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JBC:人工甜味剂或有治疗帕金森氏病的潜在功效

来源:生物谷 2013-06-18 16:55

2013年6月18日讯 /生物谷BIOON/--由真菌,细菌,藻类产生的一种糖醇--甘露糖醇也可用于医疗领域。甘露糖醇被FDA批准作为利尿剂排出多余的流体,手术过程中也可使用该物质打开通过血/脑屏障帮助其他药物通过。

近日,科学家Ehud Gazit和Daniel Segal发现甘露醇还可以防止蛋白质α-共核蛋团块在大脑中的形成。研究结果发表在Journal of Biological Chemistry杂志,提示这种人工甜味剂可能是用于治疗帕金森氏症和其他神经退行性疾病的一种新型疗法。

识别α-突触核蛋白结构特点后,研究人员开始寻找一种化合物能够抑制蛋白质结合在一起的能力。在实验室中,他们发现,甘露糖醇能最有效的防止试管中蛋白质的聚集。

接下来,为了测试甘露醇​​在活大脑中的功效,研究人员转向携带α-突触核蛋白基因的转基因果蝇工程。要为了研究果蝇的运动,他们使用了所谓的“登山测定测试”,即考察果蝇爬试管壁的能力表征其机动能力。

在最初的实验期间,72%的正常果蝇能够爬上试管,而只有38%的基因改造果蝇能爬上试管。然后,研究人员将甘露醇添加到食物给养基因改造果蝇27天后,重复实验。这一次,70%的变异果蝇能爬上试管。

此外,研究人员观察到与那些未喂食甘露醇的果蝇相比,喂食甘露醇的变异果蝇α-突触核蛋白的聚集减少70%。

这些发现在第二项研究中得到了证实,测量甘露醇对能产生人α-突触核蛋白小鼠的影响。 4个月后,研究人员发现,小鼠注射甘露醇后,α-突触核蛋白在大脑中也出现了大幅度的减少。

研究人员现在打算重新审视甘露醇化合物的结构并进行结构修改,优化其有效性。并进一步利用实验动物模型,包括行为测试考察其作用。

Segal教授说,甘露醇可与已经证明不能穿过血/脑屏障的药物进行组合,用于治疗帕金森氏症。虽然结果看起来有前途的,但这并不意味帕金森氏症患者需摄取大量的甘露醇。必须做更多的测试,以确定安全有效的剂量。(生物谷:Bioon.com)

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent  -Synuclein ( -syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD).

R. Shaltiel-Karyo, M. Frenkel-Pinter, E. Rockenstein, C. Patrick, M. Levy-Sakin, A. Schiller, N. Egoz-Matia, E. Masliah, D. Segal, E. Gazit.

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.

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