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

• Type of Material: Article
• Authors: Muhammad M. Hossain, Northeast Ohio Medical University; Blair Weig, Rutgers State University; Kenneth Reuhl, Rutgers State University; Marla Gearing, Emory University; Long-Jun Wu, Mayo Clinic; Jason R. Richardson, Northeast Ohio Medical University
• Language: English
• Date: 2018-10-01
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.expneurol.2018.07.005
• Title of Journal or Parent Work: EXPERIMENTAL NEUROLOGY
• Volume: 308
• Start Page: 111
• End Page: 119
• Grant/Funding Information: This work was supported in part by the following NIH Grants: R01ES021800, R01NS088627, P30ES005022, U01NS079249, P30NS055077 and P50AG025688. Additional support was provided by the Michael J Fox Foundation and private support from the Glenn and Karen Leppo Parkinson's Research Fund, the Richard Nicely Parkinson's Research Fund and the Alan and Janice Woll Parkinson's Research Fund.
• Keywords: Microglia; MPTP-INDUCED NEUROINFLAMMATION; Parkinson's disease; IN-VIVO; Science & Technology; Voltage-gated sodium channels; OXIDATIVE STRESS; ACTIVATION; Life Sciences & Biomedicine; NERVOUS-SYSTEM; Neuroinflammation; ANTIEPILEPTIC DRUG; GATED SODIUM-CHANNELS; TNF-alpha; MPTP; ALZHEIMERS-DISEASE; EXPRESSION; Zonisamide; Neurosciences; MODEL; Neurosciences & Neurology; gp91(phox); Na(v)1.6
• Research Categories: Psychology, Cognitive; Biology, Neuroscience

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 (Na v ), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Na v 1.6 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 Na v 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 gp91 phox , and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Na v 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 Na v 1.6 and neuroinflammation.