Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice
| Autor: | Li Yue, Chia George Hsu, John C. Elfar, Mark Noble, Loel C Turpin, M A Hassan Talukder |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
functional recovery electron microscopy of nerves Inflammation sciatic nerve denervation injury Nerve conduction velocity lcsh:RC346-429 03 medical and health sciences Route of administration 0302 clinical medicine Developmental Neuroscience Medicine 4-aminopyridine lcsh:Neurology. Diseases of the nervous system Denervation oral administration business.industry Multiple sclerosis medicine.disease Muscle atrophy 030104 developmental biology muscle mass muscle force Anesthesia Peripheral nerve injury gene expression Crush injury pharmacokinetics sciatic nerve crush injury medicine.symptom business 030217 neurology & neurosurgery Research Article |
| Zdroj: | Neural Regeneration Research, Vol 15, Iss 11, Pp 2098-2107 (2020) Neural Regeneration Research |
| ISSN: | 1673-5374 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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