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 inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON
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 sclerosisbaseline TEd (90-100 ms) 49.1 ± 1.8%; controlsTEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 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 sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON
riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON
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.