The antiepileptic ezogabine (also known as retigabine) decreases pathological motor-neuron hyperexcitability in patients with amyotrophic lateral sclerosis (ALS), new research shows. "The study showed that ezogabine can reduce neurophysiological features of the disease," lead researcher Dr. Brain Wainger of the Healey Center for ALS at Massachusetts General Hospital, in Boston, told Reuters Health by email. Ezogabine, a potassium-channel agonist, calms the excitability of nerve cells that cause seizures. Similar hyperexcitability in motor neurons may play a role in ALS. Dr. Wainger and colleagues used transcranial magnetic stimulation (TMS) and threshold-tracking nerve-conduction studies to gauge the effects of ezogabine on upper and lower motor neuron excitability in 65 people with ALS. Participants in this phase-2 randomized, double-blind, placebo-controlled trial received 600 or 900 mg ezogabine daily or matching placebo for 10 weeks. Treatment with ezogabine reduced both cortical and spinal motor-neuron excitability in a dose-dependent manner. "Large improvements in neurophysiological outcomes" were observed in the primary and key secondary TMS parameters and the main parameters from threshold-tracking nerve-conduction studies, the researchers report in JAMA Neurology. The results suggest that "neurophysiological measurements of motor neuron electrical activity can be used as biomarkers in multisite clinical trials," Dr. Wainger told Reuters Health. The study was not powered to assess clinical outcomes, so the effect of ezogabine on clinical progression and the association between these neurophysiological parameters and clinical progression are not yet known, the researchers note. However, they did detect a numerical dose-dependent preservation of compound muscle action potential (CMAP) amplitude over the trial duration. "Although the effect did not meet statistical significance in the active treatment vs placebo comparisons, it merits further consideration," they write. "Subsequent studies with drugs targeting neuronal excitability will be necessary to determine whether the effect on hyperexcitability is persistent and whether it is sufficient to yield clinical slowing of the disease or improvement," Dr. Wainger told Reuters Health. Funding for the study was provided by the ALS Association, GlaxoSmithKline, Harvard Stem Cell Institute, and the Neurological Clinical Research Institute at Massachusetts General Hospital. Dr. Wainger has received a patent for use of potassium-channel openers in neurodegenerative diseases. —Megan Brooks Source
