Title : In vitro investigations of the antiparkinsonian drug ropinirol properties on muscarinic receptors: A possible link to in vivo side effects
Abstract:
Parkinson's disease (PD), after Alzheimer's, is the second most important age-related neurodegenerative disease whose prevalence and incidence increase almost exponentially with age and reach a peak after the age of 80. PD is primarily characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which translates into progressive declines of motor functions. There are currently no disease-modifying therapies available that slow down or completely stop the neurodegenerative process, but treatments that may offer benefits regarding clinical manifestations. Pharmacological approaches are normally based on the use of Levodopa or D2 dopaminergic agonists able to restore the dopaminergic transmission at the midbrain level. Ropinirole is a non-ergoline, selective agonist for the dopamine D2/D3/D4 receptors with important antiparkinsonian properties. Ropinirole is commonly used for the symptomatic treatment of PD and has been proven to be effective both in monotherapy, in patients in the initial stages of the disease, and in combination therapy, in patients with advanced disease. However, several side effects are associated with Ropinirole treatment including hypotension, sinus node dysfunctions, hallucinations, and bone alteration. In particular, two main side effects of Ropinirole have been noticed on heart: bradycardia and atrial fibrillation. Muscarinic M2 subtype receptor (M2R) is well expressed in cardiomyocytes and is responsible of parasympathetic transmission on heart. The acetylcholine mediated physiological activation of the M2R is well known to induce a decrease in inotropy and bradycardia. Given these considerations, we wanted to explore the possibility that Ropinirole could have a direct effect on the M2 receptors. To this aim, during the last year we run a few experiments that indeed suggested that the M2 receptor could be a potential Ropinirole therapy off-target. Our preliminary results indicate that Ropinirole can increase ERK phosphorylation in cells that overexpress the M2 receptor subtype. In addition, Ropinirole causes the M2 internalization suggesting its potential binding to muscarinic M2 receptors and consequence functions.
Audience Take Away Notes:
- In this project, we aim at investigating ex-vivo, potential side effects of the antiparkinsonian Ropinirole.
- This project aims to understand the any muscarinic receptor signaling contribution in the effects of Ropinirole on heart cells.
- Our results could explain the side effects of Ropinirole treatment in PD patients.
