Gastrointestinal (GI) symptoms, such as nausea, bloating, and constipation occur in nearly every patient afflicted with Parkinson's Disease (PD) at some point in their illness. These symptoms on their own have a negative impact on quality of life, but they also affect other PD symptoms. For example, abnormal stomach coordination can cause erratic absorption of oral medications, contributing to motor fluctuations and medication side-effects.
Despite the important consequences that malfunction of the GI tract has for PD patients, there is a dearth of information concerning the pathophysiology and treatment of GI symptoms in PD because there is no laboratory model known to mimic the GI symptoms.
We propose to investigate the underlying mechanisms of GI dysfunction in PD by developing a laboratory animal model of the disorder. In the setting of a collaboration between the Depts. of Neurology (Movement disorders) and Medicine (GI division), we will evaluate rodents rendered 'parkinsonian' by environmental toxins or genetic abnormalities. GI function will be evaluated using behavioral and electrophysiological techniques, including methods to evaluate stomach emptying, bowel motility, colon function, and constipation. In both humans and rodents, these functions are under the control of a separate, relatively autonomous, nervous system located in the stomach and intestines called the "enteric nervous system", or ENS, that contains nearly as many nerve cells as the brain. We will examine the ENS in parkinsonian rodents using antibody techniques that label specific populations of ENS cells to determine which nerve cells are damaged and thus responsible for causing the GI symptoms. Armed with this novel pathological information, we will return to evaluation of live animals and tissue to confirm the functional relevance of the neuropathological abnormalities. These experiments will allow us to propose and test rational therapeutic agents for normalization of GI function in PD.
Final Outcome
Dr. Greene demonstrated altered gastrointestinal function and loss of enteric dopamine neurons in rodents exposed to an environmental toxin. In addition, rodents with genetic abnormalities giving rise to parkinsonism were also discovered to have altered gastrointestinal function. This work resulted in two potential pre-clinical models for understanding GI dysfunction in PD as well as for testing potential therapeutic agents aimed at this symptom.
Results of this project were published in the journals Experimental Neurology and the Journal of Neuroscience. Additionally, Dr. Greene received supplemental funding from MJFF to further characterize GI abnormalities in these models.
Researchers
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Jim Greene, MD, PhD