Funded Studies
Objective/Rationale:
Recently it has been suggested that ingested environmental toxins may trigger a series of events, starting in the gastrointestinal tract, that eventually result in Parkinson’s disease. Gastrointestinal dysfunctions have been recognized as occurring in many parkinsonian patients at early stages of the disease. The present project will test the hypothesis that lectins, a chemical component of many dietary plants, may themselves be the environmental toxin or, by virtue of their properties, may facilitate the entry into the brain of an unknown pathogen responsible for the development of gastrointestinal dysfunctions in environmentally-related Parkinson’s disease.
Project Description:
Pre-clinical models will be fed (three-seven consecutive days) with lectins conjugated with an identifiable tracer. Following a period of time sufficient for appropriate absorption and transport into the central nervous system, the models will be tested for proper functionality of the gastrointestinal tract using state-of-the-art techniques adapted from clinical studies (13C- breath test to study gastric emptying rate) or developed specifically for studies in experimental conditions (gastric motility studies using a miniaturized strain-gauge). At the end of the experiments, the esophagus, stomach and intestinal tissues, together with the brain will be extracted and analyzed for markers of parkinsonian-like degeneration or pathologies that can be connected to gastrointestinal dysfunctions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The proposed studies will investigate the potential first route of access of environmental toxins into the body and first site of central neuronal damage in Parkinson’s disease. Understanding the etiology of Parkinson’s disease will provide a valuable means by which the onset of Parkinson’s disease can be monitored, described and, potentially, provide a rationale for early therapeutic intervention.
Anticipated Outcome:
Idiopathic Parkinson’s disease is multifactorial in origin. Several lines of evidence suggest that environmental toxins might trigger a progressive degeneration of neural pathways starting from the periphery, entering the central nervous system and eventually causing degeneration of higher areas, such as the substantia nigra, known to relate to the typical parkinsonian movement disorders. In the present project we will test the hypothesis that lectins are themselves the environmental toxin or will facilitate the transport of as-yet-unidentified toxins into a susceptible organism.
Final Outcome
Feeding pre-clinical models with different concentrations (0.05-0.1-0.2%) of lectins from Pisum Sativum induced alterations in gastric motility reminiscent of the dismotility observed in PD patients. In particular, in the groups tested we observed a lectin-induced gastric emptying that was significantly delayed with respect to the gastric emptying observed in age-matched untreated (i.e. control) groups. Interestingly, if the lectin feeding session were conducted in young pre-clinical models, i.e. starting immediately after weaning, the delayed gastric emptying occurred ~7 weeks later; if the lectin feeding session were conducted in juvenile pre-clinical models, i.e. approximately a month after weaning, it took ~13 weeks to observe a delayed gastric emptying; conversely, if the lectin feeding session were conducted in adult pre-clinical models, we did not observe gastric emptying alterations during the 14 weeks of the experiment. These data suggest that there is a critical period of exposure to lectins, i.e. young/juvenile age, which appears to make the pre-clinical model more susceptible to the environmental insult.
Further we investigated the effects of degeneration of the substantia nigra on gastric emptying and motility. We observed that, indeed, degeneration of the substantia nigra induced a gastric dysmotility that was reminiscent of that observed in PD patients. The gastric dysmotility was accompanied by severe alterations of the physiology and neurochemistry of the brain-gut axis.
With those data in mind, we embarked on testing whether the animals fed with lectins were showing the same physiological and neurochemical alterations observed upon chemically-induced degeneration of the substantia nigra. Initial data suggests there is an altered gastric motility response upon administration of drugs known to affect gastric motility via the brain-gut axis. In particular, the response to microinjections of tyramine, a drug whose mechanism of action includes the release of dopamine in brain areas, is reduced significantly in the lectin fed animals. We interpreted these data as an indication of altered dopaminergic functionality, similar to what seen in PD patients. The neurochemical analysis of tissues from lectin fed animals is still ongoing.