Interaction of high concentrations of riluzole with recombinant skeletal muscle sodium channels and adult-type nicotinic receptor channels
Hannover Medical School, Hanover, Lower Saxony, Germany Muscle & Nerve
(Impact Factor: 2.28).
10/2002; 26(4):539-45. DOI: 10.1002/mus.10230
Riluzole is a neuroprotective drug that modulates glutamergic transmission but also blocks the inactivated state of voltage-gated neuronal sodium channels at very low concentrations (about 0.1 microM). After nausea, the most common adverse effect of riluzole is asthenia, which could be due to a block of muscle sodium channels or acetylcholine receptor channels. Using the patch-clamp technique, we applied riluzole on recombinant voltage-gated skeletal muscle sodium and adult nicotinic acetylcholine receptor channels expressed in a mammalian cell line (HEK 293). Riluzole blocked the inactivated state of voltage-gated skeletal muscle sodium channels, shifting the midpoint of the steady-state inactivation curve to more negative potentials, but only in comparatively high concentrations (> or = 0.1 mM). At these concentrations, riluzole also caused an open-channel block at acetylcholine receptor channels. We conclude that riluzole has only a mild blocking effect on the inactivated state of voltage-gated skeletal muscle sodium channels and nicotinic acetylcholine receptor channels. As the plasma concentration of riluzole in amyotrophic lateral sclerosis (ALS) patients approximates 2 microM, it seems unlikely that asthenia is caused by a block of skeletal muscle sodium channels or acetylcholine receptor channels by riluzole.
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Available from: Sheng-Nan Wu
- "It was demonstrated to reduce glutamate excitotoxicity by inhibiting glutamate release and/or modifying the postsynaptic glutamate receptor cascade (Martin et al., 1993; Mantz et al., 1994; Rothstein and Kuncl, 1995; De Sarro et al., 2000). In addition, emerging evidence has unraveled that riluzole can inhibit voltage-gated Na + channels (Hebert et al., 1994; Siniscalchi et al., 1997; Song et al., 1997; Yokoo et al., 1998; Zona et al., 1998; Mohammadi et al., 2002). This effect has been proposed to be mainly responsible for the prevention of epilepsy and cellular death caused by this drug (Hebert et al., 1994). "
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ABSTRACT: Riluzole is known to be of therapeutic use in the management of amyotrophic lateral sclerosis. In this study, we investigated the effects of riluzole on ion currents in cultured differentiated human skeletal muscle cells (dHSkMCs). Western blotting revealed the protein expression of alpha-subunits for both large-conductance Ca2+-activated K+ (BK(Ca)) channel and Na+ channel (Na(v)1.5) in these cells. Riluzole could reduce the frequency of spontaneous beating in dHSkMCs. In whole-cell configuration, riluzole suppressed voltage-gated Na+ current (I(Na)) in a concentration-dependent manner with an IC50 value of 2.3 microM. Riluzole (10 microM) also effectively increased Ca2+-activated K+ current (I(K(Ca))) which could be reversed by iberiotoxin (200 nM) and paxilline (1 microM), but not by apamin (200 nM). In inside-out patches, when applied to the inside of the cell membrane, riluzole (10 microM) increased BK(Ca)-channel activity with a decrease in mean closed time. Simulation studies also unraveled that both decreased conductance of I(Na) and increased conductance of I(K(Ca)) utilized to mimic riluzole actions in skeletal muscle cells could combine to decrease the amplitude of action potentials and increase the repolarization of action potentials. Taken together, inhibition of I(Na) and stimulation of BK(Ca)-channel activity caused by this drug are partly, if not entirely, responsible for its muscle relaxant actions in clinical setting.
Life Sciences 02/2008; 82(1-2):11-20. DOI:10.1016/j.lfs.2007.10.015 · 2.70 Impact Factor
Available from: Christopher Pittenger
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ABSTRACT: Recent advances implicate amino acid neurotransmission in the pathophysiology and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate.Although double-blind, placebo-controlled trials are lacking, several open-label trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and self-injurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.
CNS Drugs 02/2008; 22(9):761-86. DOI:10.2165/00023210-200822090-00004 · 5.11 Impact Factor
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ABSTRACT: The neuroprotective agent riluzole is used for the symptomatic treatment of motoneuron disease, which strongly affects the brainstem nucleus hypoglossus. The mechanism of action of riluzole was investigated using, as a model, patch-clamp recording from hypoglossal motoneurons of the neonatal rat brainstem slice preparation. In the presence of riluzole (10 microm), theta-rhythm oscillations evoked by nicotine continued even though the persistent inward current (comprising sodium and calcium components) was halved, but they disappeared when the high frequency of spontaneous glutamatergic currents waned. Riluzole fully inhibited the persistent sodium current and partly depressed a tetrodotoxin (TTX)-insensitive slow current antagonized by Mn(2+) or Cd(2+). Repetitive firing was inhibited by riluzole without changing single action potentials. In the presence of TTX, riluzole depressed miniature glutamatergic currents occurring at high rate. Synaptic transmission with low release probability became sensitive to riluzole if release was stimulated by high potassium solution. Miniature current frequency was depressed by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D-amino-phosphonovaleriate (50 microm), which fully occluded the action of riluzole. As riluzole is a protein kinase C (PKC) inhibitor, the PKC antagonist chelerythrine (2.5 microm) mimicked the effect of riluzole and prevented it. In summary, riluzole blocked the persistent sodium current fully, and the calcium one partly, plus it decreased glutamatergic transmission probably via inhibition of PKC that regulated presynaptic NMDA receptors having a facilitatory effect on glutamate release. Controlling NMDA receptor function and, thus, excitatory transmitter release via modulation of PKC suggests a novel potential target to contrast glutamate excitotoxicity in this motor nucleus.
European Journal of Neuroscience 06/2008; 27(10):2501-14. DOI:10.1111/j.1460-9568.2008.06211.x · 3.18 Impact Factor
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