靶向神经肌肉传递安全系数治疗重症肌无力

G. L. Odierna, William Phillips
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引用次数: 0

摘要

在重症肌无力中,自身抗体攻击神经肌肉连接处的突触后膜,引起疲劳性无力,这种无力可以减弱或减弱。当神经肌肉传递的安全系数变得微不足道时,即(突触后)终板电位不再足以可靠地触发肌纤维中的动作电位时,就会出现肌无力。胆碱酯酶抑制剂药物通过增加终板电位振幅提供暂时缓解,但需要额外的对症治疗方案。在这里,我们讨论我们最近在候选化合物的早期临床前测试的经验。使用离体小鼠神经肌肉收缩试验,随后是终板电位记录,我们检查了大麻素的作用。我们的研究结果强调了二甲基亚砜(DMSO)作为增溶剂时潜在的混淆效应。DMSO对弯曲肌肉产生剂量依赖性的恢复力,并增强微型终板电位振幅,从而在浓度低至0.1% v/v时增强神经肌肉传递的安全系数。当在没有curare的情况下检查时,dmso诱导的量子振幅增加与神经末梢释放的乙酰胆碱量子数的稳态减少相反。与DMSO相反,大麻素似乎通过大麻素受体1型来减少量子数,从而削弱了安全系数。我们的研究结果强调,在筛选神经系统疾病的新疗法时,需要考虑增溶剂本身的作用。他们还证明需要考虑突触内稳态,否则会扭曲或掩盖生物活性物质对神经传递的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting the safety factor for neuromuscular transmission to treat myasthenia gravis
In myasthenia gravis autoantibodies attack the postsynaptic membrane of the neuromuscular junction causing fatiguing weakness that can wax and wane. Weakness occurs when the safety factor for neuromuscular transmission becomes marginal, meaning that the (postsynaptic) endplate potential is no longer sufficient to reliably trigger action potentials in the muscle fiber. Cholinesterase inhibitor drugs provide temporary relief by increasing the endplate potential amplitude, but additional symptomatic treatment options are needed. Here we discuss our recent experience in early preclinical testing of candidate compounds. Using an ex vivo mouse nerve-muscle contraction assay, followed up by endplate potential recordings, we examined the effects of cannabinoids. Our findings highlighted the potentially confounding effects of dimethylsulfoxide (DMSO) when used as a solubilizing agent. DMSO produced a dose-dependent restoration of force to curarized muscle and enhanced miniature endplate potential amplitude, thus enhancing the safety factor for neuromuscular transmission at concentrations as low as 0.1% v/v. When examined in the absence of curare, the DMSO-induced increase in quantal amplitude was opposed by a homeostatic reduction in the number of quanta of acetylcholine released by the nerve terminal. In contrast to DMSO, cannabinoids appear to work via cannabinoid receptor type 1 to reduce quantal number, thereby weakening the safety factor. Our results highlight the need to consider the effects of solubilizing agents per se when screening new therapeutics for neurological diseases. They also demonstrate the need to take synaptic homeostasis into account, which can otherwise distort or mask the effects of bioactive agents upon neurotransmission.
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