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.

Public Health Relevance

It is increasingly becoming clear that exposure to different war zone chemicals increases the risk of having Parkinson's disease (PD). Here, based on our exciting preliminary results, we will examine therapeutic efficacy of cinnamon and its metabolite sodium benzoate (NaB), an FDA-approved drug and a widely-used food additive, in MPTP mouse models of PD. Furthermore, from the academic point of view, we will also investigate a novel mode of action of cinnamon and NaB at the molecular level. 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 with easily available cinnamon powder or its metabolite NaB as primary or adjunct therapy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003033-02
Application #
9206096
Study Section
Neurobiology E (NURE)
Project Start
2015-10-01
Project End
2019-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Jesse Brown VA Medical Center
Department
Type
Independent Hospitals
DUNS #
010299204
City
Chicago
State
IL
Country
United States
Zip Code
60612