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Text
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URL Address
<a href="http://doi.org/10.1016/j.expneurol.2018.07.005" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.expneurol.2018.07.005</a>
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Pages
111-119
Volume
308
Dublin Core
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Title
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The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6.
Publisher
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Experimental neurology
Date
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2018
2018-10
Subject
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Female; Humans; Male; Animals; Mice; Aged; *gp91(phox); *Microglia; *MPTP; *Na(v)1.6; *Neuroinflammation; *Parkinson's disease; *TNF-alpha; *Voltage-gated sodium channels; *Zonisamide; Inflammation/metabolism; Neuroprotective Agents/pharmacology; Antiparkinson Agents/*pharmacology; Inbred C57BL; Microglia/drug effects/*metabolism; NAV1.6 Voltage-Gated Sodium Channel/*biosynthesis; Parkinsonian Disorders/*metabolism/pathology; Zonisamide/*pharmacology
Creator
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Hossain Muhammad M; Weig Blair; Reuhl Kenneth; Gearing Marla; Wu Long-Jun; Richardson Jason R
Description
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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 (20mg/kg, i.p. every 4hx3) following a single injection of MPTP (12.5mg/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-alpha 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 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.
Identifier
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<a href="http://doi.org/10.1016/j.expneurol.2018.07.005" target="_blank" rel="noreferrer noopener">10.1016/j.expneurol.2018.07.005</a>
*gp91(phox)
*Microglia
*MPTP
*Na(v)1.6
*Neuroinflammation
*Parkinson's disease
*TNF-alpha
*Voltage-gated sodium channels
*Zonisamide
2018
Aged
Animals
Antiparkinson Agents/*pharmacology
Experimental neurology
Female
Gearing Marla
Hossain Muhammad M
Humans
Inbred C57BL
Inflammation/metabolism
Male
Mice
Microglia/drug effects/*metabolism
NAV1.6 Voltage-Gated Sodium Channel/*biosynthesis
Neuroprotective Agents/pharmacology
Parkinsonian Disorders/*metabolism/pathology
Reuhl Kenneth
Richardson Jason R
Weig Blair
Wu Long-Jun
Zonisamide/*pharmacology