Given the severe medical consequences of a resulting increase in the propensity for falls, investigating the pathophysiology underlying falls and the development of treatments to reduce fall risk are important objectives (Albin et al.
In addition to the nigrostriatal dopamine (DA) deficiency and the associated efficacy of dopaminergic replacement therapy (DRT) to reduce motor symptoms, progressing Parkinson disease (PD) is characterized by neurodegeneration in non-DA systems and associated DRT nonresponsive features such as gait and balance disorder, postural instability, and cognitive impairments. TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle. As before, DL rats fell more frequently than sham-operated control rats. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats. We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Rats with dual cholinergic-DA losses (“DL rats”) were previously demonstrated to model PD falls and associated impairments of gait and balance. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. In addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls.
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