Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1

Fumagalli, Elena; Funicello, Marcella; Rauen, Thomas; Gobbi, Marco; Mennini, Tiziana

doi:10.1016/j.ejphar.2007.10.023

Cited by 222 publications

(169 citation statements)

References 28 publications

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“…3 and 4). 4,31,40 Even though studies have demonstrated that riluzole can upregulate GLT-1 on cultured astrocytes, 3,22 even in the absence of neurons, 8 riluzole does not alter the expression of striatal GLT-1 in a rodent model of Parkinson's disease when given at a dosage (4 mg/kg) comparable to that used here. 9 Therefore, it can be hypothesized that upregulation of spinal GLT-1 with riluzole treatment after a painful nerve root com- pression is likely a secondary mechanism of its neuroprotective properties (Figs.…”

Section: Discussionmentioning

confidence: 90%

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: Discussionmentioning

confidence: 90%

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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“…Riluzole regulates glutamate release, postsynaptic receptor activation, and inhibits voltage-sensitive channels (2, 10). Riluzole also was found to increase significantly glutamate uptake in a dose-dependent manner in the mouse CNS, facilitating the buffering of excessive extracellular glutamate and suggesting that the neuroprotective action of riluzole might be partly mediated by its activating effect on glutamate uptake (51). Treatment with riluzole decreased the plasma levels of excitatory amino acids during late stages of ALS in patients (101), although these data should not be considered conclusive (2).…”

Section: Amyotrophic Lateral Sclerosis and Glutamatementioning

confidence: 99%

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Foran

Trotti²

2009

Antioxidants & Redox Signaling

251

141

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Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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“…Although the primary mechanism of action of riluzole is believed to be presynaptic inhibition of glutamate release, it may also increase glutamate reuptake through the enhancement of glial excitatory amino-acid transporter functioning (Fumagalli et al, 2008;Valentine and Sanacora, 2009). Thus, riluzole may rapidly enhance glutamate-glutamine cycling, while increasing clearance of glutamate from the synapse.…”

Section: Association With Clinical Responsementioning

confidence: 99%

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

Brennan

Hudson

Jensen

et al. 2009

Neuropsychopharmacol

153

109

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Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100-200 mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm 3 voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d ¼ 3.4; po0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohen's d ¼ 1.2; p ¼ 0.023). NAA levels increased significantly from baseline to week 6 (d ¼ 1.2; p ¼ 0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d ¼ 1.4; p ¼ 0.053), but was negatively associated in the POC (d ¼ 9.6; po0.001). Riluzole seems to rapidly increase Gln/Glu ratiosFsuggesting increased glutamate-glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted.

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Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1

Cited by 222 publications

References 28 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 Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

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