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.

Zonisamide-loaded triblock copolymer nanomicelles as a novel drug delivery system for the treatment of acute spinal cord injury

“…44 In addition to the antioxidant effects, it was also shown that ZNS has the ability to promote neurite elongation in mouse primary motor neurons in a dosedependent manner. 38 In this study, we found that the axon lengths of neurons were obviously elongated in the ZNS and (Figure 7). Enhanced neurite elongation in primary motor neurons and axonal regeneration may partially account for the enhancements of BDNF and Ntrk2 by ZNS, 38 although the underlying mechanisms remain unknown.…”

“…38 In this study, we found that the axon lengths of neurons were obviously elongated in the ZNS and (Figure 7). Enhanced neurite elongation in primary motor neurons and axonal regeneration may partially account for the enhancements of BDNF and Ntrk2 by ZNS, 38 although the underlying mechanisms remain unknown.…”

“…A recent study suggested that ZNS is able to enhance neurite elongation and neurite regeneration of primary motor neurons. 38 Thus, we expect that the drug function mechanism of ZNS will play a role in the treatment of SCI.…”

Efficacy of a novel drug, zonisamide, in the modulation of oxidative stress in Parkinson's disease

“…17 In addition, zonisamide has other pharmacological effects, including neuroprotective effects in dopaminergic neurons, 18 neuroprotection against cerebral ischemia, 19 free radical scavenging activities 2021 and protective effects against oxidative stress-induced cell death in primary motor neurons. 22 The findings of the present study suggest that antioxidant effects might induce neuroprotective effects, with regard to increasing levels of urinary 8-OHdG in PD. These results feature several limitations, particularly as the majority of patients received a combination of drugs.…”

“…Although zonisamide has been globally prescribed for the treatment of epilepsy, it is also an effective antiparkinsonian agent, especially for resting tremor, in Japan . In addition, zonisamide has other pharmacological effects, including neuroprotective effects in dopaminergic neurons, neuroprotection against cerebral ischemia, free radical scavenging activities and protective effects against oxidative stress‐induced cell death in primary motor neurons . The findings of the present study suggest that anti‐oxidant effects might induce neuroprotective effects, with regard to increasing levels of urinary 8‐OHdG in PD.…”