Ma Lin, Pan Lizhen, Liu Wuchao, Liu Ying, Xiang Xuerui, Pan Yougui, Zhang Xiaolong, Jin Lingjing
Department of Interventional Radiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Neurotoxin Research Center, Tongji University School of Medicine, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education of the People's Republic of China, Shanghai, China.
Front Cell Dev Biol. 2020 Jan 30;8:15. doi: 10.3389/fcell.2020.00015. eCollection 2020.
Botulinum neurotoxin (BoNT) has become a powerful therapeutic tool, and is extensively used in aesthetic medicine and in the treatment of neurological disorders. However, its duration of effect is limited, mainly owing to nerve sprouting. Inhibition of nerve sprouting to prolong the effective duration of BoNT is therefore of great clinical interest. However, appropriate interventional strategies to accomplish this are currently unavailable. In this study, we determined the role of the neurogenic regulator agrin in BoNT type A (BoNT/A)-induced nerve sprouting in a rat model. We then determined whether agrin could be used as an interventional target for prolonging the duration of effect of BoNT/A, and made a preliminary study of the upstream and downstream regulatory mechanisms by which agrin could influence the effective duration of BoNT/A. Our results showed that agrin was involved in the regulation of BoNT/A-induced nerve sprouting, and blocking of agrin function with anti-agrin antibody temporarily could delay muscle strength recovery and prolong the duration of BoNT/A effect. Moreover, agrin influenced the duration of BoNT/A effect by regulating downstream myogenic muscle-specific receptor tyrosine kinase (MuSK), and was simultaneously regulated by upstream miR-144. In conclusion, agrin could regulate BoNT/A-induced nerve sprouting through miR-144-agrin-MuSK signaling; it influences the effective duration of BoNT/A, and could find clinical application as an interventional target for prolonging the effect of BoNT/A.
肉毒杆菌神经毒素（BoNT）已成为一种强大的治疗工具，广泛应用于美容医学和神经系统疾病的治疗。然而，其作用持续时间有限，主要是由于神经发芽。因此，抑制神经发芽以延长BoNT的有效持续时间具有重大的临床意义。然而，目前尚无实现这一目标的合适干预策略。在本研究中，我们在大鼠模型中确定了神经源性调节因子聚集蛋白在A型肉毒杆菌毒素（BoNT/A）诱导的神经发芽中的作用。然后，我们确定聚集蛋白是否可以作为延长BoNT/A作用持续时间的干预靶点，并对聚集蛋白影响BoNT/A有效持续时间的上下游调节机制进行了初步研究。我们的结果表明，聚集蛋白参与了BoNT/A诱导的神经发芽的调节，用抗聚集蛋白抗体暂时阻断聚集蛋白功能可延迟肌肉力量恢复并延长BoNT/A的作用持续时间。此外，聚集蛋白通过调节下游的成肌细胞特异性受体酪氨酸激酶（MuSK）影响BoNT/A的作用持续时间，同时受上游miR-144的调节。总之，聚集蛋白可通过miR-144-聚集蛋白-MuSK信号通路调节BoNT/A诱导的神经发芽；它影响BoNT/A的有效持续时间，并有望作为延长BoNT/A作用的干预靶点应用于临床。
