The Effects of the KCNQ Openers Retigabine and Flupirtine on Myotonia in Mammalian Skeletal Muscle Induced by a Chloride Channel Blocker

Su, Tzu Rong; Zei, Wen Shan; Su, Ching Chyuan; Hsiao, George; Lin, Min Jon

doi:10.1155/2012/803082

Cited by 11 publications

(13 citation statements)

References 37 publications

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“…Both the current study and a previous study found that treatment of myotonic muscle with retigabine to open KCNQ (Kv7) channels, lessened myotonia (Su, et al, 2012). Retigabine has also been shown to improve motor function in R6/2 transgenic Huntington's disease mice (Cao, et al, 2015).…”

Section: The Mechanism Underlying Efficacy Of Retigabine In Treating supporting

confidence: 65%

“…Kv7 channels are present in skeletal muscle (Iannotti, et al, 2010) such that treatment with retigabine would be expected to reduce muscle excitability. Consistent with this, a previous study found that retigabine reduced myotonia in a pharmacologic model of myotonia congenita (Su, et al, 2012). We examined the mechanism of retigabine's efficacy against myotonia, its effect on in vivo myotonic muscle contraction, and its potential to treat myotonia congenita.…”

Section: Introductionsupporting

confidence: 61%

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Treatment of myotonia congenita with retigabine in mice

Dupont

Denman

Hawash

et al. 2019

Experimental Neurology

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Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na + current. However, other approaches such as increasing K + currents might also be effective. For example, the K + channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons. In this study, we found that retigabine greatly reduced the duration of myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten myotonia by activating K + current during trains of action potentials. Retigabine also greatly reduced the severity of myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.

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Section: The Mechanism Underlying Efficacy Of Retigabine In Treating supporting

confidence: 65%

Section: Introductionsupporting

confidence: 61%

Treatment of myotonia congenita with retigabine in mice

Dupont

Denman

Hawash

et al. 2019

Experimental Neurology

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“…Addition of Flu reduced the peak amplitude of I K(DR) as well as increased the inactivation time course of this current recorded from NSC-34 cells. The present observations would clearly initiate further studies to understand the Flu effects on electrical activity of motor neurons [4, 24, 25]. Whether Flu used in treating patients with Creutzfeld-Jakob disease [1–3, 26] relates to an inhibition of I K(DR) needs further evaluations.…”

Section: Discussionmentioning

confidence: 89%

“…Notably, this compound was previously demonstrated to be beneficial in treating the patients with human prion diseases [ 2 , 3 ]. A recent study showed the ability of Flu to reduce the myotonic membrane hyperexcitability induced by a Cl − channel blocker [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K⁺Currents in Motor Neuron-Like Cells

Hsu

Liao

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K+ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K+ current (I K(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of I K(DR) inactivation rate was about 9.8 μM. Neither linopirdine (10 μM), NMDA (30 μM), nor gabazine (10 μM) reversed Flu-induced changes in I K(DR) inactivation. Addition of Flu shifted the inactivation curve of I K(DR) to a hyperpolarized potential. Cumulative inactivation for I K(DR) was elevated in the presence of this compound. Flu increased the amplitude of M-type K+ current (I K(M)) and produced a leftward shift in the activation curve of I K(M). In another neuronal cells (NG108-15), Flu reduced I K(DR) amplitude and enhanced the inactivation rate of I K(DR). The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K+ channels in motor neurons. Flu-induced block of I K(DR) is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K+ channels are not limited to its action on M-type K+ channels.

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“…Up today, the study of potential countermeasures against myotonia induced by 9-AC has been performed only in vitro (Dengler and Rudel, 1979; van Lunteren et al., 2011; Su et al., 2012). Therefore one important novelty of the model described here is that drugs are tested in vivo in conscious animals.…”

Section: Discussionmentioning

confidence: 99%

In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia

et al. 2013

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The sodium channel blocker mexiletine is considered the first-line drug in myotonic syndromes, a group of muscle disorders characterized by membrane over-excitability. We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, block voltage-gated sodium channels in a manner reminiscent to mexiletine, whereas salbutamol and nadolol do not. We now developed a pharmacological rat model of myotonia congenita to perform in vivo preclinical test of antimyotonic drugs. Myotonia was induced by i.p. injection of 30 mg/kg of anthracene-9-carboxylic acid (9-AC), a muscle chloride channel blocker, and evaluated by measuring the time of righting reflex (TRR). The TRR was prolonged from <0.5 s in control conditions to a maximum of ∼4 s, thirty minutes after 9-AC injection, then gradually recovered in a few hours. Oral administration of mexiletine twenty minutes after 9-AC injection significantly hampered the TRR prolongation, with an half-maximum efficient dose (ED50) of 12 mg/kg. Both propranolol and clenbuterol produced a dose-dependent antimyotonic effect similar to mexiletine, with ED50 values close to 20 mg/kg. Antimyotonic effects of 40 mg/kg mexiletine and propranolol lasted for 2 h. We also demonstrated, using patch-clamp methods, that both propranolol enantiomers exerted a similar block of skeletal muscle hNav1.4 channels expressed in HEK293 cells. The two enantiomers (15 mg/kg) also showed a similar antimyotonic activity in vivo in the myotonic rat. Among the drugs tested, the R(+)-enantiomer of propranolol may merit further investigation in humans, because it exerts antimyotonic effect in the rat model, while lacking of significant activity on the β-adrenergic pathway. This study provides a new and useful in vivo preclinical model of myotonia congenita in order to individuate the most promising antimyotonic drugs to be tested in humans.

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The Effects of the KCNQ Openers Retigabine and Flupirtine on Myotonia in Mammalian Skeletal Muscle Induced by a Chloride Channel Blocker

Cited by 11 publications

References 37 publications

Treatment of myotonia congenita with retigabine in mice

Treatment of myotonia congenita with retigabine in mice

Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K⁺Currents in Motor Neuron-Like Cells

In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia

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The Effects of the KCNQ Openers Retigabine and Flupirtine on Myotonia in Mammalian Skeletal Muscle Induced by a Chloride Channel Blocker

Cited by 11 publications

References 37 publications

Treatment of myotonia congenita with retigabine in mice

Treatment of myotonia congenita with retigabine in mice

Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K+Currents in Motor Neuron-Like Cells

In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia

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Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K⁺Currents in Motor Neuron-Like Cells