Asanuma and coworkers (Ann. Neurol., 2010) investigated the involvement of glutathione (GSH) in the long-term therapeutic efficacy of zonisamide (ZNS) in Parkinson's disease. Repeated administration of ZNS sodium salt (30mg/kg/day) for 14 days significantly increased GSH levels and S100-positive astrocytes in normal mouse basal ganglia. Moreover, a 7 day treatment of hemiparkinsonian mice induced increased system xc- expression in activated astrocytes and decreased dopaminergic neurodegeneration in the 6-hydroxydopamine (6-OHDA) lesioned side. System xc- exchanges intracellular glutamate for extracellular cystine.
Cystine is intracellularly reduced into cysteine, the rate-limiting substrate in GSH synthesis. Correspondingly increased GSH levels are observed in treated animals, possibly accounting for the protective effects observed in the 6-OHDA model. However, this hypothesis is in conflict with our earlier work, showing that mice lacking the
functional xCT subunit of system xc- (xCT-/-) were less
susceptible to 6-OHDA-induced neurodegeneration in the substantia nigra compared to wildtype mice (xCT+/+), probably explained by a 70% decrease in striatal extracellular glutamate levels. However, in our hands chronic administration of 30mg/kg/day ZNS sodium salt for 14 days neither increased GSH levels in striatum and midbrain of xCT-/-, nor in their xCT+/+ littermates. In addition, in xCT+/+ mice ZNS did not increase xCT protein levels. In vitro, 100 µM ZNS for 24 h did not increase activity of system xc- in HT22 cells and did not protect against oxidative glutamate toxicity. These results suggest that neuroprotective effects of ZNS are achieved by other mechanisms than activation of system xc- and increase of GSH
Original languageEnglish
Publication statusPublished - 2013
Event10th bi-annual meeting of the Belgian Society for Neuroscience - Jette, Belgium
Duration: 31 May 201331 May 2013

Conference

Conference10th bi-annual meeting of the Belgian Society for Neuroscience
CountryBelgium
CityJette
Period31/05/1331/05/13

ID: 22132222