Lazo-Gomez Rafael, Tapia Ricardo
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito exterior s/n, Ciudad Universitaria, Coyoacán, 04510 Ciudad de México, Mexico.
Transl Neurodegener. 2017 Nov 21;6:31. doi: 10.1186/s40035-017-0102-8. eCollection 2017.
Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders. Effective therapeutic strategies are an unmet need for these disorders. Polyphenols, such as quercetin and resveratrol, are plant-derived compounds that activate sirtuins (SIRTs) and have shown promising results in some models of neuronal death, although their effects have been scarcely tested in models of motor neuron degeneration.
In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the rat spinal cord tissue. Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days. Then, animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures.
We found that the chronic infusion of AMPA [1 mM] caused a progressive motor neuron degeneration, accompanied by astrogliosis and microgliosis, and motor deficits and paralysis of the rear limbs. Quercetin infusion ameliorated AMPA-induced paralysis, rescued motor neurons, and prevented both astrogliosis and microgliosis, and these protective effects were prevented by EX527, a very selective SIRT1 inhibitor. In contrast, neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration, albeit both reduced gliosis.
These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism, and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.
兴奋性毒性是运动神经元疾病所特有的选择性运动神经元变性中最重要的机制。有效的治疗策略是这些疾病尚未满足的需求。多酚类物质，如槲皮素和白藜芦醇，是植物衍生化合物，可激活沉默调节蛋白（SIRTs），并且在一些神经元死亡模型中已显示出有前景的结果，尽管它们在运动神经元变性模型中的作用很少得到测试。
在这项研究中，我们通过向大鼠脊髓组织慢性输注α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA），研究了槲皮素和白藜芦醇在兴奋性毒性运动神经元死亡的体内模型中的作用。槲皮素和白藜芦醇与AMPA共同输注，每天评估运动行为和肌肉力量，持续长达十天。然后，将动物处死，通过组织学和免疫细胞学法分析腰段脊髓组织。
我们发现，慢性输注AMPA[1 mM]会导致进行性运动神经元变性，伴有星形胶质细胞增生和小胶质细胞增生，以及后肢运动功能障碍和瘫痪。输注槲皮素可改善AMPA诱导的瘫痪，挽救运动神经元，并预防星形胶质细胞增生和小胶质细胞增生，而一种非常选择性的SIRT1抑制剂EX527可阻止这些保护作用。相比之下，单独使用白藜芦醇或EX527均未改善运动行为缺陷或减少运动神经元变性，尽管两者都减少了胶质细胞增生。
这些结果表明，槲皮素通过SIRT1介导的机制发挥其有益作用，因此SIRT1在兴奋性毒性神经变性中起重要作用，因此其药理调节可能为运动神经元疾病的治疗提供机会。
