title: Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo.
abstract: Zonisamide has been reported to have protective effects on epilepsy and Parkinson׳s disease and to work via various mechanisms of action, such as inhibition of monoamine oxidase-B and enhancement of tyrosine hydroxylase. Recently, it has been suggested that zonisamide itself shows neuroprotective actions. Therefore, in the present study we investigated the neuroprotective effects of zonisamide against endoplasmic reticulum (ER) stress. We used human neuroblastoma (SH-SY5Y) cells and investigated the protective effects of zonisamide against tunicamycin- and thapsigargin-induced neuronal cell death. In addition, we investigated the effect of zonisamide against 1-methyl-4-phenylpyridinium (MPP⁺)-induced cell death and the mechanism of protection against ER stress. In vivo, we investigated the effect of zonisamide (20 mg/kg, p.o.) in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson׳s disease. Zonisamide not only suppressed MPP⁺-induced cell death, but also inhibited ER stress-induced cell death and suppressed the expression of ER stress-related factors such as C/EBO homologous protein (CHOP) in vivo. Furthermore, zonisamide inhibited the activation of caspase-3 in vitro. These results suggest that zonisamide affected ER stress via caspase-3. We think that ER stress, particularly the mechanism via caspase-3, is involved in part of the neuroprotective effect of zonisamide against the experimental models of Parkinson׳s disease.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Tsujii
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Ishisaka
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Laboratory of Drug Metabolism & Pharmacokinetics, Faculty of Pharmacy, Osaka Ohtani University, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hashizume
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan. Electronic address: hidehara@gifu-pu.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000097:blood / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019284:Thapsigargin / Q000037:antagonists & inhibitors / Q000633:toxicity; D014415:Tunicamycin / Q000037:antagonists & inhibitors / Q000633:toxicity; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D000978:Antiparkinson Agents; D007555:Isoxazoles; D018696:Neuroprotective Agents; D014415:Tunicamycin; D000078305:Zonisamide; D019284:Thapsigargin
keywords: Endoplasmic reticulum stress; Parkinson׳s disease; Zonisamide