Chapter 14 Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole

Schwartz, Gwen; Fehlings, Michael G.

doi:10.1016/s0079-6123(02)37016-x

Cited by 114 publications

(67 citation statements)

References 95 publications

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“…4 Riluzole, a neuroprotective drug licensed for the treatment of amyotrophic lateral sclerosis (ALS) patients, has also been tested in a rat model of SCI in a number of laboratories, including our own. 5,6 Riluzole acts on multiple molecular targets to improve functional recovery, although its mechanism of action has not been fully delineated. 6,7 Riluzole may offer neuroprotection after SCI by reducing excitotoxicity via the inhibition of presynaptic glutamate release.…”

Section: Introductionmentioning

confidence: 99%

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

Satkunendrarajah

Teng

et al. 2013

Journal of Neurotrauma

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104

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Riluzole, a sodium/glutamate antagonist has shown promise as a neuroprotective agent. It is licensed for amyotrophic lateral sclerosis and is in clinical trial development for spinal cord injury (SCI). This study investigated the therapeutic time-window and pharmacokinetics of riluzole in a rodent model of cervical SCI. Rats were treated with riluzole (8 mg/kg) at 1 hour (P1) and 3 hours (P3) after injury or with vehicle. Afterward, P1 and P3 groups received riluzole (6 (mg/kg) every 12 hours for 7 days. Both P1 and P3 animals had significant improvements in locomotor recovery as measured by open field locomotion (BBB score, BBB subscore). Von Frey stimuli did not reveal an increase in at level or below level mechanical allodynia. Sensory-evoked potential recordings and quantification of axonal cytoskeleton demonstrated a riluzole-mediated improvement in axonal integrity and function. Histopathological and retrograde tracing studies demonstrated that delayed administration leads to tissue preservation and reduces apoptosis and inflammation. High performance liquid chromatography (HPLC) was undertaken to examine the pharmacokinetics of riluzole. Riluzole penetrates the spinal cord in 15 min, and SCI slowed elimination of riluzole from the spinal cord, resulting in a longer half-life and higher drug concentration in spinal cord and plasma. Initiation of riluzole treatment 1 and 3 hours post-SCI led to functional, histological, and molecular benefits. While extrapolation of post-injury time windows from rat to man is challenging, evidence from SCI-related biomarker studies would suggest that the post-injury time window is likely to be at least 12 hours in man.

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Section: Introductionmentioning

confidence: 99%

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

Satkunendrarajah

Teng

et al. 2013

Journal of Neurotrauma

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104

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“…At the cellular level, impairments include ionic imbalance, peroxidation of membrane lipids, formation of free radicals and release of toxic levels of the excitatory neurotransmitter glutamate. 4 Neuroprotective agents act to mitigate secondary injury mechanisms to reduce the extent of neural damage.…”

Section: What Mechanisms Underlie Neural Injury and Repair?mentioning

confidence: 99%

“…31 In preclinical models of spinal cord injury, riluzole mitigates secondary injury by blocking pathological activation of sodium channels and reducing the release of neuronal glutamate. 4 A phase I/II trial evaluating the safety and pharmacokinetics of riluzole for injuries in humans began in 2010 and was completed in January 2012, with full results awaiting publication. 32,33 Minocycline Minocycline, a chemically modified form of tetracycline, has shown to be neuroprotective in animal injury models, although its exact mechanisms of action remain incompletely understood.…”

Section: Riluzolementioning

confidence: 99%

Emerging therapies for acute traumatic spinal cord injury

Wilson

Forgione

Fehlings

2012

CMAJ

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175

122

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There are currently about 85 000 Canadians living with spinal cord injuries, more than half of which are secondary to trauma.1 As the population ages, the incidence and prevalence of traumatic spinal cord injury are expected to increase, primarily as a result of fall-related injuries among older adults 2 . Therefore, treating spinal cord injuries is relevant not only to spine surgeons and physiatrists, but also to the general clinician who will increasingly encounter such patients in the emergency department or family practice.Here, we review relevant pathophysiology and recent evidence pertaining to the medical, surgical and cellular-based treatment of acute traumatic spinal cord injury. Most of the identified pharmacologic studies were randomized trials or early phase nonrandomized pro spective studies. Research relating to the remaining topics was predominately observational in design (Box 1).

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“…These processes, beginning immediately after the primary injury, include free radical formation, cellular ionic imbalance, cell membrane lipid peroxidation, release of excitotoxic glutamate, as well as vascular phenomenon, such as vasospasm and perfusion reperfusion injury [16][17][18][19]. The end result is the gradual expansion of the initial lesion, in a rostro-caudal direction from the epicenter of the initial force, furthering gray matter loss and white matter degeneration, at the expense of neurologic function [20]. Because the temporal evolution of secondary injury unfolds for a duration of several weeks, a therapeutic time window exists, during which mitigation of the aforementioned processes can lead to reduced neural tissue destruction and improved clinical outcomes.…”

Section: Pathophysiologymentioning

confidence: 99%

Emerging Approaches to the Surgical Management of Acute Traumatic Spinal Cord Injury

Wilson

Fehlings

2011

Neurotherapeutics

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Summary: Traumatic, spinal cord injury (SCI) is a potentially catastrophic event causing major impact at both a personal and societal level. To date, virtually all therapies that have shown promise at the preclinical stage of study have failed to translate into clinically effective treatments. Surgery is performed in the setting of SCI, with the goals of decompressing the spinal cord and restoring spinal stability. Although a consensus regarding the optimal timing of surgical decompression for SCI has not been reached, much of the preclinical and clinical evidence, as well as a recent international survey of spine surgeons, support performing early surgery (<24 hours). Results of the multicenter, Surgical Trial in Acute Spinal Cord Injury Study (STASCIS), expected later this year, should further clarify this important management issue. The overall goal of this review is to provide an update regarding the current status of surgical therapy for traumatic SCI by reviewing relevant pathophysiology, laboratory, and clinical evidence, as well as to introduce radiologic and clinical tools that aid in the surgical decision-making process.

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Chapter 14 Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole

Cited by 114 publications

References 95 publications

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

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

Emerging therapies for acute traumatic spinal cord injury

Emerging Approaches to the Surgical Management of Acute Traumatic Spinal Cord Injury

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