Autonomic dysfunctions, especially gastrointestinal motility disorders, occur frequently in parkinsonian patients and are often prodromic to the clinical diagnosis of Parkinson?s disease (PD). Chronic constipation and delayed gastric emptying are observed in many parkinsonian patients and are especially troublesome; the latter provides an additional unresolved complication to the absorption and appropriate therapeutic dosing regimen of L-DOPA, i.e. the main therapy used to treat PD-related motor dysfunctions. In the quest to elucidate the treatment of parkinsonian-related gastroparesis, it is necessary to understand the factors, including the environmental influences, which contribute to the etiology and development of idiopathic PD. Several epidemiological studies have associated an increased incidence of PD with pesticide or herbicide exposure and rural location/lifestyle. Similarly, studies have indicated that vegetarians who follow a diet high in plant seed lectins have a higher incidence of PD compared to non-vegetarians. Of note, some vegetable cultivars in SE Asia have enriched lectin concentrations of up to 1%. Based on our preliminary studies that indicate impaired gastric motility upon administration of subthreshold doses of lectins and the herbicide paraquat, we propose the following novel hypothesis: ?lectin- mediated retrograde transport of environmental toxins disrupts the brain-gut axis through a vagally-dependent ENS-DMV-SNpc pathway? prior to the development of PD-related motor dysfunctions. To investigate this novel hypothesis, we will use a combination of in vivo optogenetic, electrophysiological, anatomical and behavioral approaches in rodents to investigate on the gastric-related neural pathways affected in parkinsonian-related gastric dysfunctions.

Public Health Relevance

In recent years, many studies have led to the recognition that gastrointestinal (GI) dysfunctions, including delayed gastric emptying and constipation, occur up to 20 years prior to the diagnosis of Parkinson?s disease (PD). The mechanisms and pathophysiology, however, are unclear, which hampers the diagnosis and clinical treatment of PD-related GI dysfunctions. Many studies show that prolonged environmental exposure to toxins predisposes individuals to the development of Parkinson?s disease. The present proposal aims to investigate the neural pathophysiology of gastric dysmotility induced by exposure to subthreshold doses of environmental factors known to induce PD at significantly higher doses. Results from these studies will provide important translational information that will be used to target gastric dysfunctions in Parkinsonian patients specifically, and may provide a potential means by which vulnerable patients may be identified prior to the development of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055530-17
Application #
9516998
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
1998-09-05
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
17
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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