Estrada-Valencia Rubén, Hurtado-Díaz María Ester, Rangel-López Edgar, Retana-Márquez Socorro, Túnez Isaac, Tinkov Alexey, Karasu Cimen, Ferrer Beatriz, Pedraza-Chaverri José, Aschner Michael, Santamaría Abel
Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular Y Nanotecnología, Instituto Nacional de Neurología Y Neurocirugía, Insurgentes Sur 3877, 14269, Mexico City, Mexico.
Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Neurotox Res. 2022 Apr;40(2):573-584. doi: 10.1007/s12640-022-00493-8. Epub 2022 Apr 5.
The development, at the experimental level, of therapeutic strategies based on natural products to attenuate neurological alterations in degenerative disorders has gained attention. Antioxidant molecules exhibit both anti-inflammatory and neuroprotective properties. Alpha-mangostin (α-Man) is a natural xanthonoid isolated from the mangosteen tree with demonstrated antioxidant and cytoprotective properties. In this study, we investigated the antioxidant and protective properties of α-Man, both ex vivo and in vivo. We assessed the mitochondrial reductant capacity and oxidative damage to lipids in rat cortical slices, and several endpoints characteristic of physiological stress in the nematode, Caenorhabditis elegans (C. elegans), upon exposure to the parkinsonian neurotoxin, 6-hydroxydopamine (6-OHDA). In rat cortical slices, α-Man (25 and 50 µM) reduced the 6-OHDA (100 µM)-induced oxidative damage to lipid levels, but failed to reverse loss in cell viability. In wild-type (N2) C. elegans, α-Man (5-100 µM) protected against 6-OHDA (25 mM)-induced decrease in survival when administered either as pre- or post-treatment. Protective effects of α-Man were also observed on survival in the VC1772 strain (skn-1 KO) exposed to 6-OHDA, though the extent of the protection was lesser than in the wild-type N2 strain. However, α-Man (5-50 µM) failed to attenuate the 6-OHDA-induced motor alterations in the N2 strain. The loss of lifespan induced by 6-OHDA in the N2 strain was fully reversed by high concentrations of α-Man. In addition, while 6-OHDA decreased the expression of glutathione S-transferase in the CL2166 C. elegans strain, α-Man preserved and stimulated the expression of this protein. α-Man (25 µM) also prevented 6-OHDA-induced dopaminergic neurodegeneration in the BZ555 C. elegans strain. Altogether, our novel results suggest that α-Man affords partial protection against several, but not all, short-term toxic effects induced by 6-OHDA in cortical slices and in a skn-1-dependent manner in C. elegans.
在实验层面，基于天然产物开发治疗策略以减轻退行性疾病中的神经学改变已受到关注。抗氧化分子兼具抗炎和神经保护特性。α-山竹黄酮（α-Man）是从山竹树中分离出的一种天然呫吨酮，具有已证实的抗氧化和细胞保护特性。在本研究中，我们在体外和体内研究了α-Man的抗氧化和保护特性。我们评估了大鼠皮质切片中的线粒体还原能力以及脂质的氧化损伤，以及线虫秀丽隐杆线虫（C. elegans）在暴露于帕金森神经毒素6-羟基多巴胺（6-OHDA）后生理应激的几个特征终点。在大鼠皮质切片中，α-Man（25和50μM）降低了6-OHDA（100μM）诱导的脂质水平氧化损伤，但未能逆转细胞活力的丧失。在野生型（N2）秀丽隐杆线虫中，α-Man（5 - 100μM）在预处理或后处理时均可保护其免受6-OHDA（25 mM）诱导的存活率下降。在暴露于6-OHDA的VC1772菌株（skn-1基因敲除）中也观察到了α-Man对存活率的保护作用，尽管保护程度低于野生型N2菌株。然而，α-Man（5 - 50μM）未能减轻N2菌株中6-OHDA诱导的运动改变。高浓度的α-Man完全逆转了N2菌株中6-OHDA诱导的寿命缩短。此外，虽然6-OHDA降低了CL2166秀丽隐杆线虫菌株中谷胱甘肽S-转移酶的表达，但α-Man保留并刺激了该蛋白的表达。α-Man（25μM）还预防了BZ555秀丽隐杆线虫菌株中6-OHDA诱导的多巴胺能神经变性。总之，我们的新结果表明，α-Man对6-OHDA在皮质切片中诱导的几种但并非全部短期毒性作用具有部分保护作用，并且在秀丽隐杆线虫中以skn-1依赖的方式发挥作用。
