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PubMed1998

Riluzole, a glutamate release inhibitor, and motor behavior.

Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the alpha-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.

Animals↗
PubMed1999

Antioxidative and proapoptotic effects of riluzole on cultured cortical neurons.

Riluzole is used clinically in patients with amyotrophic lateral sclerosis. As oxidative stress, in addition to excitotoxicity, may be a major mechanism of motoneuron degeneration in patients with amyotrophic lateral sclerosis, we examined whether riluzole protects against nonexcitotoxic oxidative injury. Probably reflecting its weak antiexcitotoxic effects, riluzole (1-30 microM) attenuated submaximal neuronal death induced by 24-h exposure to 30 microM kainate or NMDA, but not that by 100 microM NMDA, in cortical cultures. Riluzole also attenuated nonexcitotoxic oxidative injury induced by exposure to FeCl3 in the presence of MK-801 and CNQX. Consistent with its antioxidative effects, riluzole reduced Fe3+-induced lipid peroxidation, and inhibited cytosolic phospholipase A2. By contrast, riluzole did not attenuate neuronal apoptosis induced by staurosporine. Rather unexpectedly, 24-48-h exposure to 100-300 microM riluzole induced neuronal death accompanied by nuclear and DNA fragmentations, which was attenuated by caspase inhibitor carbobenzyloxy-Val-Ala-Asp-fluoromethyl ketone but not by protein synthesis inhibitor cycloheximide. The present study demonstrates that riluzole has direct antioxidative actions, perhaps in part by inhibiting phospholipase A2. However, in the same neurons, riluzole paradoxically induces neuronal apoptosis in a caspase-sensitive manner. Considering current clinical use of riluzole, further studies are warranted to investigate its potential cytolethal effects.

Animals↗
PubMed1994

A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group. CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.

Adult↗
PubMed1996

Riluzole, a novel neuroprotective agent, attenuates both neurologic motor and cognitive dysfunction following experimental brain injury in the rat.

Several potential mechanisms are involved in mediating the pathophysiology of traumatic brain injury (TBI), including inflammatory processes and excitotoxicity. In the present study, we evaluated the ability of the use-dependent sodium channel inhibitor Riluzole to attenuate cognitive and neurologic motor deficits and reduce regional cerebral edema and histologic cell damage following lateral fluid-percussion (FP) brain injury in rats (n = 109). In study 1, 58 anesthetized male Sprague-Dawley rats (350-400 g) were subjected to FP brain injury of moderate severity (2.3-2.5 atm). Fifteen minutes following brain injury, animals randomly received an i.v. bolus of either Riluzole (4 mg/kg, n = 11), Riluzole (8 mg/kg, n = 11), or glycol vehicle (n = 20), followed by 6 h and 24 h s.c. injections (identical dose). Surgically prepared but uninjured animals received vehicle (n = 16) and served as controls. Animals were evaluated for cognitive deficits at 48 h postinjury and killed for assessment of regional brain edema. Administration of vehicle or Riluzole (4 mg/kg x 3) had no significant effect on memory or edema, whereas Riluzole (8 mg/kg x 3) significantly attenuated post-traumatic cognitive dysfunction (p < 0.05). In study 2, a second group of animals (n = 25) was injured, treated with Riluzole (8 mg/kg x 3 doses, n = 13) or vehicle (n = 12), and evaluated for neurologic motor function over 2 weeks. Animals treated with Riluzole demonstrated significantly improved motor scores beginning 1 week postinjury (p < 0.05). In study 3, brain-injured animals were treated with Riluzole (8 mg/kg x 3 doses, n = 10) or vehicle (n = 10), and posttraumatic lesion volume was assessed at 48 h postinjury using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with Riluzole had no significant effect on posttraumatic lesion volume. The present study demonstrates that use-dependent sodium channel inhibitors, such as Riluzole, can attenuate both cognitive and neuromotor dysfunction associated with brain trauma.

Animals↗
PubMed1995

Inhibition by riluzole of glycinergic postsynaptic currents in rat hypoglossal motoneurones.

1. Riluzole has been shown to have beneficial effects in motoneurone disease, yet its effect on motoneurones is not known. To address this question, we investigated synaptic modulation by riluzole in hypoglossal motoneurones by recording glycinergic inhibitory postsynaptic currents evoked by stimulation of nearby single interneurones. 2. Glycinergic inhibitory postsynaptic currents were evoked by electrical stimulation of single interneurones and were recorded from visually identified hypoglossal motoneurones. Riluzole (10 microM) inhibited mean amplitude of evoked glycinergic inhibitory postsynaptic currents by 87%. 3. We found that riluzole suppressed sodium currents in brainstem interneurones by 23.8%. Riluzole did not modulate barium currents through voltage-activated calcium channels (98% of control). Therefore, the effect of riluzole on synaptic transmission may be mediated, in part, by stabilizing presynaptic neurones through inhibition of voltage-activated sodium currents. 4. In the presence of tetrodotoxin (0.5 microM), riluzole reduced the frequency (1.2 Hz in control to 0.6 Hz in riluzole) of spontaneous transmitter release recorded in motoneurones. 5. Riluzole was found to have no effect on mean miniature inhibitory postsynaptic current amplitude, therefore the reduction in spontaneous transmitter release cannot be due to an action on postsynaptic glycine receptors. 6. We conclude that riluzole inhibits synaptic transmission presynaptically, independent of a reduction in the excitation of presynaptic neurones.

Animals↗
PubMed1994

Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole.

The effects of riluzole, a novel neuroprotective drug with anticonvulsant and anti-ischemic properties, were studied on currents carried by cloned rat brain IIA sodium channel alpha subunits expressed in Xenopus oocytes. (i) When the oocytes were held at strongly hyperpolarized potentials to close the sodium channels and riluzole was added to the external solution, the current elicited by test depolarizing pulses was reduced within a few minutes and recovered upon washout of the riluzole. Although the currents were reduced, riluzole did not shift the peak current-voltage relationship. An inhibitory constant of 30 microM was estimated for the low affinity block of closed channels. (ii) Riluzole did not affect the time course of inactivation, and repetitive stimulation at frequencies that did not result in significant accumulation of inactivation did not affect current block. These results suggest that riluzole did not block open channels. (iii) Riluzole increased steady state inactivation by shifting its voltage dependence in the hyperpolarizing direction, by prolonging the recovery from inactivation, and by blocking more effectively at high stimulation frequencies. According to the modulated receptor theory, these results suggest that riluzole binds selectively to inactivated channels, with an inhibitory constant estimated at 0.2 microM. These results show that the riluzole binding site is on the alpha subunit of the sodium channel, and they suggest that stabilization of the inactivated state may underlie the neuroprotective properties of riluzole.

Animals↗
PubMed1997

Riluzole: a new agent for amyotrophic lateral sclerosis.

OBJECTIVE: To provide a comprehensive review of riluzole, including its mechanism of action, pharmacokinetics, adverse drug reactions, drug interactions, efficacy, and administration. A brief review of amyotrophic lateral sclerosis (ALS) is also included. DATA SOURCES: A computerized search of the MEDLINE database in May 1996 was used to identify publications regarding ALS, riluzole, and metabolism by CYP1A2. Manufacturer's information on riluzole was used when there was no primary literature. DATA SYNTHESIS: Riluzole is approximately 90% absorbed following an oral dose. Its bioavailability is 60%. Peak concentrations occur within 1-1.5 hours of administration. Riluzole extensively binds to lipoproteins and albumin. This agent primarily undergoes CYP1A2 hydroxylation and glucuronidation, after which it is eliminated by the kidneys. Clearance is reduced in native Japanese healthy subjects and may be reduced in patients with hepatic impairment. Two trials with a total of 1114 patients addressed the efficacy of riluzole in ALS. Riluzole extended the time to tracheostomy or death, and the effect was greatest with dosages of 100 mg/d or greater. No effect on patients' symptoms or global assessment was detected at 18 or 21 months. Several flaws in these trials have led to questions concerning the validity of these results. The most commonly reported adverse effects of riluzole have been transient elevation of liver enzyme concentrations (2-5 times the upper limit of normal), worsening of asthenia, nausea, vomiting, diarrhea, anorexia, dizziness, vertigo, somnolence, and mouth paresthesia. Not as commonly reported, but still very serious, is neutropenia, which occurred in 3 of 4000 patients. CONCLUSIONS: Although the benefits of riluzole are questionable and it is expensive, this agent may extend the time to tracheostomy or death in patients with ALS. At present, this is the only agent approved for the treatment of ALS and should be made available for these patients.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis.

Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.

Administration, Oral↗
PubMed1997

Involvement of human CYP1A isoenzymes in the metabolism and drug interactions of riluzole in vitro.

Cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes involved in riluzole oxidation and glucuronidation were characterized in (1) kinetic studies with human hepatic microsomes and isoenzyme-selective probes and (2) metabolic studies with genetically expressed human CYP isoenzymes from transfected B-lymphoblastoid and yeast cells. In vitro incubation of [14C]riluzole (15 microM) with human hepatic microsomes and NADPH or UDPGA cofactors resulted in formation of N-hydroxyriluzole (K(m) = 30 microM) or an unidentified glucuroconjugate (K(m) = 118 microM). Human microsomal riluzole N-hydroxylation was most strongly inhibited by the CYP1A2 inhibitor alpha-naphthoflavone (IC50 = 0.42 microM). Human CYP1A2-expressing yeast microsomes generated N-hydroxyriluzole, whereas human CYP1A1-expressing yeast microsomes generated N-hydroxyriluzole, two additional hydroxylated derivatives and an O-dealkylated derivative. CYP1A2 was the only genetically expressed human P450 isoenzyme in B-lymphoblastoid microsomes to metabolize riluzole. Riluzole glucuronidation was inhibited most potently by propofol, a substrate for the human hepatic UGT HP4 (UGT1.8/9) isoenzyme. In vitro, human hepatic microsomal hydroxylation of riluzole (15 microM) was weakly inhibited by amitriptyline, diclofenac, diazepam, nicergoline, clomipramine, imipramine, quinine and enoxacin (IC50 approximately 200-500 microM) and cimetidine (IC50 = 940 microM). Riluzole (1 and 10 microM) produced a weak, concentration-dependent inhibition of CYP1A2 activity and showed competitive inhibition of methoxyresorufin O-demethylase. Thus, riluzole is predominantly metabolized by CYP1A2 in human hepatic microsomes to N-hydroxyriluzole; extrahepatic CYP1A1 can also be responsible for the formation of several other metabolites. Direct glucuronidation is a relatively minor metabolic route. In vivo, riluzole is unlikely to exhibit significant pharmacokinetic drug interaction with coadministered drugs that undergo phase I metabolism.

Biotransformation↗
PubMed1996

Neuroprotective effects of riluzole on a model of Parkinson's disease in the rat.

The aim of the present study was to analyse whether riluzole, a compound that interacts with the voltage-dependent sodium channel and impairs glutamatergic transmission, would exhibit a neuroprotective activity in a model of Parkinson's disease in the rat. Impaired skilled forelimb use, circling behavior, and altered dopaminergic metabolism of the mesotelencephalic system were evaluated in unilaterally 6-hydroxydopamine-lesioned rats. Riluzole was administered twice 15 min before, and 24 h after, the lesion. Riluzole reduced both the contralateral rotations induced by apomorphine and the ipsilateral ones elicited by amphetamine. Moreover, the decreased dopaminergic metabolism seen after 6-hydroxydopamine injection was attenuated in the riluzole-treated animals, at both the striatal and nigral levels. These biochemical and behavioral results demonstrate the ability of riluzole partially to protect the degeneration of the nigrostriatal dopaminergic neurons induced by the toxin 6-hydroxydopamine. Perhaps, the most striking evidence for the protective effect of riluzole was that this compound improved the skilled paw use, a complex sensorimotor behavior which is not easily ameliorated by palliative therapies such as dopaminergic grafts. These results extend previous data showing that riluzole counteracts the toxicity induced by 1-methyl-4-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium in rodent dopaminergic neurons. The use of riluzole may be considered of potential interest for the neuroprotective therapy of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Riluzole reduces brain lesions and improves neurological function in rats after a traumatic brain injury.

Riluzole (2-amino 6-trifluoromethoxy-benzothiazole) was studied in a rat model of traumatic brain injury (TBI) induced by a fluid percussion applied laterally to the right parietal cortex. Study I: vehicle or riluzole (4 or 8 mg/kg) was administered 15 min (i.v.), 6 h and 24 h (s.c.), after TBI. Brain lesions were quantified 1 week after insult. Riluzole significantly reduced the size of TBI-induced lesions by approximately 44% with either dose regime (P < 0.05). Study II: vehicle or riluzole (8 mg/kg) was administered 15 min (i.v.), 6 h (i.p.) and then twice daily (i.p.) for 6 days, after injury. One, 2 and 3 weeks after TBI, a neurological examination was performed. Control injured rats had a significant neurological deficit at 1, 2 and 3 weeks (P < 0.001). Riluzole treatment did not modify the neurological status evaluated for the first 2 weeks after TBI. However at 3 weeks, riluzole significant improved the neurological function of injured rats (P < 0.05). These results suggest that riluzole may be beneficial in the clinical treatment of TBI. The protective action of riluzole may result from (i) stabilization of the inactivated state of voltage-dependent sodium channels, (ii) indirect action on the glutamatergic pathway, and/or (iii) indirect neurotrophic effect.

Animals↗
PubMed1997

Prodystonic effects of riluzole in an animal model of idiopathic dystonia related to decreased total power in the red nucleus?

The effects of riluzole (2-amino-6-trifluoromethoxy benzothiazole) on the severity of dystonia were examined in mutant hamsters (dtsz), an animal model of idiopathic dystonia in which dystonic attacks can be age dependently induced by mild stress. Previous studies in hamsters have shown antidystonic activity of various glutamate receptor antagonists whereas lamotrigine, considered as an inhibitor of glutamate release, exerted prodystonic effects. The latter, unexpected, finding prompted us to investigate riluzole which is thought to possess antiglutamatergic properties with mechanisms similar to those of lamotrigine. Riluzole (2, 5, 10 or 20 mg/kg i.p.) dose dependently decreased the latency to onset of dystonic attacks. A dose of 10 or 20 mg/kg significantly increased the severity of dystonia. Even in dtsz hamsters older than 70 days, i.e., after spontaneous remission of age-dependent dystonia, riluzole (10 or 20 mg/kg) provoked severe long-lasting (> 4 h) dystonic attacks. At a dose of 20 mg/kg, riluzole provoked short-lasting (< 1 h) dystonic disturbances also in non-dystonic control hamsters. Electroencephalographic recordings from depth electrodes in the red nucleus, where recent studies have shown abnormal neural activity before and during dystonic attacks in dtsz hamsters, revealed that riluzole (10 mg/kg) tended to cause a further decrease of the total power in dtsz hamsters and significantly reduced the total power in control animals. This finding may indicate that the prodystonic effects of riluzole are related to alterations of rubrospinal activity. With regard to antidystonic effects of glutamate receptor antagonists demonstrated in previous studies, the prodystonic effects of riluzole and, as shown by recent experiments, of lamotrigine also, may be due to the lack of selectivity of these drugs to inhibit glutamate release.

Animals↗
PubMed1992

Anesthetic properties of riluzole (54274 RP), a new inhibitor of glutamate neurotransmission.

It has been suggested that some anesthetic agents could exert their hypnotic/anesthetic effects by selectively blocking receptors involved in the central excitatory neurotransmission mediated by glutamate. In the present study, we analyzed whether riluzole (54274 RP), a novel compound that inhibits both the release and some postsynaptic effects of glutamate in some brain structures, has anesthetic properties in rats. For this purpose, we investigated whether 1) riluzole administered intraperitoneally (ip) at doses ranging from 2.5 to 45 mg/kg induces loss of righting reflex (LRR); 2) riluzole (2.5 and 5 mg/kg) prolongs sleep-times induced by either ketamine (30 or 80 mg/kg ip) or thiopental (25 or 35 mg/kg ip); 3) a 5-mg/kg subanesthetic riluzole dose affects the minimum alveolar concentration of halothane (MACh). Onset of drug action was defined as the period of time from the ip injection to LRR. Sleep-time was considered the period of time from LRR to restoration of righting reflex. Riluzole at doses greater than 15 mg/kg was able to induce LRR (riluzole dose for which LRR was achieved in 50% of the rats [ED50 = 25.6 mg/kg]). A positive correlation was found between the dose of riluzole and sleep-time (r = 0.92, P less than 0.001). A 5-mg/kg (but not 2.5-mg/kg) riluzole dose significantly prolonged sleep-times induced by both ketamine (30 and 80 mg/kg) and thiopental (25 but not 35 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1996

Riluzole anesthesia: use-dependent block of presynaptic glutamate fibers.

BACKGROUND: Riluzole (RP 54274) is an experimental benzothiazole with anesthetic properties, but little is known about its synaptic or cellular actions. METHODS: The authors investigated riluzole effects on synaptic response of CA 1 pyramidal neurons in rat hippocampal brain slices. Electrophysiologic recordings of population spikes (PS), excitatory postsynaptic potentials (EPSP), and fiber volleys were studied. Paired pulse stimulation (120 ms interpulse interval) was used to measure effects on gamma-amino butyric acid (GABA)-mediated synaptic inhibition, and stimulus trains (33 Hz) were used to test for use-dependent effects. RESULTS: Synaptically evoked PS discharge was blocked in a concentration-dependent manner by riluzole (2.0-20 microM), similar to effects produced by other anesthetics. Paired pulse inhibition was not altered by riluzole. In contrast, 20 microM thiopental produced a marked increase in paired pulse inhibition. Riluzole (5.0 microM) produced a 46.6 +/- 19.8% depression of glutamate-mediated EPSPs, which could account for most of the mate-mediated EPSPs, which could account for most of the depression of PS discharge (54.2 +/- 12.6%) produced by this concentration. Riluzole produced a 36 +/- 17% depression of fiver volley amplitudes, which, based on input/output analysis, could completely account for the depression of EPSPs. The depression of fiber volley amplitudes showed a marked use-dependence; the second and subsequent action potentials in a train were progressively depressed by riluzole to a greater extent than the first action potential. CONCLUSIONS: Riluzole produced a potent block of excitatory synaptic transmission via depression of presynaptic conduction in glutamatergic nerve fibers. The use-dependent depression observed resembled that produced by some local anesthetics on nerve conduction and sodium channels. The presynaptic action, together with a lack of effect on gamma-amino butyric acid-mediated inhibition, provides a unique mechanism of action for a general anesthetic.

Action Potentials↗
PubMed1997

Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels.

The effects of riluzole, a neuroprotective drug, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. At the resting potential, riluzole preferentially blocked TTX-S sodium channels, whereas at more negative potentials, it blocked both types of sodium channels almost equally. The apparent dissociation constants for riluzole to block TTX-S and TTX-R sodium channels in their resting state were 90 and 143 microM, respectively. Riluzole shifted the voltage dependence of activation of TTX-R sodium channels in the depolarizing direction more than that of TTX-S sodium channels. The voltage dependence of the fast inactivation of both types of sodium channels was shifted in the hyperpolarizing direction in a dose-dependent manner, and the apparent dissociation constants for riluzole to block the inactivated channels were estimated to be 2 and 3 microM for the TTX-S and TTX-R sodium channels, respectively, indicating a much higher affinity for the inactivated channels than for the resting channels. Riluzole was equally effective in blocking both types of sodium channels in their slow inactivated state. Since more TTX-S channels are inactivated than TTX-R channels at the resting potential, riluzole blocks TTX-S sodium channels more potently than TTX-R sodium channels. It was concluded that one of the mechanisms by which riluzole exerts its neuroprotective action is to preferentially block the inactivated sodium channel of damaged or depolarized neurons under ischemic conditions, thereby suppressing excess stimulation of the glutamatergic receptors and massive influx of Ca++.

Animals↗
PubMed1997

Riluzole reduces incidence of abnormal movements but not striatal cell death in a primate model of progressive striatal degeneration.

Riluzole has been shown recently to increase life expectancy in patients with amyotrophic lateral sclerosis. A number of experimental studies also suggest that this compound may be a neuroprotectant. We have investigated in baboons whether riluzole would protect striatal neurons from a prolonged 3-nitropropionic acid (3NP) treatment and ameliorate the associated motor symptoms. In animals receiving 3NP and the solvent of riluzole, 12 weeks of high-dose 3NP treatment resulted in the appearance of persistent leg dystonia and significant increases in the incidence of three categories of abnormal movements and in the dyskinesia index in the apomorphine test (0.5 mg/kg i.m.). Quantitative assessment of these behavioral deficits using a video movement analysis system demonstrated a significant decrease in locomotor activity and peak tangential velocity in 3NP-treated animals compared to controls. Histological analysis showed the presence of severe, bilateral, striatal lesions, localized in both caudate and putamen. Cotreatment with riluzole (4 mg/kg i.p., twice daily) significantly reduced the dyskinesia index (-35%, P < 0.02) in the apomorphine test. In the quantitative behavioral analysis, riluzole significantly ameliorated the decrease in peak tangential velocity (P < 0.02) but not the decrease in locomotor activity observed after 3NP. Comparative histological analysis of the two groups of treated animals did not demonstrate a clear neuroprotective effect of riluzole. The present study suggests that one potential therapeutic interest for riluzole in neurodegenerative disorders may reside in the reduction of motor symptoms associated with striatal lesions.

Acetylcholinesterase↗
PubMed1998

Selective inhibition by riluzole of voltage-dependent sodium channels and catecholamine secretion in adrenal chromaffin cells.

We examined the effects of riluzole, a neuroprotective drug, on voltage-dependent Na channels, nicotinic receptors, and voltage-dependent Ca channels, as well as catecholamine secretion, in comparison with those of verapamil and nicardipine, in primary cultures of bovine adrenal chromaffin cells. Riluzole inhibited veratridine-induced 22Na influx via voltage-dependent Na channels even in the presence of ouabain, an inhibitor of Na,K-ATPase. Blockade of Na channels by riluzole was concentration-dependent with an IC50 of 5.3 microM. It was associated with a similar concentration-related reduction of veratridine-induced 45Ca influx via voltage-dependent Ca channels, and of catecholamine secretion. Riluzole had no effect on 45Ca influx caused by high K, which directly activates voltage-dependent Ca channels, and on nicotine-induced 22Na influx, which passes through the nicotinic receptors. Verapamil and nicardipine attenuated 22Na influx caused by veratridine or nicotine at the same concentrations as they suppressed high K-induced 45Ca influx. The inhibitory effect of riluzole on veratridine-induced 22Na influx disappeared at high concentrations of veratridine. A potentiation of veratridine (site 2 toxin)-induced 22Na influx caused by alpha-scorpion venom (site 3 toxin), beta-scorpion venom (site 4 toxin), or brevetoxin PbTx-3 (site 5 toxin), occurred in the presence of riluzole in the same manner as in control cells. These results suggest that riluzole binds to the veratridine site in voltage-dependent Na channels. It does not impair the cooperative interaction between the functional peptide segments of Na channels, but selectively inhibits gating of Na channels, thereby reducing Ca influx via Ca channels and catecholamine secretion. In contrast, verapamil and nicardipine suppress Na influx both Na channels and nicotinic receptors.

Animals↗
PubMed1997

G-proteins are involved in riluzole inhibition of high voltage-activated calcium channels in rat dorsal root ganglion neurons.

Effects of riluzole on high voltage-activated (HVA) calcium channels of rat dorsal root ganglion neurons were studied using the whole-cell patch-clamp technique. Riluzole at 30 microM inhibited the HVA currents. The onset and offset of riluzole inhibitory effect were slow usually taking more than 3 min. Riluzole inhibition of the HVA currents was abolished and partially reduced by addition of 500 microM GDP-beta-S and 1 mM N-ethylmaleimide, respectively, to the pipette solution. Pre-treatment with pertussis toxin or application of depolarizing pre-pulses did not affect riluzole's inhibitory effect on the HVA currents. Riluzole inhibition of the HVA currents was also blocked by internal application of 50 microg/ml protein kinase A inhibitory peptide. It was concluded that pertussis toxin-insensitive G-proteins and protein kinase A may be involved in riluzole inhibition of the HVA currents.

Animals↗