Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.
Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.
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双结合肉毒杆菌分子与减轻肌肉麻痹：偏头痛的体外和体内模型评价。
DOI：
10.1007/s13311-020-00967-7
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Davletov B
中科院分区：
文献类型：
--
作者：
Andreou AP;Leese C;Greco R;Demartini C;Corrie E;Simsek D;Zanaboni A;Koroleva K;Lloyd JO;Lambru G;Doran C;Gafurov O;Seward E;Giniatullin R;Tassorelli C;Davletov B
偏头痛的患病率为15%，是最常见的神经系统疾病，也是最致残的疾病之一，考虑到残疾的生活年限。目前治疗偏头痛的口服药物效果不一，而且常常伴有难以忍受的副作用，导致患者和医生都不满意。注射疗法，包括降钙素基因相关肽靶向单克隆抗体和肉毒杆菌神经毒素A (BoNT/A)，为治疗慢性偏头痛提供了新的范例，但仅对大约50%的受试者有效。在这里，我们研究了一种新型的工程肉毒杆菌分子，它具有显著减少肌肉麻痹的特性，可能对偏头痛的治疗有益。这种具有重复结合域二元毒素AA （BiTox/AA）的钉接肉毒杆菌分子在神经元中切割突触体相关蛋白25，其效果与BoNT/ a相似；然而，肌肉注射后，与天然BoNT/A相比，BiTox/AA的麻痹效果低100倍。在偏头痛的细胞和动物模型中评估了BiTox/AA的性能。在大鼠脑膜制剂中，BiTox/AA抑制了电神经纤维的活性，而在三叉神经模型中，BiTox/AA提高了a -和c -纤维伤害感受器的电和机械刺激阈值。在大鼠三硝酸甘油（GTN）模型中，BiTox/AA在口面部福尔马林试验中证明对GTN诱导的痛觉过敏有抑制作用。我们的结论是，工程肉毒杆菌分子提供了一个有用的原型，为设计先进的未来治疗方法，以提高治疗偏头痛的疗效。在线版本包含补充材料，可在10.1007/s13311-020-00967-7获得。
With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine. The online version contains supplementary material available at 10.1007/s13311-020-00967-7.
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