title: Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model.
abstract: No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Bisei
authors.initials: B
authors.lastname: Ohkawara
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kenyu
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mikito
authors.initials: M
authors.lastname: Tsushima
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Hand Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Hand Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Noto
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kyotaro
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Imagama
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000818:Animals; D064592:Autografts / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000078305:Zonisamide
chemical_list: D007555:Isoxazoles; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D000078305:Zonisamide