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首页> 外文期刊>Neural regeneration research >Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice
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Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice

机译：人类量等效剂量的口腔4-氨基吡啶与横衰损伤的神经压碎损伤区分，并改善小鼠后损伤的功能

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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.
机译：4-氨基吡啶（4-AP）是一种用于多发性硬化症的症状治疗的FDA批准的药物，用于改善多元化脱髓鞘疾病患者的神经肌肉功能。我们最近展示了4-AP的局部，透皮或可注射形式的4-AP改善小鼠创伤外周神经损伤后的髓鞘，神经传导速度，肌肉萎缩和电机功能。虽然口腔4-AP是临床中最常用的，但是未知人类等效口服剂量的4-AP是否对动物的创伤周围神经损伤分化，髓鞘导致，肌肉萎缩，功能性回收和动物后损伤后炎症过程有影响。坐骨神经粉碎或非腹腔内的小鼠接受口腔或腹腔4-AP（10μg）或单独的载体，并检查了药代动力学，运动功能，肌肉质量，固有肌肉力，神经形态和基因表达谱。图4-AP显​​示了线性药代动力学和最大血浆4-AP浓度与4-AP剂量成比例。急性单剂量的口服4-AP给药诱导运动功能的快速瞬态改善，在创伤外周神经损伤中有或没有神经连续性，慢性每日口腔4-AP治疗显着增强后粉碎损伤电机功能恢复和这种效果与改善的髓鞘形成，肌肉质量和离体肌肉力相关。具有碎神经的聚合酶链反应阵列分析显示了轴突炎症和再生中的基因的显着改变。这些发现提供了令人信服的证据，即不管给药途径，4-AP可以急性区分创伤性外周神经损伤，或没有神经连续性，可以提高体内功能恢复，并更好地保存髓鞘，肌肉质量和肌肉力。 2017年3月31日，罗切斯特大学（Ucar-2009-019）的动物研究（UCAR）大学委员会批准了动物实验。

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