The benefits of riluzole, an approved treatment for amyotrophic lateral sclerosis (ALS), is thought to partly lie in its antioxidant effects. A new study now reports that this activity can be enhanced by combining it with agents like Radicava that provide protection via different pathways.
The study, “Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes,” was published in the journal Clinical Psychopharmacology and Neuroscience.
Riluzole — marketed as Rilutek by Sanofi and Tiglutik by ITF Pharma — was the only ALS treatment available until the approval of Radicava (edaravone, sold in the U.S. by Mitsubishi Tanabe Pharma America) in 2017.
It was shown to help delay the need for assisted ventilation in ALS patients. However, the therapy’s underlying mechanism remains unclear.
Riluzole is known to work by blocking sodium channels in the central nervous system — the brain and spinal cord — resulting in reduced calcium transport into nerve cells and excessive glutamate receptor stimulation. Work in rat models also suggest that the therapy can increase glutamate uptake in the spinal cord, and riluzole is associated with antioxidant benefits.
Whether such antioxidant properties result from a direct effect, or from riluzole’s suppression of the toxic glutamatergic signaling, remains to be determined.
The antioxidant activity of Radicava seen in ALS patients suggests that its use with treatments that are able to reduce oxidative stress — an imbalance between the production and clearance of potentially harmful reactive oxygen species (ROS) — may further slow ALS progression. Radicava is a ROS scavenger.
A team in Italy experimented with neuroblastoma cells (brain cancer cells), due to their insensitivity to damage caused by overt excitation, to better understand the antioxidant properties of riluzole.
They exposed these cells for 24 hours to molecules that would induce gluatamate receptor activation. This had no impact on cell survival, confirming an insensitivity to hyperactivation of gluatamate signals. In contrast, these cells were very sensitive when exposed to high ROS levels, and only 50% of them were still alive after 24 hours.
Researchers next evaluated cells that had been genetically modified to have familial ALS related to the G93A mutation in the SOD1 gene. These particular cells produced twice the amount of ROS compared to non-modified cells.
Interestingly, riluzole treatment prevented cell death and partly abolished the increased ROS levels in the non-modified cells, but was ineffective in reversing ROS effects in cells carrying the G93A SOD1 mutation.
This lack of efficacy in cells with the SOD1 mutation is in line with results in an ALS mouse model and is likely due to differences in the underlying disease-related processes.
“Our data support a direct antioxidant action of riluzole,” the researchers wrote. Taken together with the ALS animal results, the team said these findings support the idea that “riluzole could really express a synergistic therapeutic potential when in add-on with other drugs,” such as Radicava.