Hsu Chia George, Talukder M A Hassan, Yue Li, Turpin Loel C, Noble Mark, Elfar John C
Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Center for Orthopaedic Research and Translational Science, Penn State Hershey College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
Neural Regen Res. 2020 Nov;15(11):2098-2107. doi: 10.4103/1673-5374.280319.
4-Aminopyridine (4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP (10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research (UCAR) at the University of Rochester (UCAR-2009-019) on March 31, 2017.
4-氨基吡啶（4-AP）是一种经美国食品药品监督管理局（FDA）批准用于多发性硬化症症状治疗的药物，用于改善患有各种脱髓鞘疾病患者的神经肌肉功能。我们最近证明，局部、经皮或注射形式的4-AP可改善小鼠创伤性周围神经损伤后的髓鞘形成、神经传导速度、肌肉萎缩和运动功能。虽然口服4-AP在临床上最为常用，但尚不清楚与人类等效的口服剂量4-AP对动物创伤性周围神经损伤的分化、髓鞘形成、肌肉萎缩、功能恢复以及损伤后炎症过程是否有影响。坐骨神经挤压或去神经损伤的小鼠接受口服或腹腔注射4-AP（10μg）或单独的赋形剂，并检测其药代动力学、运动功能、肌肉质量、固有肌力、神经形态和基因表达谱。4-AP显示出线性药代动力学，血浆4-AP最大浓度与4-AP剂量成正比。急性单次口服4-AP给药可使运动功能迅速短暂改善，这在有或没有神经连续性的创伤性周围神经损伤中有所不同，慢性每日口服4-AP治疗可显著增强挤压伤后运动功能的恢复，且这种作用与髓鞘形成改善、肌肉质量和离体肌肉力量增加有关。对挤压神经进行聚合酶链反应阵列分析发现，参与轴突炎症和再生的基因有显著改变。这些发现提供了令人信服的证据，即无论给药途径如何，4-AP均可急性区分有或没有神经连续性的创伤性周围神经损伤，并可增强体内功能恢复，更好地保留髓鞘、肌肉质量和肌肉力量。动物实验于2017年3月31日获得罗切斯特大学动物研究大学委员会（UCAR）批准（UCAR-2009-019）。
