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At the same time, it is also one of the safest therapeutic agents used for the treatment of several human disorders and in aesthetic medicine. Notwithstanding great effectiveness, strategies to accelerate the onset and prolong BoNT\/A action would significantly ameliorate its pharmacological effects with beneficial outcomes for clinical use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Here, we combined BoNT\/A with two fast\u2010acting inhibitors of excitation\u2013contraction coupling inhibitors (ECCI), either the \u03bc\u2010conotoxin CnIIIC or dantrolene, and tested the effect of their co\u2010injection on a model of hind\u2010limb paralysis in rodents using behavioural, biochemical, imaging and electrophysiological assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The BoNT\/A\u2010ECCI combinations accelerated the onset of muscle relaxation. Surprisingly, they also potentiated the peak effect and extended the duration of the three BoNT\/A commercial preparations OnabotulinumtoxinA, AbobotulinumtoxinA and IncobotulinumtoxinA. ECCI co\u2010injection increased the number of BoNT\/A molecules entering motoneuron terminals, which induced a faster and greater cleavage of SNAP\u201025 during the onset and peak phases, and prolonged the attenuation of nerve\u2010muscle neurotransmission during the recovery phase. We estimate that ECCI co\u2010injection yields a threefold potentiation in BoNT\/A pharmacological activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Overall, our results show that the pharmacological activity of BoNT\/A can be combined and synergized with other bioactive molecules and uncover a novel strategy to enhance the neuromuscular effects of BoNT\/A without altering the neurotoxin moiety or intrinsic activity, thus maintaining its exceptional safety profile.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17367","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T01:25:12Z","timestamp":1728609912000},"page":"564-580","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Excitation\u2013contraction coupling inhibitors potentiate the actions of botulinum neurotoxin type A at the neuromuscular 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