Reducing falls in Parkinson's disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. (18th August 2016)

• Record Type: Journal Article
• Authors: Kucinski, Aaron; de Jong, Inge E. M.; Sarter, Martin
• Editors: Foxe, John
• Is Part Of: European journal of neuroscience. Volume 45:Number 2(2017)
• Page Start: 217
• Page End: 231
• Publication Date: 2016-08-18
• Subjects: attention -- donepezil -- falls -- idalopirdine -- Parkinson's disease -- rat; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13354
• Languages: English
• ISSNs: 0953-816X

Abstract

Abstract: Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa‐insensitive cause of hospitalization and long‐term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic–dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5‐HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro‐cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle‐treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall‐prone moments suggested that this treatment improved the efficacy and speed of re‐instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait. Abstract : Following short freezes, rats with dual cortical cholinergic and striatal dopaminergic deafferentation resumed forward movement relatively slowly, generally with the tail positioned relatively low and with a slouched posture, yielding slips and falls. When treated with donepezil and idalopirdine (DON + IDL), such rats resumed forward movement, sometimes starting with a hop, they quickly regaining regular traversal speed and fluid forward movement, with high and firm tail position and upright posture, thereby preventing slips and falls.