Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis

Abstract

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na + channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na + channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibition baseline 0.5 ± 1.8%; short interval intracortical inhibition ON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0.45) or motor evoked potential amplitude (P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosis baseline TEd (90-100 ms) 49.1 ± 1.8%; controls TEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosis baseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosis baseline 30.1 ± 2.3%; amyotrophic lateral sclerosis ON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosis baseline 98.7 ± 10.7%; amyotrophic lateral sclerosis ON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na + conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system. © 2013 The Author).