA; 1 to 100 µM) was tested in adult nematodes. As this eCB had no protective effects on the 6-OHDA-induced increased neurodegeneration, an alternative treatment was tested by exposing worms to JZL184, an inhibitor of the enzyme fatty acid amide hydrolase-4 (FAAH-4). In contrast to AEA, this compound readily induced a protective effect in dopaminergic neurons exposed to 6-OHDA, also increasing worm survival. JZL184 also improved the ability of nematodes to detect food, a behavioral task associated with an intact dopaminergic system. The protective activity induced by FAAH-4 inhibition was also confirmed using the mutant OD3609 strain, a faah-4 gene knockout nematode. This strain was more resistant to 6-OHDA compared to the wild-type N2 strain, in parameters of survival and food seeking behavior. In the CL2166 strain, pretreatment with JZL184 increased the expression of the gst-4 gene at 3 and 24 h following the exposure to 6-OHDA, indicating an antioxidant response. The effects of JZL184 (50 µM) and the endocannabinoid 2-arachidonoylglycerol (2-AG; 1-100 µM) were evaluated on 6-OHDA-induced reactive oxygen species (ROS) generation. This was based on the hypothesis that the protective effects observed following FAAH-4 inhibition may be mediated by 2-AG. Both JZL-184 and 2-AG attenuated ROS formation 24 h after 6-OHDA exposure. Altogether, these results suggest that the use of the pharmacological inhibitor of eCB degradation is effective in affording neuroprotection, also indicating that the activation of antioxidant responses mediated by the ECS is a process conserved through the evolution in the nematode.
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能神经元逐渐丧失。调节内源性大麻素系统（ECS）的药物成为减轻该疾病症状和/或进展的有前景的工具。在此，在秀丽隐杆线虫中评估了ECS调节对6-羟基多巴胺（6-OHDA）诱导的神经元损伤的保护潜力。首先，在成年线虫中测试了内源性大麻素花生四烯酸乙醇胺（AEA；1至100 μM）的作用。由于这种内源性大麻素对6-OHDA诱导的神经退行性变增加没有保护作用，因此通过将线虫暴露于脂肪酸酰胺水解酶-4（FAAH-4）的抑制剂JZL184来测试另一种治疗方法。与AEA相反，该化合物在暴露于6-OHDA的多巴胺能神经元中很容易诱导出保护作用，也提高了线虫的存活率。JZL184还改善了线虫检测食物的能力，这是一项与完整多巴胺能系统相关的行为任务。使用突变体OD3609菌株（一种faah-4基因敲除线虫）也证实了FAAH-4抑制诱导的保护活性。在存活和觅食行为参数方面，该菌株比野生型N2菌株对6-OHDA更具抗性。在CL2166菌株中，用JZL184预处理在暴露于6-OHDA后3小时和24小时增加了gst-4基因的表达，表明有抗氧化反应。评估了JZL184（50 μM）和内源性大麻素2-花生四烯酸甘油酯（2-AG；1-100 μM）对6-OHDA诱导的活性氧（ROS）生成的影响。这是基于这样的假设，即FAAH-4抑制后观察到的保护作用可能由2-AG介导。JZL-184和2-AG在6-OHDA暴露后24小时均减弱了ROS的形成。总之，这些结果表明，使用内源性大麻素降解的药理抑制剂可有效提供神经保护，也表明ECS介导的抗氧化反应的激活是线虫进化过程中保守的过程。
