Neuroprotective effects of zonisamide target astrocyte.
OBJECTIVE
Recent double-blind, controlled trials in Japan showed that the antiepileptic agent zonisamide (ZNS) improves the cardinal symptoms of Parkinson's disease. Glutathione (GSH) exerts antioxidative activity through quenching reactive oxygen species and dopamine quinone. GSH depletion within dopaminergic neurons impairs mitochondrial complex I activity, followed by age-dependent nigrostriatal neurodegeneration. This study examined changes in GSH and GSH synthesis-related molecules, and the neuroprotective effects of ZNS on dopaminergic neurodegeneration using 6-hydroxydopamine-injected hemiparkinsonian mice brain and cultured neurons or astrocytes.


RESULTS
ZNS increased both the cell number and GSH levels in astroglial C6 cells, but not in dopaminergic neuronal CATH.a cells. Repeated injections of ZNS (30mg/kg intraperitoneally) for 14 days also significantly increased GSH levels and S100beta-positive astrocytes in mouse basal ganglia. Repeated ZNS injections (30mg/kg) for 7 days in the hemiparkinsonian mice increased the expression of cystine/glutamate exchange transporter xCT in activated astrocytes, which supply cysteine to neurons for GSH synthesis. Treatment of these mice with ZNS also increased GSH levels and completely suppressed striatal levodopa-induced quinone formation. Reduction of nigrostriatal dopamine neurons in the lesioned side of hemiparkinsonian mice was significantly abrogated by repeated injections of ZNS with or without adjunctive levodopa starting 3 weeks after 6-hydroxydopamine lesioning.


CONCLUSIONS
These results provide new pharmacological evidence for the effects of ZNS. ZNS markedly increased GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation via S100beta production or secretion. ZNS acts as a neuroprotectant against oxidative stress and progressive dopaminergic neurodegeneration.
Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. asachan@cc.okayama-u.ac.jp
Masato
M
Asanuma
Ikuko
I
Miyazaki
Francisco J
FJ
Diaz-Corrales
Naotaka
N
Kimoto
Yuri
Y
Kikkawa
Mika
M
Takeshima
Ko
K
Miyoshi
Miho
M
Murata
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D002230:Carbidopa / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009414:Nerve Growth Factors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000078305:Zonisamide
D000978:Antiparkinson Agents; D005904:Glial Fibrillary Acidic Protein; D007555:Isoxazoles; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D000078305:Zonisamide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D005978:Glutathione; D002230:Carbidopa; D004298:Dopamine