title: Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity.
abstract: Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinson's disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg×4 every 2h; 3) MPTP and zonisamide, 40 mg/kg×1, 1h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100β-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP-induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100β secretion.
authors.affiliation: Department of Therapeutic Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon-Shi, Ehime 791-0295, Japan.
authors.forename: Mohammed Emamussalehin
authors.initials: ME
authors.lastname: Choudhury
authors.forename: Takashi
authors.initials: T
authors.lastname: Moritoyo
authors.forename: Madoka
authors.initials: M
authors.lastname: Kubo
authors.forename: Win Thiri
authors.initials: WT
authors.lastname: Kyaw
authors.forename: Hayato
authors.initials: H
authors.lastname: Yabe
authors.forename: Noriko
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagai
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nomoto
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D000078305:Zonisamide
chemical_list: D000975:Antioxidants; D005904:Glial Fibrillary Acidic Protein; D007555:Isoxazoles; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D000078305:Zonisamide; D004298:Dopamine