Riluzole selective antioxidant effects in cell models expressing ALS endophenotypes
Gessica Sala 1, Alessandro Arosio 1, Elisa Conti 1, Simone Beretta 1, 2, Christian Lunetta 3, Nilo Riva 4, Carlo Ferrarese 1, 2, Lucio Tremolizzo 1, 2*
1Lab. of Neurobiology, School of Medicine and Surgery and Milan Canter for Neuroscience (NeuroMI), Univ. of Milano-Bicocca, 2Neurology Unit, “San Gerardo” Hospital, Monza, 3NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milano, 4“San Raffaele” Scientific Institute, Milano
Received: May 14, 2018; Revised: August 7, 2018; Accepted: August 12, 2018; Published online: August 12, 2018.
© The Korean College of Neuropsychopharmacology. All rights reserved.

Abstract
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. The drug (1-10 µM) was able to counteract the effects of H2O2 exposure (200 µM/24 h), limiting both cell death and whole-cell 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 h), a reactive nitrogen species (RNS) donor. In 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 interventions may result more effective in ALS patients, as in the case of co-administration of Edaravone, a drug known to reduce RNS.
Keywords: riluzole, amyotrophic lateral sclerosis, antioxidant, drug


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