TY - JOUR
T1 - The anti-parkinsonian drug zonisamide reduces neuroinflammation
T2 - Role of microglial Na v 1.6
AU - Hossain, Muhammad M.
AU - Weig, Blair
AU - Reuhl, Kenneth
AU - Gearing, Marla
AU - Wu, Long Jun
AU - Richardson, Jason R.
N1 - Publisher Copyright:
© 2018
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - MPTP
KW - Microglia
KW - Na 1.6
KW - Neuroinflammation
KW - Parkinson's disease
KW - TNF-α
KW - Voltage-gated sodium channels
KW - Zonisamide
KW - gp91
UR - http://www.scopus.com/inward/record.url?scp=85050004773&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050004773&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2018.07.005
DO - 10.1016/j.expneurol.2018.07.005
M3 - Article
C2 - 30017881
AN - SCOPUS:85050004773
SN - 0014-4886
VL - 308
SP - 111
EP - 119
JO - Experimental Neurology
JF - Experimental Neurology
ER -