Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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Abstract

Congenital Myasthenic Syndromes (CMS) are a set of genetic diseases that affect the neuromuscular transmission causing muscular weakness. The standard pharmacological treatment aims at ameliorating the myasthenic symptom by acetylcholinesterase inhibitors. Most patients respond well in the short and medium term, however, over time the beneficial effects rapidly fade, and the efficacy of the treatment diminishes. Increasing evidence shows that β2-adrenergic agonists can be a suitable choice for the treatment of neuromuscular disorders, including CMS, as they promote beneficial effects in the neuromuscular system. The exact mechanism on which they rely is not completely understood, although patients and animal models respond well to the treatment, especially over extended periods. Here, we report the use of the long-lasting specific β2-adrenergic agonist formoterol in a myasthenic mouse model (mnVAChT-KD), featuring deletion of VAChT (Vesicular Acetylcholine Transporter) specifically in the α-motoneurons. Our findings demonstrate that formoterol treatment (300 μg/kg/day; sc) for 30 days increased the neuromuscular junction area, induced skeletal muscle hypertrophy and altered fibre type composition in myasthenic mice. Interestingly, β2-adrenergic agonists have shown efficacy even in the absence of ACh (acetylcholine). Our data provide important evidence supporting the potential of β2-adrenergic agonists in treating neuromuscular disorders of pre-synaptic origin and characterized by disruptions in nerve-muscle communication, through a direct and beneficial action within the motor unit.

β2-脱能选择性激动剂福莫特罗对伴有完全 VAChT 脱失的遗传性肌萎缩综合征猴子模型运动单元的影响。
先天性肌无力综合征(CMS)是一组影响神经肌肉传导、导致肌肉无力的遗传疾病。标准药物治疗的目的是通过乙酰胆碱酯酶抑制剂改善肌无力症状。大多数患者在短期和中期内反应良好,但随着时间的推移,有益作用会迅速消失,疗效也会减弱。越来越多的证据表明,β2-肾上腺素能激动剂可作为治疗包括 CMS 在内的神经肌肉疾病的合适选择,因为它们能促进神经肌肉系统的有益作用。尽管患者和动物模型对这种疗法反应良好,尤其是在长期治疗中,但它们所依赖的确切机制尚未完全明了。在此,我们报告了在肌无力小鼠模型(mnVAChT-KD)中使用长效特异性 β2-肾上腺素能激动剂福莫特罗的情况。我们的研究结果表明,福莫特罗治疗(300 μg/kg/天;sc)30 天可增加肌无力小鼠的神经肌肉接头面积、诱导骨骼肌肥大并改变纤维类型组成。有趣的是,即使在没有乙酰胆碱(ACh)的情况下,β2-肾上腺素能激动剂也有疗效。我们的数据提供了重要的证据,支持β2-肾上腺素能激动剂通过在运动单元内发挥直接和有益的作用,治疗突触前源性神经肌肉疾病的潜力。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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