lnvestigating intestinal smooth muscle dysfunction in the 6-OHDA rat model of Parkinson's disease
The neurodegenerative progression of the nigrostriatal pathway in Parkinson’s disease (PD) entails the appearance of motor and nonmotor symptoms. Nonmotor symptoms are common, having a negative impact on the quality of life of patients living with PD. Among these symptoms, autonomic dysfunction is particularly bothersome affecting the intestinal function. This thesis explores the role of the smooth muscle in the impaired enteric neurotransmission seen in PD using the 6-hydroxydopamine (6-OHDA) rat model, a well-standardized and validated model of PD. A priori experimental revision of the model demonstrated that a commonly used neuroprotective drug in 6-OHDA rat stereotaxic surgery, desipramine, interferes with the peripheral assessment of urinary bladder and intestinal motility. Therefore, it was omitted to minimize confounding factors when studying peripheral autonomic dysfunction. Ileal and colonic dysfunction was assessed by electrical field-, cholinergic, and monoaminergic stimulation in smooth muscle strips and/or segments. Colonic enhancement of electrically-induced and cholinergic-evoked contractile responses was found, correlating with previously described upregulation of muscarinic receptors. Moreover, this cholinergic impairment shown to be related to altered inhibitory signaling. In addition, serotonergic neuromodulation displayed alterations in both colon and ileum following central dopamine lesion. Catecholaminergic-induced intestinal motility, however, showed no differences despite previous studies identifying a reduction of dopaminergic and noradrenergic neurotransmission. These findings increase the understanding of complex interactions between enteric neurotransmitters after central dopamine neurodegeneration affecting the intestinal function and may contribute in the future to discover novel therapeutic approaches based on these interactions.
Parts of work
Murillo, M.D.P., Aronsson, P., Winder, M., Carlsson, T. Desipramine, commonly used as a noradrenergic neuroprotectant in 6-OHDA-lesions, leads to local functional changes in the urinary bladder and gastrointestinal tract in healthy rats. Heliyon. 6: e05472. https://doi.org/10.1016/j.heliyon.2020.e05472Murillo, M.D.P., Johansson, E., Bryntesson, V., Aronsson, P., Tobin, G., Winder, M., Carlsson, T. Alterations in smooth muscle function of colonic segments in the 6-hydroxydopamine rat model of Parkinson’s disease.Murillo, M.D.P., Aronsson, P., Tobin, G., Winder, M, Carlsson, T. Monoaminergic smooth muscle responses in colonic and ileal segments in the 6-hydroxydopamine rat model of Parkinson’s disease.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Institute of Neuroscience and Physiology. Department of Pharmacology
Onsdagen den 15 juni 2022, kl. 13.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg
Date of defence
Murillo Angarita, Maria del Pilar
enteric nervous system