The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6

Muhammad M. Hossain, Blair Weig, Kenneth Reuhl, Marla Gearing, LongJun Wu, Jason R. Richardson

Research output: Contribution to journalArticle

8 Scopus citations

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-α 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.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalExperimental Neurology
Volume308
DOIs
StatePublished - Oct 1 2018

Keywords

  • gp91
  • Microglia
  • MPTP
  • Na1.6
  • Neuroinflammation
  • Parkinson's disease
  • TNF-α
  • Voltage-gated sodium channels
  • Zonisamide

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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