Effects of riluzole on electrically evoked neurotransmitter release

Jehle, Thomas; Bauer, Judith; E, Blauth; Hummel, Astrid; Darstein, Melanie; Freiman, Thomas M.; Feuerstein, Thomas J.

doi:10.1038/sj.bjp.0703424

Cited by 68 publications

(52 citation statements)

References 40 publications

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“…Riluzole has been reported to bind to voltage-gated sodium channels and inhibit the persistent sodium current, reducing the frequency of repetitive firing of neurons. 5,36,67 This is consistent with the lower frequency of firing that was observed after its administration in this study (Fig. 5).…”

Section: Discussionsupporting

confidence: 79%

“…24 Riluzole has also been used effectively to reduce symptoms in animal models of neurodegenerative disease and neural tissue injury, which is attributed to its inhibition of presynaptic glutamate release by blocking voltagegated sodium channels. 5,15,21,36,67 Riluzole has been shown to decrease the size of spinal cord lesions; it promotes motor function recovery and restores the electrophysiological properties of spinal neurons after spinal cord injury. 62,68,76 It also has been shown to mitigate axonal degeneration and promote axonal regeneration after nerve injury.…”

mentioning

confidence: 99%

“…33,36,41,51 Sensitization of wide dynamic range (WDR) neurons, in particular, is thought to drive neuronal hyperexcitability and behavioral sensitivity after spinal cord ischemia and spinal nerve ligation. 28,48 Although increased calcitonin gene-related peptide (CGRP) and associated signaling contribute to neuronal hyperexcitability after painful neural trauma, 7,51 painful root compression decreases CGRP in the superficial dorsal horn.…”

mentioning

confidence: 99%

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Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

Nicholson

Zhang

Gilliland

et al. 2014

SPI

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Object Cervical radiculopathy is often attributed to cervical nerve root injury, which induces extensive degeneration and reduced axonal flow in primary afferents. Riluzole inhibits neuro-excitotoxicity in animal models of neural injury. The authors undertook this study to evaluate the antinociceptive and neuroprotective properties of riluzole in a rat model of painful nerve root compression. Methods A single dose of riluzole (3 mg/kg) was administered intraperitoneally at Day 1 after a painful nerve root injury. Mechanical allodynia and thermal hyperalgesia were evaluated for 7 days after injury. At Day 7, the spinal cord at the C-7 level and the adjacent nerve roots were harvested from a subgroup of rats for immunohistochemical evaluation. Nerve roots were labeled for NF200, CGRP, and IB4 to assess the morphology of myelinated, peptidergic, and nonpeptidergic axons, respectively. Spinal cord sections were labeled for the neuropeptide CGRP and the glutamate transporter GLT-1 to evaluate their expression in the dorsal horn. In a separate group of rats, electrophysiological recordings were made in the dorsal horn. Evoked action potentials were identified by recording extracellular potentials while applying mechanical stimuli to the forepaw. Results Even though riluzole was administered after the onset of behavioral sensitivity at Day 1, its administration resulted in immediate resolution of mechanical allodynia and thermal hyperalgesia (p < 0.045), and these effects were maintained for the study duration. At Day 7, axons labeled for NF200, CGRP, and IB4 in the compressed roots of animals that received riluzole treatment exhibited fewer axonal swellings than those from untreated animals. Riluzole also mitigated changes in the spinal distribution of CGRP and GLT-1 expression that is induced by a painful root compression, returning the spinal expression of both to sham levels. Riluzole also reduced neuronal excitability in the dorsal horn that normally develops by Day 7. The frequency of neuronal firing significantly increased (p < 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels. Conclusions These findings suggest that early administration of riluzole is sufficient to mitigate nerve root–mediated pain by preventing development of neuronal dysfunction in the nerve root and the spinal cord.

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Section: Discussionsupporting

confidence: 79%

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confidence: 99%

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confidence: 99%

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Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

Nicholson

Zhang

Gilliland

et al. 2014

SPI

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“…106 Although it has significant effects on glutamatergic function, riluzole is not a purely an antiglutamatergic agent. In vitro studies suggest that it also modulates release of acetylcholine and dopamine, 107 potentiates receptors for GABA and glycine, 108,109 and enhances expression of BDNF.…”

Section: Preliminary Clinical Studies Of Glutamate-modulating Agents mentioning

confidence: 99%

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Pittenger

Krystal

Coric

2006

NeuroRX

195

128

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Summary:Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD.These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

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“…Although this effect could be related to the ability of riluzole to inhibit dopamine and acetylcholine release [21], again in vivo administration of riluzole failed to alter dopamine and DOPAC extracellular levels. Therefore, the effects of riluzole on spontaneous and amphetamine-induced locomotion may be unrelated to a specific inhibition of the dopaminergic system, making it less likely to be efficient on schizophrenia through this mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Effect of Riluzole on MK-801 and Amphetamine-Induced Hyperlocomotion

Silva¹,

Hoffmann²,

Dietrich³

et al. 2003

Neuropsychobiology

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N-methyl-D aspartate (NMDA) antagonists, such as MK-801, and the dopamine indirect agonist amphetamine are pharmacological models used for the evaluation of putative new treatments for schizophrenia. Since the psychotomimetic effects of NMDA antagonists have recently been linked to their ability to increase glutamate release and since the glutamate release inhibitor riluzole prevented NMDA antagonist neurotoxicity, we evaluated the effect of riluzole on hyperlocomotion induced by MK-801 (0.25 mg/kg) and amphetamine (2.5 mg/kg). Mice pretreated with riluzole (3 mg/kg) did not influence baseline or MK-801-induced behavior, but 10 mg/kg produced moderate hypolocomotion alone and somewhat prolonged MK-801-induced hyperlocomotion. Pretreatment with riluzole 10 mg/kg, but not 3 mg/kg, had a moderately depressant effect both on spontaneous and amphetamine-induced locomotion. Taken together, these results suggest that riluzole would not be particularly effective as a treatment for schizophrenia and the neurotoxic and behavioral effect of NMDA antagonists do not clearly correlate.

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Effects of riluzole on electrically evoked neurotransmitter release

Cited by 68 publications

References 40 publications

Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

Effect of Riluzole on MK-801 and Amphetamine-Induced Hyperlocomotion

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