Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
Grupo Investigación Biodiscovery, IDIS, 27002 Lugo, Spain.
ACS Chem Neurosci. 2022 Aug 17;13(16):2449-2463. doi: 10.1021/acschemneuro.2c00208. Epub 2022 Jul 28.
Neuroprotective properties of five previously described furanoditerpenes -, isolated from were evaluated in an oxidative stress model in SH-SY5Y cells. Dose-response treatments revealed that - improved cell survival at nanomolar concentrations through the restoration of mitochondrial membrane potential and the reduction of reactive oxygen species. Their ability to prevent the mitochondrial permeability transition pore opening was also assessed, finding that and inhibited the channel at 0.001 μM. This inhibition was accompanied by a decrease in the expression of cyclophilin D, the main regulator of the pore, which was also reduced by and . However, the activation of ERK and GSK3β, upstream modulators of the channel, was not affected by compounds. Therefore, their ability to bind cyclophilin D was evaluated by surface plasmon resonance, observing that - presented equilibrium dissociation constants in the micromolar range. All compounds also showed affinity for cyclophilin A, being selective toward this isoform, while and exhibited selectivity for cyclophilin D. When the effects on the intracellular expression of cyclophilins A-C were determined, it was found that only decreased cyclophilin A, while cyclophilins B and C were diminished by most compounds, displaying enhanced effects under oxidative stress conditions. Results indicate that furanoditerpenes - have mitochondrial-mediated neuroprotective properties through direct interaction with cyclophilin D. Due to the important role of this protein in oxidative stress and inflammation, compounds are promising drugs for new therapeutic strategies against neurodegeneration.
五种先前描述的呋喃二萜类化合物的神经保护特性，从 中分离出来，在 SH-SY5Y 细胞的氧化应激模型中进行了评估。剂量反应处理表明，-在纳摩尔浓度下通过恢复线粒体膜电位和减少活性氧来提高细胞存活率。还评估了它们防止线粒体通透性转换孔（MPTP）开放的能力，发现 和 在 0.001 μM 时抑制了该通道。这种抑制伴随着亲环蛋白 D 的表达减少，亲环蛋白 D 是孔的主要调节因子， 和 也降低了亲环蛋白 D 的表达。然而，通道的上游调节剂 ERK 和 GSK3β 的激活不受化合物影响。因此，通过表面等离子体共振评估了它们与亲环蛋白 D 结合的能力，观察到 -在微摩尔范围内呈现出平衡解离常数。所有化合物也对亲环蛋白 A 具有亲和力，对该同工型具有选择性，而 和 对亲环蛋白 D 具有选择性。当确定对细胞内亲环蛋白 A-C 表达的影响时，发现只有 降低了亲环蛋白 A，而大多数化合物降低了亲环蛋白 B 和 C，在氧化应激条件下显示出增强的作用。结果表明，呋喃二萜类化合物 - 通过与亲环蛋白 D 的直接相互作用具有线粒体介导的神经保护特性。由于该蛋白在氧化应激和炎症中的重要作用，化合物是针对神经退行性变的新治疗策略有前途的药物。
