Gastrointestinal and Urinary Dysfunction in Animal Models of Parkinson's Disease

Parkinson’s disease (PD) is a common neurodegenerative disease resulting from the loss of dopaminergic neurons in the nigrostriatal tract. Classical motoric symptoms of tremor, instability, hunched posture, and slowness of movement are most commonly associated with the disease. Non-motor symptoms (NMS) of PD have historically been under-recognised, despite mentions of many NMS such as sleep disturbances, autonomic dysfunction, and pain in James Parkinson’s original description of the disease. NMS are also largely treated currently by symptomatic therapies. Holistic treatments are not possible due to our lack of understanding of the link between pathophysiology of motor and non-motor symptoms. Gastrointestinal and urinary symptoms greatly affect the quality of life of patients with PD and present important challenges to the management of the disease as it progresses. The most frequently reported issues with these systems are bladder dysfunction in the form of nocturia, increased frequency, increased urgency and gastrointestinal dysfunction presenting as constipation, excess salivation and dysphagia. Research into NMS is necessary not only to aid therapeutic intervention to the debilitating symptoms, but to understand at risk populations and identify biomarkers for progression of disease. We have chosen to use different models of Parkinson’s disease in different animals to unearth common changes in their pathology which may lead to GI dysfunction. We have looked at models with differing extents of pathology, as NMSs are present at various stages of the disease. Our work has focussed on evaluation of overt local adaptive changes that may occur because of central dopaminergic loss, using various ex vivo assays. To characterise the functional effects of Kv7 modulation in the gastrointestinal tract we used a mouse ex vivo motility assay. We determined that pharmacological inhibition of Kv7 channels increased peristaltic like motor activity and Kv7 activation diminished peristaltic like motor activity in the ileum and colon. Kv7.4 expression was visualised to be present on smooth muscle cells and myenteric neurons of the gastrointestinal tract via. In the same ex vivo assay set up we found that the ileum of MPTP treated animals were more active in our motility assay compared to the ileum tissue from sham treated controls. Animals treated with 6-OHDA intrastriatally, to induce a partial lesion, showed significant changes in the dorsal motor nucleus of vagus (DMV) and alterations in nitrergic transmission in the bladder and ileum. We also observed functional consequences of increased Kv7 channel expression in the bladder. Finally, rare tissues obtained from MPTP treated marmoset revealed a potential vulnerability to neurodegenerative insults in dopaminergic neurons of the substantia nigra that contain the Kv7.4 channel. The Kv7.4 channel was also affected in peripheral tissues in this model with reduced expression in various cell types of the ileum and increased expression in the bladder detrusor muscle. The results suggest that central nigrostriatal dopaminergic denervation is associated with overactivity in both the bladder and ileum in these models. This can result in dysregulated smooth muscle motor activity, leading to gastrointestinal and urinary dysfunction such as constipation and urinary urgency. The mechanisms that we have uncovered here require further validation, to assess their role in the human condition, and understand whether they can be targeted to alleviate the autonomic symptoms of PD. Our findings will hopefully enable future assessments to be performed in human samples and lead to a translational path from pre-clinical to clinical therapeutic interventions.