Riluzole elevates GLT-1 activity and levels in striatal astrocytes

Carbone, Marica; Duty, Susan; Rattray, Marcus

doi:10.1016/j.neuint.2011.10.017

Cited by 101 publications

(81 citation statements)

References 55 publications

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“…EAAT2 upregulation, we note that not all studies have confirmed that EAAT2 can be upregulated by ceftriaxone (39,40). Similarly, our study found only marginal upregulation of EAAT2 with ceftriaxone administration to mice ( Figure 3F).…”

Section: Methodssupporting

confidence: 59%

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Kong¹,

Chang²,

Takahashi³

et al. 2014

J. Clin. Invest.

125

136

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Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.

show abstract

Section: Methodssupporting

confidence: 59%

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Kong¹,

Chang²,

Takahashi³

et al. 2014

J. Clin. Invest.

125

136

View full text Add to dashboard Cite

show abstract

“…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: 62%

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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“…Riluzole upregulates GLT-1 levels and activity in cultured primary mouse striatal astrocytes, independent of actions on ion channels [142]. In one study, cultured C6 astroglial cells were used to examine three independent intracellular pathways of glutamate metabolism, confirming that riluzole stimulates glutamate uptake and is an enhancer of EAAT1, dependent on the PKC, fibroblast growth factor receptor (FGFR) and phosphatidylinositol 3-kinase (PI3K) pathways [143].…”

Section: +mentioning

confidence: 99%

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

Blasco¹,

Mavel²,

Corcia³

et al. 2014

CMC

143

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Riluzole elevates GLT-1 activity and levels in striatal astrocytes

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Cited by 101 publications

References 55 publications

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

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

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

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