Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071

Abstract

Rationale In addition to the disease-defining motor symptoms, patients with Parkinson's disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. 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. Rats with dual cholinergic-DA losses ("DL rats") were previously demonstrated to model PD falls and associated impairments of gait and balance. Objectives We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats. Results Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. 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. Conclusions 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.

Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease

“…These factors likely account for their relatively modest effects on cognitive impairments and little effect on gait-balance impairments (Mancini et al, 2019;Seppi et al, 2019). Both preclinical and clinical experiments suggests that subtype specific agonists are worth pursuing for treatment of these DRT-refractory features of PD (Albin et al, 2021;Koshy Cherian et al, 2019;Kucinski and Sarter, 2021).…”

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

“…M1 potentiation effects may correlate with enhanced function of cortical, hippocampal, and striatal circuits associated with executive function and cognition (23). An M1 PAM ameliorated falls in a rat model of Parkinson's disease gait-balance disorders (75). Similarly, combination therapy with a cholinesterase inhibitor and a subtype selective serotonin receptor antagonist reduced falls in the same model (76).…”

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

“…Apart from the nAchR, preclinical studies have also evaluated muscarinic M1 acetylcholine receptors (mAchRs) as a potential neural target, especially in view of their putative role in the cognitive-motor aspects of gait and balance. Using rat models, administration of the M1 mAchR PAM TAK-071 was shown to be beneficial in reducing falls [ 72 ]. Currently, a Phase 2 study involving healthy controls and PD patients at risk for falls is being conducted to test the efficacy and safety of this agent in improving balance and reducing the propensity for falls (NCT04334317) [ 73 ].…”