Abstract
Zonisamide, an anti-epileptic and anti-Parkinson's disease drug, displays neurotrophic activity on cultured motor neurons and facilitates axonal regeneration after peripheral nerve injury in mice, but its underlying mechanisms remain unclear. In this study, zonisamide enhanced neurite outgrowth from cultured adult rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner (1 μM < 10 μM < 100 μM), and its activity was significantly attenuated by co-treatment with a phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002 or a mitogen-activated protein kinase (MAPK) inhibitor U0126. In agreement with these findings, 100 μM zonisamide for 1 h induced phosphorylation of AKT and ERK1/2, key molecules of PI3K and MAPK signaling pathways, respectively in mouse neuroblastoma × rat DRG neuron hybrid cells ND7/23. In contrast, zonisamide failed to promote proliferation or migration of immortalized Fischer rat Schwann cells 1 (IFRS1). These findings suggest that the beneficial effects of zonisamide on peripheral nerve regeneration may be attributable to its direct actions on neurons through PI3K and MAPK pathways, rather than the stimulation of Schwann cells.