Clin Psychopharmacol Neurosci.  2019 Aug;17(3):438-442. 10.9758/cpn.2019.17.3.438.

Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes

Affiliations
  • 1Labaratory of Neurobiology, School of Medicine and Surgery and Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Milano, Italy. lucio.tremolizzo@unimib.it
  • 2Neurology Unit, San Gerardo Hospital, Monza, Italy.
  • 3NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milano, Italy.
  • 4San Raffaele Scientific Institute, Milano, Italy.

Abstract

OBJECTIVE: Until recently, riluzole was the only drug licensed for amyotrophic lateral sclerosis (ALS). In spite of its efficacy, the mechanism of action remains elusive, and both blocking of glutamate release and antioxidant properties have been postulated. Here we characterized human SH-SY5Y neuroblastoma cell lines, taking advantage of their insensitivity to excitotoxic insults, in order to selectively assess the presence of a direct antioxidant effect of riluzole.
METHODS
SH-SY5Y cells, either parental or overexpressing the G93A SOD1 mutation, were exposed for 24 hours to the selected stimuli.
RESULTS
Riluzole (1–10 μM) was able to counteract the effects of H₂O₂ exposure (200 μM/24 hr), limiting both cell death and whole-cell reactive oxygen species (ROS) increase. The same experiments were repeated using SH-SY5Y cells carrying the familial ALS-related G93A-SOD1 mutation and constitutively expressing two-fold increased whole-cell ROS levels with respect to wild-type cells: riluzole was ineffective in this paradigm. Analogously, riluzole was ineffective in preventing cell death induced by exposing SH-SY5Y cells to 3-morpholino-sydnonimine (SIN-1, 1.5 mM/24 hr), a reactive nitrogen species (RNS) donor.
CONCLUSION
Our data support a direct antioxidant action of riluzole. Furthermore, the lack of efficacy of riluzole observed in the SOD1 cell model mirrors the lack of efficacy already demonstrated in cognate mouse models of ALS, plausibly reflecting differences in the underlying pathogenic mechanisms. Finally, riluzole inefficacy against nitrosative stress might support the idea that a combined therapeutic intervention may result more effective in ALS patients, as in the case of co-administration of edaravone, a drug known to reduce RNS.

Keyword

Riluzole; Amyotrophic lateral sclerosis; Antioxidants; Drug
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