POSTER: Neuroprotective effects of zonisamide against lactacystin-induced neurodegeneration do not involve changes in system xc- expression

Eduard Mihai Bentea, Joeri Van Liefferinge, Thomas Demuyser, Sho Kobayashi, Lauren Deneyer, Giulia Albertini, Ellen Merckx, Katrien Maes, Hideyo Sato, Ilse Julia Smolders, Jan Lewerenz, Ann Massie

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)


Zonisamide (ZNS), an anti-epileptic drug used in the symptomatic treatment of Parkinson’s disease (PD), has been recently linked with neuroprotective properties in toxin- and genetic-based models of PD. One of the mechanisms proposed to mediate the neuroprotective effects of ZNS involve an increase in expression of the cystine/glutamate antiporter system xc-, leading to enhanced cystine supply for astrocytic glutathione synthesis (Asanuma et al. Ann Neurol 2010 67(2):239-49). At the same time, however, enhancement of system xc- might trigger excitotoxicity due to pathological astrocytic glutamate release, leading to non-cell autonomous neuronal death (Massie et al. FASEB J 2011 25(4):1359-69). In order to gain further insights into the neuroprotective properties of ZNS and elucidate the role of system xc-, we have employed the lactacystin (proteasome inhibition) mouse model of PD. Our findings indicate that chronic treatment with ZNS (30mg/kg; i.p.) protects against lactacystin-induced neurodegeneration, confirming the neuroprotective properties of ZNS, for the first time in a model based on proteasome inhibition. The neuroprotective effects of ZNS were accompanied by an improvement in sensorimotor function, as evaluated using the adhesive removal test. ZNS treatment failed, however, to modulate the expression of system xc- in midbrain and striatum of lactacystin treated mice, indicating that the neuroprotective action of ZNS do not involve changes in system xc- expression. Similarly, we found that chronic treatment with ZNS did not influence system xc- expression or glutathione levels in the basal ganglia of control (untreated) mice. Finally, in vitro studies indicated that ZNS treatment did not change system xc- activity in HT22 cells or primary astrocytes, and did not influence glutathione levels in astroglial C6 cells. In conclusion, our study revealed neuroprotective and symptomatic effects of chronic ZNS treatment in a PD model based on proteasome inhibition. Our top-down approach investigating the effect of ZNS treatment in pathological and physiological conditions and in cell culture, failed to reveal any significant effect on system xc- expression or activity. We thereby propose that the neuroprotective actions of ZNS are not mediated via system xc-. Instead, other pathways are likely to be involved, such as the proposed anti-inflammatory, anti-oxidant and neurotrophic properties of ZNS. Future studies in this regard will be important in understanding the mechanisms of neuroprotection of ZNS. Nevertheless, our findings support the use of ZNS as a symptomatic and possible disease-modifying therapy in PD.
Original languageEnglish
Title of host publication45th Annual Meeting of the Society for Neuroscience, 17-21 October 2015, Chicago, USA.
Publication statusPublished - 17 Oct 2015
Event45th Annual Meeting of the Society for Neuroscience - Chicago, United States
Duration: 17 Oct 201521 Oct 2015


Conference45th Annual Meeting of the Society for Neuroscience
Country/TerritoryUnited States


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