Riluzole display glutamate-independent antioxidant properties: relevance for ALS

Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease for which, at the moment, no effective therapies exist. Riluzole is the only drug currently licensed for ALS, at the dose of 100 mg/day. Uncertainties regarding the exact mechanism of action of this drug hinder any attempt of designing more potent drugs able to increase significantly life expectancy in ALS. Riluzole specifically blocks tetrodotoxin-sensitive sodium channels reducing calcium influx and excessive glutamate receptor stimulation within the SNC. However, albeit antioxidant properties of this molecule have already been hypothesized, previous works conceivably did not distinguish between direct and indirect antioxidant effects (the latter due to the known anti-glutamatergic properties). In this work we used a neuroblastoma cell model (SH-SY5Y), initially demonstrating its insensitivity to various excitotoxic insults. In contrast, when these cells were exposed to an acute oxidative insult (H2O2 200 AμM/24 h), cell viability was reduced of about 50% and whole-cell ROS were increased three-fold; riluzole co-administration elicited a significant rescue starting from the concentration of 0.5-1 AμM. Neuroblastoma cells carrying the SOD1- G93A ALS-related mutation showed a twofold increase in whole-cell ROS production with respect to wild type cells, that was unaffected by riluzole co-administration. In this work we used an excitotoxicity-insensitive model in order to demonstrate that riluzole possesses direct antioxidant properties. However, in our experimental condition, this was not sufficient to protect against SOD1-related chronic damage. These results cast doubts on the potential efficacy of antioxidant molecules in ALS prompting to look for different mechanisms of action for discovering a cure.