Riluzole, a drug approved for the treatment of amyotrophic lateral sclerosis (ALS), might reverse genetic changes often observed in patients with Alzheimer’s disease and age-related cognitive decline. The findings support a clinical trial now exploring if riluzole is beneficial for Alzheimer’s patients.
Researchers at Rockefeller University have previously shown that riluzole can prevent memory loss in aging rats by inducing structural brain changes. Now, the team led by Ana Pereira, an instructor in clinical medicine in Bruce McEwen’s laboratory at Rockefeller, further explored how the drug might affect the neurotransmitter glutamate in the hippocampus, a brain region crucial for memory processing.
“In aging and Alzheimer’s, the chemical signal glutamate can accumulate between neurons, damaging the circuitry,” Dr. Pereira said in a press release. “When we treated rats with riluzole, we saw a suite of changes. Perhaps most significantly, expression of molecules responsible for clearing excess glutamate returned to more youthful levels.”
The team studied the gene expression signatures of aging rats and, in an article in the journal Molecular Psychiatry, noted that when treating the animals with riluzole, the levels of numerous genes started to resemble patterns in younger rats.
Riluzole has been shown to increase the activity of EAAT2, a transport protein that removes excess glutamate from outside neurons. In rats, the gene expression of the transporter becomes lower with age and has been linked to Alzheimer’s disease. The study, “Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole,” showed that riluzole treatment returned the expression of the EAAT2 gene in the hippocampus to healthy levels.
“The essence is we used a drug known to modulate glutamate, and when we gave it to old rats, we saw it reversed many of the changes that begin in middle age in the hippocampus,” said Jason Gray, the study’s first author. “We saw a similar pattern when we compared the riluzole-induced changes to data from Alzheimer’s patients — in a number of key pathways in the hippocampus, the drug produced an effect opposing that of the disease.”
Since the drug is already approved for another neurological condition, safety and tolerability data for it exist, and starting clinical trials is relatively straightforward. Pereira and her team have already initiated a Phase 2 clinical trial (NCT01703117) testing the drug in Alzheimer’s patients at The Rockefeller University Hospital in New York. The trial is now recruiting people with mild Alzheimer’s disease.
“We hope to use a medication to break the cycle of toxicity by which glutamate can damage the neurons that use it as a neurotransmitter, and our studies so far suggest that riluzole may be able to accomplish this,” Dr. Pereira says. “We found that in addition to recovering the expression of EAAT2, the drug restored genes critical for neural communication and plasticity, both of which decline with aging and even more significantly in Alzheimer’s disease.”