Researchers at the University of Tokyo demonstrated that the FDA-approved anti-epileptic drug perampanel is able to prevent the progression of amyotrophic lateral sclerosis (ALS) and normalize the death of motor neurons in an animal model of the disease.
The findings indicate the drug may be a potential candidate for ALS treatment and should be explored in clinical trials.
The research paper, “The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice,” was published in Scientific Reports.
More than 30 genes have been identified as being linked to ALS, but the majority of patients with sporadic ALS, which accounts for most ALS patients, do not carry mutations in these ALS-linked genes. Most drugs are developed targeting these mutations and have proven to be mostly ineffective, so it is essential to evaluate ALS biomarkers to improve drug development.
In this study, researchers based their research on evidence of faulty mechanisms within motor neurons of ALS patients, especially the mislocalization of the TDP-43 protein, observed in the vast majority of ALS patients and considered a pathological hallmark of the disease. Researchers also focused on an RNA editing failure observed in the motor neurons of ALS patients.
Researchers used an anti-epileptic drug, perampanel, to repair this faulty mechanism in mouse models and used the normalization of TDP-43 mislocalization as a marker for the effectiveness of the treatment.
Experimental results showed the drug was able to prevent the death of motor neurons and normalized the localization of TDP-43 with the cells. Moreover, long-term administration of the drug in mice also led to visible improvement of motor dysfunction in the treated mice, as compared to the control mice.
The scientists also highlighted that perampanel is an approved drug, with a long half-life and proven safety, which would render it a promising drug for the treatment of ALS.
“… efficacy of perampanel would be expected in some form of familial ALS patients. We believe that the present results provide a rationale for clinical trials of perampanel in ALS patients,” the researchers concluded.