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

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Mickaël Machicoane, Marika Tonellato, Marica Zainotto, Paul Onillon, Marco Stazi, Mattia Dal Corso, Aram Megighian, Ornella Rossetto, Jean-Marc Le Doussal, Marco Pirazzini
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引用次数: 0

Abstract

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.

兴奋-收缩耦联抑制剂可增强 A 型肉毒杆菌神经毒素在神经肌肉接头处的作用。
背景和目的:A1 型肉毒杆菌神经毒素(BoNT/A)是已知最有效的神经毒素之一。同时,它也是用于治疗多种人类疾病和美容医学的最安全的治疗剂之一。尽管BoNT/A具有很强的功效,但如果能加快BoNT/A的起效时间并延长其作用时间,就能显著改善其药理作用,从而对临床应用产生有益的结果:在此,我们将 BoNT/A 与两种快速起效的兴奋-收缩偶联抑制剂(ECCI)(μ-神经毒素 CnIIIC 或丹曲林)相结合,并使用行为学、生物化学、影像学和电生理学实验测试了它们联合注射对啮齿动物后肢麻痹模型的影响:主要结果:BoNT/A-ECCI 组合加速了肌肉松弛的开始。令人惊讶的是,它们还增强了三种 BoNT/A 商业制剂 OnabotulinumtoxinA、AbobotulinumtoxinA 和 IncobotulinumtoxinA 的峰值效应并延长了持续时间。联合注射 ECCI 增加了进入运动神经元末梢的 BoNT/A 分子数量,从而在起始和峰值阶段诱导 SNAP-25 更快、更大程度的裂解,并延长了恢复阶段神经-肌肉神经传递的衰减时间。我们估计,联合注射 ECCI 可使 BoNT/A 的药理活性增强三倍:总之,我们的研究结果表明,BoNT/A 的药理活性可与其他生物活性分子相结合并产生协同效应,同时还发现了一种新的策略,可在不改变神经毒素分子或内在活性的情况下增强 BoNT/A 的神经肌肉效应,从而保持其卓越的安全性。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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