Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

Wu, Yongchao; Satkunendrarajah, Kajana; Teng, Yang; Chow, Diana; Buttigieg, Josef; Fehlings, Michael G.

doi:10.1089/neu.2012.2622

Cited by 81 publications

(111 citation statements)

References 40 publications

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“…Riluzole has been shown previously to cross the blood-brain barrier rapidly and to reduce spinal glutamate and mechanical hyperalgesia within 1 hour after an intraperitoneal injection. 15,26,76 After spinal cord contusion, riluzole alleviates pain when it is systemically administered or by an intracerebroventricular injection; yet, it is ineffective in alleviating behavioral sensitivity when it is directly administered into the intrathecal space of the spinal cord. 26 Therefore, the effects of riluzole on supraspinal glutamate appear to play a critical role in reducing pain associated with spinal cord injury.…”

Section: Discussionmentioning

confidence: 99%

“…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. 17,54,73 These results suggest that riluzole may inhibit the axonal degeneration that is induced after a painful root compression.…”

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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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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: 99%

mentioning

confidence: 99%

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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“…The evoked potential amplitudes were measured as the voltage difference from the peak of the first positive peak to the peak of the N1. 20 Recordings were acquired using Keypoint Portable (Dantec Biomed, Denmark).…”

Section: Electrophysiologymentioning

confidence: 99%

A New Acute Impact-Compression Lumbar Spinal Cord Injury Model in the Rodent

Moonen

Satkunendrarajah

Wilcox

et al. 2016

Journal of Neurotrauma

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Traumatic injury to the lumbar spinal cord results in complex central and peripheral nervous tissue damage causing significant neurobehavioral deficits and personal/social adversity. Although lumbar cord injuries are common in humans, there are few clinically relevant models of lumbar spinal cord injury (SCI). This article describes a novel lumbar SCI model in the rat. The effects of moderate (20 g), moderate-to-severe (26 g) and severe (35 g, and 56 g) clip impactcompression injuries at the lumbar spinal cord level L1-L2 (vertebral level T11-T12) were assessed using several neurobehavioral, neuroanatomical, and electrophysiological outcome measures. Lesions were generated after meticulous anatomical landmarking using microCT, followed by laminectomy and extradural inclusion of central and radicular elements to generate a traumatic SCI. Clinically relevant outcomes, such as MR and ultrasound imaging, were paired with robust morphometry. Analysis of the lesional tissue demonstrated that pronounced tissue loss and cavitation occur throughout the acute to chronic phases of injury. Behavioral testing revealed significant deficits in locomotion, with no evidence of hindlimb weight-bearing or hindlimb-forelimb coordination in any injured group. Evaluation of sensory outcomes revealed highly pathological alterations including mechanical allodynia and thermal hyperalgesia indicated by increasing avoidance responses and decreasing latency in the tail-flick test. Deficits in spinal tracts were confirmed by electrophysiology showing increased latency and decreased amplitude of both sensory and motor evoked potentials (SEP/MEP), and increased plantar H-reflex indicating an increase in motor neuron excitability. This is a comprehensive lumbar SCI model and should be useful for evaluation of translationally oriented pre-clinical therapies.

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“…11 This is largely due to an increased awareness of the complications associated with high dose steroid use, and the failure of subsequent studies to confirm the results of the NASCIS II. [11][12][13][14][15][16][17][18][19] Although alternative neuroprotective pharmacologic treatments, such as riluzole, are being developed and have shown promise in animal trials, [20][21][22][23] clinical trials are still in the early stages. 24,25 Although the use of different neuroprotective medications is unclear, one of the widely available and accepted treatments used to limit the secondary injury from an acute SCI is ensuring spinal cord perfusion with induced hypertension (HTN).…”

Section: Introductionmentioning

confidence: 99%

The effect of preexisting hypertension on early neurologic results of patients with an acute spinal cord injury

et al. 2015

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Study design: Retrospective case-control. Objectives: To characterize changes in American Spinal Injury Association Motor Score (AMS) in patients treated with relative hypertension (HTN) (mean arterial pressure (MAP) 4 85 mm Hg for 5 days) with and without preexisting HTN. Setting: A regional spinal cord injury (SCI) center in Pennsylvania, United States. Methods: All patients with an acute SCI who were treated with induced HTN (MAP goal above 85) in the intensive care unit (ICU) for at least 5 days were identified. Patients were stratified based on the presence of preexisting HTN, and the change in the AMS between admission and day 5 was determined. Predictors of outcome were identified using correlation analysis and multiple linear regression. Results: Ninety-two patients met inclusion criteria of which 22 had a previous history of HTN. HTN was a predictor of poor early outcome. Patients with HTN had an average decline in their AMS of 7.6, compared with an average decrease of only 0.6 in the AMS of patients without HTN (P = 0.04). HTN had no effect (P40.05) on other in-hospital variables including length of stay, length of stay in the ICU, complications or mortality. Additionally, multiple linear regression analysis demonstrated that diabetes, coronary artery disease and pulmonary disease had no effect on the change in AMS. Conclusion: Chronic HTN is an independent risk factor for poor early neurologic recovery in patients treated with relative HTN for an acute SCI. This is independent of age and other comorbidities.

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Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

Cited by 81 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

A New Acute Impact-Compression Lumbar Spinal Cord Injury Model in the Rodent

The effect of preexisting hypertension on early neurologic results of patients with an acute spinal cord injury

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