Jouha Jabrane, Loubidi Mohammed, Bouali Jamila, Hamri Salha, Hafid Abderrafia, Suzenet Franck, Guillaumet Gérald, Dagcı Taner, Khouili Mostafa, Aydın Fadime, Saso Luciano, Armagan Güliz
Institut de Chimie Organique et Analytique, Université d'Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067, Orléans cedex 2, France; Laboratoire de Chimie Organique et Analytique, Université Sultan Moulay Slimane, Faculté des Sciences et Techniques, BP 523, 23000, Beni-Mellal, Morocco.
Institut de Chimie Organique et Analytique, Université d'Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067, Orléans cedex 2, France.
Eur J Med Chem. 2017 Mar 31;129:41-52. doi: 10.1016/j.ejmech.2017.02.019. Epub 2017 Feb 11.
Neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease affect millions of people in the world. Thus several new approaches to treat brain disorders are under development. The aim of the present study is to synthesize potential neuroprotective heterocyclic compounds based on pyrazolopyridine derivatives and then to evaluate their effects in MPP-induced neurodegeneration in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in apoptosis-related proteins including bax, Bcl-2, Bcl-xl and caspase-3 were investigated by western blot technique. Based on the cell viability results obtained by MTT assay, the percentage of neuroprotection-induced by compounds against MPP-induced neurotoxicity in SH-SY5Y cells was between 20% and 30% at 5 μM concentrations of all synthesized compounds. Moreover, the downregulation in pro-apoptotic proteins including bax and caspase-3 were found following the novel synthesized compounds treatments and these effects were observed in a dose-dependent manner. Our results provide an evidence that these heterocyclic compounds based on pyrazolopyridine derivatives may have a role on dopaminergic neuroprotection via antiapoptotic pathways.
包括阿尔茨海默病、帕金森病和亨廷顿舞蹈症在内的神经退行性疾病影响着全球数百万人。因此，几种治疗脑部疾病的新方法正在研发中。本研究的目的是合成基于吡唑并吡啶衍生物的潜在神经保护杂环化合物，然后评估它们在人神经母细胞瘤细胞系（SH-SY5Y细胞）中对MPP诱导的神经退行性变的影响。通过MTT法测定化合物对细胞活力的影响，并通过蛋白质印迹技术研究凋亡相关蛋白（包括bax、Bcl-2、Bcl-xl和caspase-3）的变化。基于MTT法获得的细胞活力结果，在所有合成化合物浓度为5μM时，化合物对SH-SY5Y细胞中MPP诱导的神经毒性的神经保护诱导百分比在20%至30%之间。此外，在新型合成化合物处理后，发现促凋亡蛋白（包括bax和caspase-3）下调，并且这些作用呈剂量依赖性。我们的结果提供了证据，表明这些基于吡唑并吡啶衍生物的杂环化合物可能通过抗凋亡途径对多巴胺能神经保护起作用。
