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.
Highlights
Motor paralyses due to damage to the peripheral and central nervous systems, especially those due to motor nerve damage, cause serious disabilities in ADL, but no PLOS ONE | DOI:10.1371/journal.pone.0142786 November 16, 2015Zonisamide Enhances Neurite Elongation of Primary Motor NeuronsAbbreviations: FDA, Food and Drug Administration; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; HCS, high content screening; GABA, gamma-aminobutyric acid.effective treatment has been established for this condition
The cells were fixed after 48 h of culture, and the axons were fluorescently immunostained for Tau, followed by automatic measurement of the neurite lengths using the ArrayScan VTI HCS Reader
We found that zonisamide consistently elongated neurites of primary motor neurons (S1 Fig)
Summary
Motor paralyses due to damage to the peripheral and central nervous systems, especially those due to motor nerve damage, cause serious disabilities in ADL (activities of daily living), but no PLOS ONE | DOI:10.1371/journal.pone.0142786 November 16, 2015Zonisamide Enhances Neurite Elongation of Primary Motor Neuronseffective treatment has been established for this condition. Laminins and cadherin-11 promote the axonal elongation of motor neurons [5,6,7,8] These molecules, cannot be used in clinical settings, because local administration would be the only available option and their half-lives in our body are very short [9,10,11]. Small molecule compounds that were reported to improve motor nerve damage include ibuprofen, a non-steroidal anti-inflammatory drug [20]; valproic acid, an anti-epileptic drug [21]; and Y27632, an inhibitor of Rho-associated kinase (ROK) [22] These are promising compounds, none has yet been available in clinical settings
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