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Partial block by riluzole of muscle sodium channels in myotubes from amyotrophic lateral sclerosis patients.

Deflorio C, Onesti E, Lauro C, Tartaglia G, Giovannelli A, Limatola C, Inghilleri M, Grassi F - Neurol Res Int (2014)

Bottom Line: The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced.Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect.Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.

ABSTRACT
Denervated muscles undergo fibrillations due to spontaneous activation of voltage-gated sodium (Na(+)) channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS). Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na(+) channels, but its effects on muscle Na(+) channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na(+) channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs) in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 μM, a therapeutic concentration) reduced Na(+) current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole.

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Related in: MedlinePlus

Fibrillation potentials in an ALS patient before and after riluzole suspension. Electromyography recordings performed in one ALS patient during riluzole therapy (top trace) and after a 1-week suspension of treatment (bottom trace). Notice that fibrillation potentials showed no significant change.
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fig3: Fibrillation potentials in an ALS patient before and after riluzole suspension. Electromyography recordings performed in one ALS patient during riluzole therapy (top trace) and after a 1-week suspension of treatment (bottom trace). Notice that fibrillation potentials showed no significant change.

Mentions: All patients were treated with riluzole (average treatment duration, 13.8 months) and suspended treatment for one week for this study. This time is adequate for riluzole washout, estimated to be complete within about 40 hours of withdrawal [29]. Multiple Fibs were detected in all patients' anterior tibialis muscle (Figure 3). Across the 3 insertions performed, their number had small fluctuations in all but Patients 5 and 7, which suggests that variability due to needle position is limited. In the second recording session, one week after riluzole withdrawal, clinical status and CMAP amplitude were unchanged for all patients (Table 1), indicating that no relevant alteration in muscle innervation took place. Fibs continued to be present in all patients, and variability between insertions did not change. When compared to the first recording session, the total number of Fibs changed by less than 25% in six patients; in the other 5, changes ranged between a 55% increase (Patient 2) and a 70% decrease (Patient 1). Overall, there was no statistically significant variation in the number of Fibs upon riluzole treatment suspension (P = 0.69) (Table 1). The effect of riluzole withdrawal showed no correlation with patients' age, sex, disease duration, or Fibs frequency at baseline (data not shown).


Partial block by riluzole of muscle sodium channels in myotubes from amyotrophic lateral sclerosis patients.

Deflorio C, Onesti E, Lauro C, Tartaglia G, Giovannelli A, Limatola C, Inghilleri M, Grassi F - Neurol Res Int (2014)

Fibrillation potentials in an ALS patient before and after riluzole suspension. Electromyography recordings performed in one ALS patient during riluzole therapy (top trace) and after a 1-week suspension of treatment (bottom trace). Notice that fibrillation potentials showed no significant change.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4273590&req=5

fig3: Fibrillation potentials in an ALS patient before and after riluzole suspension. Electromyography recordings performed in one ALS patient during riluzole therapy (top trace) and after a 1-week suspension of treatment (bottom trace). Notice that fibrillation potentials showed no significant change.
Mentions: All patients were treated with riluzole (average treatment duration, 13.8 months) and suspended treatment for one week for this study. This time is adequate for riluzole washout, estimated to be complete within about 40 hours of withdrawal [29]. Multiple Fibs were detected in all patients' anterior tibialis muscle (Figure 3). Across the 3 insertions performed, their number had small fluctuations in all but Patients 5 and 7, which suggests that variability due to needle position is limited. In the second recording session, one week after riluzole withdrawal, clinical status and CMAP amplitude were unchanged for all patients (Table 1), indicating that no relevant alteration in muscle innervation took place. Fibs continued to be present in all patients, and variability between insertions did not change. When compared to the first recording session, the total number of Fibs changed by less than 25% in six patients; in the other 5, changes ranged between a 55% increase (Patient 2) and a 70% decrease (Patient 1). Overall, there was no statistically significant variation in the number of Fibs upon riluzole treatment suspension (P = 0.69) (Table 1). The effect of riluzole withdrawal showed no correlation with patients' age, sex, disease duration, or Fibs frequency at baseline (data not shown).

Bottom Line: The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced.Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect.Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.

ABSTRACT
Denervated muscles undergo fibrillations due to spontaneous activation of voltage-gated sodium (Na(+)) channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS). Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na(+) channels, but its effects on muscle Na(+) channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na(+) channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs) in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 μM, a therapeutic concentration) reduced Na(+) current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na(+) currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole.

No MeSH data available.


Related in: MedlinePlus