This grant builds upon the research from a prior grant: Evaluation of gastrointestinal motility in parkinsonian rodents
Objective/Rationale:
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 and also negatively affect PD motor symptoms. Unfortunately, there is a dearth of information concerning the causes and treatment of GI symptoms in PD because there is no laboratory model known to mimic the GI symptoms.
Project Description:
In the setting of a collaboration between the Depts. of Neurology (Movement disorders) and Medicine (GI division), we will evaluate GI function in rodents rendered ‘parkinsonian’ by environmental toxins or genetic abnormalities. In both humans and rodents, GI motility is under the control of a separate, relatively autonomous, ‘enteric nervous system’ (ENS) located in the stomach and intestines 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 physical damage.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Treatment of GI problems in PD patients is very difficult and rarely complete. Knowing which types of GI nerve cells are damaged in PD rodents will allow us to propose new treatments with a higher likelihood of success. An animal system that mimics parkinsonian GI dysfunction would provide a platform for testing such a treatment.
Anticipated Outcome:
We anticipate that Parkinson’s rodents will have damage to GI nerve cells resulting in abnormal GI function. Determining the type of nerve damage and the GI symptoms related to it will provide valuable information for treatment of GI symptoms in patients with PD.
Final Outcome
Having previously received MJFF funding to demonstrate GI abnormalities in two rodent models of PD, Dr. Greene went on to demonstrate that the model exposed to an environmental toxin displayed delayed gastric emptying, a prominent GI symptom in PD patients. This behavioral abnormality occurred prior to any motor abnormalities and was associated with dysfunction in the enteric nervous system. This has provided an animal model for delayed gastric emptying in PD potentially useful for testing therapeutic compounds.
In addition, the model whose parkinsonism was induced by genetic abnormalities was shown to express synuclein in the enteric nervous system in a distribution similar to that seen in human PD, possibly providing a neuropathological model for synuclein accumulation in the GI tract that is commonly observed in PD.
Results of this project were published in the journal Experimental Neurology.
Researchers
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Jim Greene, MD, PhD