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

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-HT 6 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.

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

“…Consistent with this possibility, the severity of cholinergic neuronal loss in the PPN correlates with the severity of parkinsonian symptoms in PD and lesions involving the PPN manifest with gait disturbances (Aziz et al, 1998; Rinne et al, 2008). We have recently demonstrated that the combination of idalopirdine and donepezil reduces falls in an animal model of PD with dual dopaminergic and cholinergic lesions (Kucinski et al, 2017). This, together with the activation of the PPT in the current study, would suggest that the combination treatment might have beneficial effects on gait and posture through activation of the brainstem cholinergic system.…”

Falls in Parkinson's disease: A complex and evolving picture

“…An animal model carrying a dual cholinergic‐dopaminergic loss (“DL rats”) was assessed for falls associated with traversing dynamic surfaces and distractors using a behavioral test system (Michigan Complex Motor Control Task) . These models are now used to test medical treatments …”

Compensatory dopaminergic-cholinergic interactions in conflict processing: Evidence from patients with Parkinson's disease

“…For example, in a dual-lesion (cortical-cholinergic and striatal-dopaminergic) model of PD, the cholinergic lesion significantly affected rodents' vulnerability to distraction and falls only in combination with caudate dopaminergic lesions and vice versa -neither cholinergic nor dopaminergic lesions had much impact on these measures by themselves (Kucinski et al, 2013). Pharmacologic enhancement of cholinergic function (donepezil and idalopirdine) improved the ability to recover from distractor effects, especially the ability to re-instate correct performance after a short disruption (Kucinski et al, 2017). In contrast, large dopaminergic lesions (without a cholinergic lesion) led to low vigor for and control over movement, but without apparent effects on attention-motor interactions (Kucinski et al, 2015).…”