Cinnamon and its metabolite sodium benzoate in Parkinsonism

 描述(由申请人提供)： 帕金森氏病(PD)是一种常见的神经退行性疾病，在美国有多达100万人受到影响。据估计，帕金森氏症的发病率在每10万人中有18到182人，使其成为仅次于阿尔茨海默病的第二大神经退行性疾病。越来越清楚的是，暴露在不同战区化学品中会增加患帕金森氏症(PD)的风险。因此，许多越南退伍军人接触了许多被统称为橙剂的有毒化学物质，目前正在变老，并显示出帕金森病的迹象。然而，尽管进行了广泛的研究，但还没有有效的治疗方法来阻止帕金森病或其他神经退行性疾病的进展。尽管对帕金森病的发病机制进行了广泛的研究，但目前还没有有效的治疗方法来阻止这种毁灭性的神经退变过程。胶质细胞源性神经营养因子(GDNF)是促进多巴胺能神经元存活和生长的重要因子。因此，脑中GDNF产生的减少已被证明在帕金森病患者的黑质纹状体变性中起重要作用。因此，提高黑质纹状体中营养因子GDNF的水平被认为是阻止帕金森病神经变性的重要步骤。虽然基因操作和直接脑内立体定向注射GDNF是可行的选择，但从治疗的角度来看，最好的选择是在PD患者的中枢神经系统内刺激/诱导GDNF的产生。真的有可能吗？我们的新结果表明，肉桂是一种在世界各地使用了几个世纪的常用天然香料和调味料，其代谢物苯甲酸钠(NAB)是FDA批准的治疗高氨血症的药物，也是一种广泛使用的食品添加剂。我们发现，口服肉桂粉增加了正常小鼠和MPTP中毒小鼠(PD动物模型)中枢神经系统中GDNF和神经突触蛋白(NTN)的水平。同样，肉桂代谢物NAB也上调了人和小鼠星形胶质细胞中GDNF和NTN的表达。因此，从学术角度出发，我们致力于研究新型营养因子--肉桂上调活性背后的分子机制。由于肉桂增加了营养因子GDNF和NTN的水平，我们专门研究了口服肉桂和NAB是否能减轻慢性MPTP小鼠模型和A53T a-syn转基因PD小鼠模型的病理事件和改善运动能力。我们发现肉桂和NAB通过PPARa诱导GDNF和NTN。因此，特定的目标III被用来描述肉桂和NAB是否需要PPARa-GDNF/NTN途径来保护多巴胺能神经元。总而言之，这项赠款提案的积极结果将突出NAB和肉桂的未被发现的特性，并增加将肉桂、其代谢物NAB或PPARa激动剂作为主要或辅助治疗方法治疗帕金森病或其他神经退行性疾病患者的可能性。

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurodegenerative disease affecting up to a million people in the United States. Estimates of incidence of PD range from 18 to 182 per 100,000, making it the second-most neurodegenerative disease after Alzheimer's disease. It is increasingly becoming clear that exposure to different war zone chemicals increases the risk of having Parkinson's disease (PD). Accordingly, many of the Vietnamese Veterans who were exposed to a number of toxic chemicals collectively called "Agent Orange" and are currently getting old and are exhibiting signs of PD. However, in spite of extensive research, no effective therapy is available to halt the progression of PD or other neurodegenerative disorders. In spite of extensive research on the pathogenesis of PD, no effective therapy is available to halt this devastating neurodegenerative process. Glial cell line-derived neurotrophic factor (GDNF) is a potent factor for survival and growth of dopaminergic neurons. Accordingly a decrease in GDNF production in the brain has been shown to play an important role in nigrostriatal degeneration in PD. Therefore, increasing the level of trophic factor GDNF in the nigrostriatum is considered as an important step in halting the neurodegeneration in PD. Although gene manipulation and stereotaxic injection of GDNF directly into the brain are available options, it seems from the therapeutic angle, the best option would be to stimulate/induce the production of GDNF in vivo in the CNS of patients with PD. Is it really possible? Our novel results show that it is possible with cinnamon, a commonly used natural spice and flavoring material used for centuries throughout the world, and its metabolite sodium benzoate (NaB), an FDA-approved drug for hyperammonemia and a widely-used food additive. We have found that oral feeding of ground cinnamon increases the level of GDNF and neurturin (NTN) in the CNS of normal mice and MPTP-intoxicated mice, an animal model of PD. Similarly, cinnamon metabolite NaB also upregulates the expression of GDNF and NTN in human and mouse astrocytes. Therefore, from the academic angle, we have dedicated Specific aim I to investigate molecular mechanisms behind novel trophic factor- upregulating activity of cinnamon. Because cinnamon increased the level of trophic factors GDNF and NTN, we have devoted Specific aim II to investigate if oral administration of cinnamon and NaB attenuates pathological events and improves locomotor activities in chronic MPTP mouse model and A53T a-syn transgenic mouse model of PD. We have discovered that cinnamon and NaB induce GDNF and NTN via PPARa. Therefore, Specific aim III has been enshrined to delineate if cinnamon and NaB requires the PPARa - GDNF/NTN pathway to protect dopaminergic neurons. Taken together, a positive outcome of this grant proposal will highlight undiscovered properties of NaB and cinnamon, and enhance the possibility of treating patients with PD or other neurodegenerative disorders with cinnamon, its metabolite NaB or agonists of PPARa as primary or adjunct therapy.