Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes

Azbill, Robert D.; Mu, Xiaojun; Springer, Joe E.

doi:10.1016/s0006-8993(00)02430-6

Cited by 166 publications

(105 citation statements)

References 35 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: 61%

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: 61%

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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“…Although GTs also regulate aspartate uptake, only glutamate will be mentioned in the following to simplify the discussion. Several lines of evidence support a critical role of regulating GT expression and uptake activity in maintaining in vivo glutamate homeostasis as indicated in in vitro studies (Semba and Wakuta, 1998;Azbill et al, 2000;Jabaudon et al, 2000;Lievens et al, 2000;Matthews et al, 2000;Mu et al, 2000). First, in a previous study downregulation of spinal GTs induced by chronic morphine administration resulted in the exacerbated response to exogenous glutamate (Mao et al, 2002b).…”

Section: Overall Consideration On Data Interpretationmentioning

confidence: 74%

“…An in vitro spinal synaptosome preparation was used to assess glutamate uptake activity of spinal GTs according to the previously published method (Mitrovic et al, 1999;Azbill et al, 2000;Mu et al, 2000). In brief, animals were killed after being exposed to a CO 2 chamber, and fresh tissue samples from the L 4 and L 5 spinal dorsal horns were removed as quickly as possible by laminectomy.…”

Section: In Vitro Glutamate Uptake Assaymentioning

confidence: 99%

“…Both supernatants were combined and again centrifuged at 13,000 rpm for 10 min at 4°C. The so-obtained synaptosomal pellets, which contain both neuronal and glial GTs (Mitrovic et al, 1999;Azbill et al, 2000;Mu et al, 2000), were suspended in 2 ml of Locke's buffer containing (in mM) 154 NaHCO 3 , 5.6 glucose, 5 HEPES, pH 7.2, and saturated with 95% O 2 /5% CO 2 . The protein concentration of final synaptosome pellets was measured by the Bradford method and was adjusted to 200 g/ml in Locke's buffer.…”

Section: In Vitro Glutamate Uptake Assaymentioning

confidence: 99%

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Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

2003

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The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors in rats. CCI induced an initial GT upregulation up to at least postoperative day 5 primarily within the ipsilateral spinal cord dorsal horn, which was followed by a GT downregulation when examined on postoperative days 7 and 14 by Western blot and immunohistochemistry. Intrathecal administration of the tyrosine kinase receptor inhibitor K252a and the mitogen-activated protein kinase inhibitor PD98059 for postoperative days 1-4 reduced and nearly abolished the initial GT upregulation in CCI rats, respectively. Prevention of the CCI-induced GT upregulation by PD98059 resulted in exacerbated thermal hyperalgesia and mechanical allodynia reversible by the noncompetitive NMDA receptor antagonist MK-801, indicating that the initial GT upregulation hampered the development of neuropathic pain behaviors. Moreover, CCI significantly reduced glutamate uptake activity of spinal GTs when examined on postoperative day 5, which was prevented by riluzole (a positive GT activity regulator) given intrathecally twice a day for postoperative days 1-4. Consistently, riluzole attenuated and gradually reversed neuropathic pain behaviors when the 4 d riluzole treatment was given for postoperative days 1-4 and 5-8, respectively. These results indicate that changes in the expression and glutamate uptake activity of spinal GTs may play a critical role in both the induction and maintenance of neuropathic pain after nerve injury via the regulation of regional glutamate homeostasis, a new mechanism relevant to the pathogenesis of neuropathic pain.

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“…A concrete mechanism of action is yet to be elucidated; however, it appears to act on glutamate transporters to facilitate the extracellular clearance of the excitotoxic neurotransmitter (42), as well as inhibiting the presynaptic cell from releasing glutamate (43). Synergistically, both of these actions would serve to decrease the glutamate load in the extrasynaptic space and thus attenuate the proposed cellular excitotoxic effects involved in disease pathogenesis.…”

Section: Murine Models Of Familial Alsmentioning

confidence: 99%

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

Zwiegers

Shaw

2015

jcbmr

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Amyotrophic lateral sclerosis (ALS) is a devastatingly progressive neurodegenerative disorder with multiple underlying etiological factors contributing to disease pathogenesis. Despite intensive research efforts and therapeutic development, disease presentation in ALS remains largely intractable to intervention. To date, the most common rodent model used in preclinical drug development accounts for a small proportion of the affected patient population and is predicated upon the significant overexpression of a mutant form of the human antioxidant protein, superoxide dismutase 1 (mSOD1). After more than 50 clinical trials, there is an alarming paucity of positive outcomes at the clinical level of ALS therapeutics with strong supporting pre-clinical data in mSOD1 models. Potential reasons for the negative clinical results are multifactorial in nature and include an overly reductionist model system that is heavily influenced by individual transgene level variation, as well as attempting to widely apply findings derived from a model of specific genetic causality to a patient population where the majority of cases are of unknown etiology. With such a tremendous disease burden and a lack of therapeutic options, it is critical that the research community re-evaluate the dependence on mSOD1 pre-clinical models as the gold standard prior to translating findings at the clinical level. Here we briefly review both the clinical and pre-clinical findings of select therapeutics, discuss the limitations of pre-clinical mSOD1 models, and suggest future stratagems that could aid in the clinical translation of efficacious therapeutic agents.

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Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes

Cited by 166 publications

References 35 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

Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

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