Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS

Abstract

Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na⁺ channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.

Key words:

• Riluzole
• cortical hyperexcitability
• short interval intracortical inhibition
• treatment

Acknowledgements

This study was supported in part by a research grant from the Motor Neuron Disease Research Institute of Australia (Geevasinga), National Health and Medical Research Council of Australia [Project grant numbers 510233, 1024915, 1055778 Kiernan and Vucic; and Program Grant #1037746 is gratefully acknowledged]. The principal investigator, S. Vucic, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of interest

There are no conflicts of interest among any of the authors.