Investigating a Novel Strategy to Potentiate Botulinum Neurotoxin Therapy Using Excitation-Contraction Coupling Inhibitors

Botulinum neurotoxin type A1 (BoNT/A1) is a potent neurotoxin widely used in clinics and aesthetic medicine to attenuate neuromuscular activity. Despite the numerous advantages of this treatment, accelerating and prolonging the pharmacological effect of BoNT/A1 in neuromuscular applications could improve its efficacy. This study investigated the effects of combining BoNT/A1 with fast-acting muscle blockers, notably excitation-contraction coupling inhibitors (ECCIs), including μ-conotoxin IIIC (CnIIIC) and dantrolene (DAN). In addition to accelerating the onset of myorelaxation, the BoNT/A1-ECCI combination enhanced the peak effect and prolonged the duration of BoNT/A1 pharmacological action. This effect, which is associated to an increased number of BoNT/A1 molecules entering the motor neuron, is applicable to different formulations, and can be achieved using various postsynaptic blockers. Overall, these findings highlighted a novel strategy to potentiate BoNT pharmacological action in neuromuscular applications, while preserving its safety, through rapid inhibition of muscle contraction.