title: Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc<sup/>.
abstract: Zonisamide (ZNS), an anticonvulsant drug exhibiting symptomatic effects in Parkinson's disease (PD), was recently reported to exert neuroprotection in rodent models. One of the proposed neuroprotective mechanisms involves increased protein expression of xCT, the specific subunit of the cystine/glutamate antiporter system xc-, inducing glutathione (GSH) synthesis. Here, we investigated the outcome of ZNS treatment in a mouse model of PD based on intranigral proteasome inhibition, and whether the observed effects would be mediated by system xc-. The proteasome inhibitor lactacystin (LAC) was administered intranigrally to male C57BL/6J mice receiving repeated intraperitoneal injections of either ZNS 30mgkg-1or vehicle. Drug administration was initiated three days prior to stereotaxic LAC injection and was maintained until six days post-surgery. One week after lesion, mice were behaviorally assessed and investigated in terms of nigrostriatal neurodegeneration and molecular changes at the level of the basal ganglia, including expression levels of xCT. ZNS reduced the loss of nigral dopaminergic neurons following LAC injection and the degree of sensorimotor impairment. ZNS failed, however, to modulate xCT expression in basal ganglia of lesioned mice. In a separate set of experiments, the impact of ZNS treatment on system xc-was investigated in control conditions in vivo as well as in vitro. Similarly, ZNS did not influence xCT or glutathione levels in naive male C57BL/6J mice, nor did it alter system xc-activity or glutathione content in vitro. Taken together, these results demonstrate that ZNS treatment provides neuroprotection and behavioral improvement in a PD mouse model based on proteasome inhibition via system xc-independent mechanisms.
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bentea
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joeri
authors.initials: J
authors.lastname: Van Liefferinge
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lise
authors.initials: L
authors.lastname: Verbruggen
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: Martens
authors.affiliation: Department of Food and Applied Life Sciences, Yamagata University, Yamagata, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Lauren
authors.initials: L
authors.lastname: Deneyer
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Demuyser
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Albertini
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Maes
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Technology, Niigata University, Niigata, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: Ann.Massie@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D027182:Amino Acid Transport System y+ / Q000187:drug effects*; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000517:prevention & control* / Q000523:psychology; D004856:Postural Balance / Q000187:drug effects; D013238:Stereotaxic Techniques; D013378:Substantia Nigra; D000078305:Zonisamide
chemical_list: D027182:Amino Acid Transport System y+; D015853:Cysteine Proteinase Inhibitors; D007555:Isoxazoles; D018696:Neuroprotective Agents; C492255:Slc7a11 protein, mouse; C067713:lactacystin; D000078305:Zonisamide; D005978:Glutathione; D000111:Acetylcysteine
keywords: Glutathione; Lactacystin; Neuroprotection; Parkinson's disease; Zonisamide; xCT