Cinnamon and its metabolite sodium benzoate in Parkinsonism

肉桂及其代谢物苯甲酸钠在帕金森病中的作用

• 批准号: 8922264
• 负责人: KALIPADA PAHAN
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922264
• 关键词: Affect; Agonist; Alpha-Synuclein transgenic mouse; Alzheimer' s Disease; Animal Model; Applications Grants; Astrocytes; Attenuated; Benzoates; Bradykinesia; Brain; CREB1 gene; Chemicals; Chronic; Cinnamon - dietary; Corpus striatum structure; Disease Progression; Event; Exhibits; Exposure to; FDA approved; Flavoring; Food Additives; Genes; Genetic Transcription; Gliosis; Growth; Human; Hyperammonemia; Impairment; Incidence; Inclusion Bodies; Injection of therapeutic agent; Intoxication; Investigation; Lewy Bodies; Mediating; Modeling; Molecular; Motor Activity; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurotransmitters; Oral; Oral Administration; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Plasma; Play; Poison; Powder dose form; Process; Production; Property; Research; Risk; Role; Sodium; Spices; Symptoms; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tremor; United States; Up-Regulation; Veterans; War; agent orange; alpha synuclein; base; dopaminergic neuron; effective therapy; enhancing factor; fatty acid oxidation; feeding; glial activation; glial cell-line derived neurotrophic factor; improved; in vivo; mouse model; neuroprotection; neurturin; nigrostriatum; novel; public health relevance; synuclein

 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.