β-二氢沉香呋喃倍半萜抗Aβ_(25-35)诱导的神经细胞凋亡和氧化损伤的保护作用（英文）

Protective effects of β-dihydroagarofuran-type sesquiterpene against Aβ_(25-35)-induced neuronal apoptosis and oxidative damage

大脑中β-淀粉样蛋白(β-amyloid,Aβ)过量积累与神经细胞的凋亡和氧化应激密切相关,是导致阿尔茨海默病(AD)发病的有害因素。因此,寻找能够对抗Aβ诱导的神经毒性的小分子活性化合物作为先导化合物或候选化合物,是治疗或延缓AD病情发展的重要策略。我们使用MTT法在SH-SY5Y细胞上检测到CF-1((1R,2S,4R,5S,7R,9S,10S)-1,15-diacetoxy-2-benzoyloxy-9-cinnamoyloxy-β-di-hydroagarofuran)能够浓度依赖地缓解Aβ_(25-35)造成的神经毒性;DAPI染色提示CF-1的神经保护作用与其抗细胞凋亡作用有关;Western blot方法检测到CF-1可以显著抑制Aβ_(25-35)诱导的cleaved Caspase-3的表达,佐证了其抗凋亡的作用;CF-1预处理能够显著降低Aβ_(25-35)引起的胞内ROS积累,但对DPPH无清除作用。总之,我们的研究首次证明,化合物CF-1可通过阻止Aβ诱导的细胞凋亡和氧化应激作用来发挥神经保护作用。因此,CF-1作为AD治疗的先导化合物或候选化合物具有潜在价值。

Excessive beta-amyloid （Aβ） plays a detrimental role in the pathogenesis of Alzheimer＇s disease （AD）, which is closely associated with apoptosis and oxidative stress in neurons. Therefore, identification of active small molecules with potent effects on neutralizing Aβ-induced neurotoxicity would be a promising strategy for delaying or preventing AD progression. In the present study, we discovered that pretreatment with CF-1 （（1R,2S,4R,5S,7R,9S, IOS）-1,15-diacetoxy-2-benzoyloxy-9-cinnamoyloxy- β-di-hydroagarofuran）, a sesquiterpene isolated from the seeds of Celastrus flagellaris, attenuated Aβ25_35-induced reduction in cell viability in a concentration-dependent manner, as evaluated by the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） assay. Above neuroprotective effect of CF-1 was associated with a significant decrease of apoptotic cells as measured by 4,6-diamidino-2-phenylindole （DAPI） staining, which concurrently happened with marked inhibition in the level of cleaved Caspase-3, an apoptotic executive protein. CF-1 pretreatment also markedly reduced the intracellular accumulation of reactive oxygen species （ROS） following Aβ exposure in SH-SY5Y neuroblastoma cells, but such pretreatment had no notable influence on 2,2-diphenyl-l-picrylhydrazyl （DPPH） scavenging. In conclusion, we demonstrated that a novel natural product, CF-1, possessed promising effects against Aβ-induced neuronal apoptosis and oxidative stress, which could be a potential drug lead or candidate for the treatment of Aβ-associated neurotoxicity.