Cinnamon and its metabolite sodium benzoate in Parkinsonism

 描述（由申请人提供）： 帕金森病（PD）是一种常见的神经退行性疾病，在美国影响多达一百万人。PD的发病率估计为每10万人18至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，暴露于不同的战区化学品会增加患帕金森病（PD）的风险。因此，许多越南退伍军人谁是暴露于一些有毒化学品统称为“代理橙子”，目前正在变老，并表现出迹象的PD。然而，尽管进行了广泛的研究，但没有有效的治疗方法可以阻止PD或其他神经退行性疾病的进展。尽管对PD的发病机制进行了广泛的研究，但没有有效的治疗方法可以阻止这种破坏性的神经退行性过程。胶质细胞源性神经营养因子（GDNF）是多巴胺能神经元存活和生长的有效因子。因此，脑中GDNF产生的减少已被证明在PD的黑质纹状体变性中起重要作用。因此，增加黑质纹状体中营养因子GDNF的水平被认为是阻止PD神经变性的重要步骤。虽然基因操作和直接将GDNF立体定位注射到脑中是可用的选择，但从治疗角度来看，最好的选择是在PD患者的CNS中体内刺激/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，其代谢产物苯甲酸钠（NaB）是FDA批准的高氨血症药物和广泛使用的食品添加剂。我们已经发现，口服肉桂粉增加了正常小鼠和MPTP中毒小鼠（PD动物模型）CNS中GDNF和neurturin（NTN）的水平。类似地，肉桂代谢物NaB也上调人和小鼠星形胶质细胞中GDNF和NTN的表达。因此，从学术的角度，我们有专门的具体目标一，探讨背后的新的营养因子的分子机制-肉桂上调活性。由于肉桂增加了营养因子GDNF和NTN的水平，我们致力于特定目标II以研究肉桂和NaB的口服施用是否减轻慢性MPTP小鼠模型和PD的A53 T a-syn转基因小鼠模型中的病理事件并改善运动活动。我们已经发现肉桂和NaB通过PPARa诱导GDNF和NTN。因此，具体目标III已被规定为描绘肉桂和NaB是否需要PPARa-GDNF/NTN途径来保护多巴胺能神经元。总之，这项拨款提案的积极成果将突出NaB和肉桂的未发现特性，并提高用肉桂、其代谢物NaB或PPARa激动剂作为主要或辅助疗法治疗PD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.