LAUSR

Abstract Parkinson's disease (PD), the second most common age‐related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an‐anti‐convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO‐B). However, zonisamide has additional targets, including voltage‐gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post‐mortem PD brain and of mice treated with the parkinsonism‐inducing neurotoxin MPTP. Administration of zonisamide (20 mg/kg, i.p. every 4 h × 3) following a single injection of MPTP (12.5 mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba‐1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro‐inflammatory cytokine TNF‐&agr; and gp91phox, and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down‐regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO‐B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation. HighlightsNav 1.6 is highly expressed in activated microglia.Zonisamide decreases microglial Nav 1.6 expression.Zonisamide reduces neuroinflammation.