Excitation-contraction coupling inhibitors potentiate the actions of botulinum neurotoxin type A at the neuromuscular junction.

Autor: Machicoane M; Fastox Pharma SA, Lausanne, Switzerland., Tonellato M; Department of Biomedical Sciences, University of Padova, Padova, Italy., Zainotto M; Department of Biomedical Sciences, University of Padova, Padova, Italy., Onillon P; Fastox Pharma SA, Lausanne, Switzerland., Stazi M; Department of Biomedical Sciences, University of Padova, Padova, Italy., Corso MD; Department of Biomedical Sciences, University of Padova, Padova, Italy., Megighian A; Department of Biomedical Sciences, University of Padova, Padova, Italy.; Padova Neuroscience Center, University of Padova, Padova, Italy., Rossetto O; Department of Biomedical Sciences, University of Padova, Padova, Italy.; Institute of Neuroscience, Italian Research Council, University of Padova, Padova, Italy.; Interdepartmental Research Center of Myology CIR-Myo, University of Padova, Padova, Italy., Le Doussal JM; Fastox Pharma SA, Lausanne, Switzerland., Pirazzini M; Department of Biomedical Sciences, University of Padova, Padova, Italy.; Interdepartmental Research Center of Myology CIR-Myo, University of Padova, Padova, Italy.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1111/bph.17367
Abstrakt: Background and Purpose: Botulinum neurotoxin type A1 (BoNT/A) is one of the most potent neurotoxins known. 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.
Experimental Approach: Here, we combined BoNT/A with two fast-acting inhibitors of excitation-contraction coupling inhibitors (ECCI), either the μ-conotoxin CnIIIC or dantrolene, and tested the effect of their co-injection on a model of hind-limb paralysis in rodents using behavioural, biochemical, imaging and electrophysiological assays.
Key Results: The BoNT/A-ECCI 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-injection increased the number of BoNT/A molecules entering motoneuron terminals, which induced a faster and greater cleavage of SNAP-25 during the onset and peak phases, and prolonged the attenuation of nerve-muscle neurotransmission during the recovery phase. We estimate that ECCI co-injection yields a threefold potentiation in BoNT/A pharmacological activity.
Conclusions and Implications: 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.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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