Objective/Rationale:
Impaired gastric emptying is commonly found in Parkinson's disease and impacts the effectiveness of oral treatment given to PD patients. Blocking opiate receptors improves the anti-parkinsonian actions of treatment drugs. Our objective is to demonstrate disturbances of gastric transit in an experimental model of PD and to assess whether new peripheral- or whole-body-acting opiate antagonists will improve the altered gastric emptying and normalize the occurrence of treatment drug in the blood.
Project Description:
We will examine alterations of gastric motor function in a pre-clinical model of PD that overexpresses a protein involved in neurodegenerative disease including PD. In Aim 1, we will test whether the PD mice exhibit delayed gastric emptying (GE) compared to non-PD mice. Gastric emptying of a non nutrient semi-liquid meal and nutrient solid food will be monitored using methods that we have developed previously in our lab. Assuming GE is delayed in these mice, in Aim 2 we will use selective drugs that block the opiate receptors either in the whole body, or selectively in the periphery, to examine whether they alleviate the impairment of GE. Lastly, we will administer levodopa orally and test whether those drugs increase the recovery in the blood of treatment drug due to the normalization of transit in the stomach.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Prominent among gastrointestinal (GI) problems caused by Parkinson's disease is delayed GE. The GE fluctuation can greatly reduce the effectiveness of oral levodopa therapy, because the longer levodopa is retained in the stomach, the more the drug is metabolized, and the less drug reaches the duodenum to be absorbed into the blood. Delayed levodopa absorption can result in erratic treatment of the motor symptoms of PD. Our studies will validate the opiate receptor as a new target for drugs to improve treatment efficiency of PD patients.
Anticipated Outcome:
We will 1) further characterize the transgenic PD model as valuable to display alterations of gut transit as commonly observed in PD; 2) Establish in this experimental model that opiate antagonists can be efficient to alleviate these transit disorders; and 3) establish opiate antagonists' association with a better recovery of L-DOPA in the blood. This will provide preclinical evidence to initiate clinical testing with opiate antagonists to improve efficacy of PD treatment.