Aymerich María S, Rojo-Bustamante Estefanía, Molina Carmen, Celorrio Marta, Sánchez-Arias Juan A, Franco Rafael
Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, 31008, Spain.
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pío XII 55, 31008, Pamplona, Spain.
Mol Neurobiol. 2016 May;53(4):2312-9. doi: 10.1007/s12035-015-9213-3. Epub 2015 May 15.
Growing evidence suggests that the endocannabinoid system plays a role in neuroprotection in Parkinson's disease. Recently, we have shown the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL184 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. However, further investigation is needed to determine the neuroprotective mechanisms of the endocannabinoid system on the nigrostriatal pathway. The aim of this work was to investigate whether the neuroprotective effect of JZL184 in mice could be extended to an in vitro cellular model to further understand the mechanism of action of the drug. The SH-SY5Y cell line was selected based on its dopaminergic-like phenotype and its susceptibility to 1-methyl-4-phenylpyridinium iodide (MPP(+)) toxicity. Furthermore, SH-SY5Y cells express both cannabinoid receptors, CB1 and CB2. The present study describes the neuroprotective effect of MAGL inhibition with JZL184 in SH-SY5Y cells treated with MPP(+). The effect of JZL184 in cell survival was blocked by AM630, a CB2 receptor antagonist, and it was mimicked with JWH133, a CB2 receptor agonist. Rimonabant, a CB1 receptor antagonist, did not affect JZL184-induced cell survival. These results demonstrate that the neuroprotective effect of MAGL inhibition with JZL184 described in animal models of Parkinson's disease could be extended to in vitro models such as SH-SY5Y cells treated with MPP(+). This represents a useful tool to study mechanisms of neuroprotection mediated by MAGL inhibition, and we provide evidence for the possible involvement of CB2 receptors in the improvement of cell survival.
越来越多的证据表明，内源性大麻素系统在帕金森病的神经保护中发挥作用。最近，我们已经证明，在慢性1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中，用JZL184抑制单酰甘油脂肪酶（MAGL）具有神经保护作用。然而，需要进一步研究以确定内源性大麻素系统对黑质纹状体通路的神经保护机制。这项工作的目的是研究JZL184在小鼠中的神经保护作用是否可以扩展到体外细胞模型，以进一步了解该药物的作用机制。基于其多巴胺能样表型及其对1-甲基-4-苯基吡啶碘化物（MPP(+)）毒性的敏感性，选择了SH-SY5Y细胞系。此外，SH-SY5Y细胞同时表达大麻素受体CB1和CB2。本研究描述了用JZL184抑制MAGL在经MPP(+)处理的SH-SY5Y细胞中的神经保护作用。CB2受体拮抗剂AM630阻断了JZL184对细胞存活的影响，而CB2受体激动剂JWH133模拟了这种影响。CB1受体拮抗剂利莫那班不影响JZL184诱导的细胞存活。这些结果表明，在帕金森病动物模型中描述的用JZL184抑制MAGL的神经保护作用可以扩展到体外模型，如经MPP(+)处理的SH-SY5Y细胞。这是研究由MAGL抑制介导的神经保护机制的有用工具，并且我们提供了CB2受体可能参与改善细胞存活的证据。
