Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc(-)

Eduard Bentea, Joeri Van Liefferinge, Lise Verbruggen, Katleen Martens, Lauren Deneyer, Thomas Demuyser, Giulia Albertini, Katrien Maes, Hideyo SATO, Ilse Smolders, Jan Lewerenz, Ann Massie

Research output: Contribution to journalArticle

10 Citations (Scopus)

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(-1) or 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.

Original languageEnglish
Pages (from-to)15-28
Number of pages14
JournalExperimental Neurology
Volume290
DOIs
Publication statusPublished - 24 Dec 2016

Keywords

  • zonisamide
  • Neuroprotection
  • Parkinson Disease
  • lactacystin
  • xCT
  • glutatione

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