Efficacy of riluzole in the treatment of spinal cord injury: a systematic review of the literature

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OBJECTIVE

Riluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains heterogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.

METHODS

The PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.

RESULTS

A total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18–70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor function, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1–10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.

CONCLUSIONS

SCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.

ABBREVIATIONS AIS = American Spinal Injury Association Impairment Scale; ALS = amyotrophic lateral sclerosis; SCI = spinal cord injury.

OBJECTIVE

Riluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains heterogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.

METHODS

The PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.

RESULTS

A total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18–70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor function, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1–10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.

CONCLUSIONS

SCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.

Spinal cord injury (SCI) remains a devastating problem, with traumatic SCI affecting 12,400 individuals annually and 250,000 living survivors reported to reside in the United States in July 2005.13 The prevalence of nontraumatic SCI is estimated to be 3–4 times greater than traumatic SCI.36 A variety of complications, including genitourinary and respiratory complications, often occur after SCI with rehospitalization rates of up to 55% in the 1st year after SCI and around 37% for every year thereafter for 20 years.8 Moreover, while 58.1% of patients are employed before injury, only 12.1% remained employed 1 year after injury. As a manifestation of both indirect and direct cost, patients sustaining an SCI at age 25 years can expect a lifetime cost of $4.6 million for high tetraplegia and $2.3 million for paraplegia.13 There remains a need to improve recovery after SCI, considering its high incidence and these associated complications.

The pathophysiology involved in SCI includes multiple mechanisms such as the shearing of axons,45 followed by neural death due to ischemia,28 production of inflammatory molecules,12 and the rise of extracellular glutamate contributing to excitotoxicity.43 Current acute management strategies of SCI include surgical decompression,19 maintenance of arterial pressure with fluids and vasoconstrictors,52 and methylprednisolone, an antiinflammatory corticosteroid that inhibits transmigration of neutrophils and macrophages into the spinal cord, thereby reducing peroxidation of lipids in the cell membrane.3 However, there remains a need for greater neuroprotective agents to promote long-term recovery after SCI.

Riluzole, a glutamatergic modulator used primarily in amyotrophic lateral sclerosis (ALS),26 is currently being evaluated for use in SCI. Riluzole activates guanosine triphosphate–binding signal transduction proteins (G-proteins), resulting in inhibition of neurotransmitter release.14 Riluzole also indirectly inhibits phospholipase A2 (PLA2), preventing release of arachidonic acid, and directly inhibits protein kinase C (PKC).42 Recent studies have suggested that riluzole is neuroprotective in neurodegenerative and traumatic injuries through its blockade of sodium channel overactivation and modulation of glutamate uptake,4 as well as its stimulation of brain-derived neurotrophic factor expression.29 The use and effects of riluzole specifically in SCI, however, remain relatively new.

In this article, we aim to provide an overview of riluzole’s potential effectiveness in SCI and review current pharmacological, animal study, and clinical trial findings with this treatment.

Methods

A systematic review to analyze the use of riluzole in SCI was performed through PubMed with articles dating from 1996 to September 2018 (Fig. 1). The search term was “riluzole Spinal Cord Injury.” This search yielded 99 results. Articles were included within this review if they presented primary human or animal data or investigated the pharmacology of riluzole in spinal cord injury. By this method, 37 experimental studies met the inclusion and exclusion criteria.

Fig. 1.
Fig. 1.

Ninety-nine clinical studies regarding the use of riluzole in spinal cord injury were initially identified. Twenty-seven articles were removed for inadequate access to the full article. Seventy-two papers were fully reviewed. After applying inclusion and exclusion criteria, 37 articles were selected for review and analysis.

The extracted articles were then divided into 3 categories: 1) animal studies describing therapeutic benefit, 2) clinical studies describing outcomes, and 3) pharmacological studies. Two studies contributed findings to both pharmacology and therapeutic benefit in animals.39,58 Animal studies were evaluated for study design (in vivo vs in vitro); animal type; injury model; number of animals included in experimental and control groups; dose; timing and route of administration; and outcomes measured by behavior, histopathology, and electrophysiology. Clinical trials were reviewed for study design, number of patients in experimental and control groups, SCI level, American Spinal Injury Association Impairment Scale (AIS) grade, average age, timing and route of administration, dosage, adverse events, and outcomes measured by sensory and motor functional tests. Pharmacological studies were evaluated for study design, subject type, injury model, number of patients in experimental and control groups, timing and route of administration dosage, adverse effects and outcomes measured by electrophysiology, neurotransmitter uptake, receptor expression, and pharmacokinetics.

Results

Pharmacological Studies

Despite extensively published research on the pharmacology of riluzole, there are few studies reporting its effects on SCI. In this review, 8 studies on the pharmacological effect of riluzole in SCI were included. Pharmacological studies described the mechanisms of action and pharmacokinetics of riluzole in vivo, in vitro, and in human studies. The major findings included decreased riluzole bioavailability in the spinal cord after SCI,10,15 with 1 study suggesting the opposite;58 blockage of sodium currents with riluzole after SCI;25 and increase in glutamate uptake and expression,3,38,53 with 1 study suggesting no effect of riluzole on glutamate release after SCI.35 A full description of the pharmacology articles within this study can be found in Table 1.

TABLE 1.

Pharmacology of riluzole in SCI

Authors & YearTitleStudy DesignSubject TypeInjury ModelExperimental GrpControl GrpDoseTimingRouteAdverse EffectsMain Findings
Dulin et al., 2013The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cordIn vivoRatModerate contusion/compression injury at T10 w/ Infinite Horizon Spinal Impactor DeviceGrp 1 (n = 7): SCI + riluzole; grp 2 (n = 8): SCI + riluzole + licofelone (total: 15)Sham + riluzole (n = 7)8 mg/kg3 hrs postinjury & once daily for 3 daysIPTx-associated mortality of 30% in riluzole grp1) PgP immunoreactivity & genetic expression ↑ in epicenter & distant rostrocaudal areas post-SCI; 2) riluzole bioavailability (spinal cord/plasma ratio) is significantly lower post-SCI; 3) knocking out PgP genetically & attenuating PgP expression w/ licofelone causes ↑ delivery of riluzole to spinal cord
Wu et al., 2013Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injuryIn vivoRatC7–T1 spinal cord compression extradurally w/ modified aneurysm clipGrp 1 (n = 6): 8 mg/kg 1 hr postinjury, then 8 mg/kg BID for 7 days; grp 2 (n = 10): 6 mg/kg 1 hr postinjury, then 6 mg/kg BID for 7 days; grp 3 (n = 6): 4 mg/kg 1 hr postinjury, then 4 mg/kg BID for 7 days; grp 4 (n = 12) (p1): 8 mg/kg at 1 hr postinjury, then 6 mg/kg BID for 7 days; grp 5 (n = 12) (p3): 8 mg/kg at 3 hrs postinjury, then 6 mg/kg BID for 7 days (total: 46)Grp 6 (n = 12): no injury + vehicle8, 6, 4 mg/kg1 or 3 hrs postinjury & BID for 7 daysIPNARiluzole is substantially higher in spinal cord than plasma & half-life ↑ post-SCI
Chow et al., 2012Pharmacology of riluzole in acute spinal cord injuryPhase 1 clinical trialHumanHumanGrp 1 (n = 36): riluzoleGrp 2 (n = 36): control50 mgBIDPO & nasogastric14–70% had elevated liver enzymes & bilirubin levelsMax concentration & systemic exposure of riluzole are lower in SCI pts than in ALS pts on same dose; riluzole has higher clearance & larger vol of distribution in SCI
Harvey et al., 2006Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult ratsIn vitro & in vivoRatAcute SCI: transection at S2 in vivo; chronic SCI: transection at S2 at age 40–55 daysGrp 1 (n = 41): acute SCI in vivo; grp 2 (n = 24): chronic SCI in vivo; grp 3 (n = 9): in vitro (total: 74)20 μMPost-tissue harvestingIn vitroNARiluzole blocks persistent inward currents of sodium in in vitro sacrocaudal spinal cord segments
McAdoo et al., 2005The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage → glutamate release → damage → glutamate release → etc.In vivoRatWeight drop on MASCIS impactor (T10)Grp 1 (n = 6): riluzoleGrp 2 (n = 6): control2.0 mMContinuous from preinjury to 4 hrs postinjuryMicrodialysis fiberNARiluzole does not affect glutamate release post-SCI
Sung et al., 2003Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in ratsIn vivoRatChronic constriction nerve injuryGrp 1 (n = 6): CCI + 1 mg/kg riluzole pre-Tx; grp 2 (n = 6): CCI + 4 mg/kg riluzole pre-Tx; grp 3 (n = 6): CCI + 1 mg/kg post-Tx; grp 4 (n = 6): CCI + 4 mg/kg post-Tx (total: 24)Grp 5 (n = 6): CCI + vehicle; grp 6 (n = 6): sham + 4 mg/kg post-Tx (total: 12)1 or 4 mg/kgPre-Tx (grps 1 & 2): starts immediately postinjury; post-Tx (grps 3 & 4): starts 5 DPI; BID for 4 days for both grpsIPNASCI induces significant expression of spinal glutamate transporters (EAAC1, GLST, GLT-1) in ipsilesional spinal cord dorsal horn; riluzole significantly ↑ glutamate uptake in ipsilesional spinal cord dorsal horn; riluzole administered immediately postinjury or 5 DPI attenuates neuropathic behaviors including thermal hyperalgesia & mechanical allodynia
Azbill et al., 2000Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomesIn vitro & in vivoRatNoneGrp 1 (n = 6): riluzoleGrp 2 (n = 6): saline8 mg/kg2× w/ 2 hrs btwn injection (euthanasia 2 hrs after last injection)IPNARiluzole ↑ glutamate uptake in spinal cord synaptosomes at 1 & 0.1 μM in vitro but not at higher doses; 0.1 μM riluzole causes 21% ↓ in Km & 31% ↑ in Vmax of glutamate
Mu et al., 200039Riluzole improves measures of oxidative stress following traumatic spinal cord injuryIn vivoRabbitContusion injury (impactor rod at T10)Grp 1 (n = 9): riluzole; grp 2 (n = 9): riluzole + methylprednisolone (total: 18)Grp 3 (n = 9): vehicle; grp 4 (n = 9): methylprednisolone (total: 18)8 mg/kg15 mins & 2 hrs postinjuryIPNARiluzole ↑ glutamate & glucose uptake post-SCI

BID = twice daily; CCI = chronic constriction injury; DPI = days postinjury; grp = group; IP = intraperitoneal; MASCIS = Multicenter Animal Spinal Cord Injury Study; max = maximum; NA = not available; PO = by mouth; pts = patients; p1 = rats treated with riluzole at 1 hour postinjury; p3 = rats treated with riluzole at 3 hours postinjury; Tx = treatment; ↑ = increase/increases/increased/increasing; ↓ = decrease/decreases/decreased/decreasing.

Eight studies with 6 in vivo experiments, 3 in vitro experiments, and 1 human study.

Animal Studies

Twenty-six animal studies describing the therapeutic effects of riluzole after SCI were included. There were 24 in vivo studies, 1 in vitro study, and 1 mixed study. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatments for comparison. The average dose of riluzole used was 6.5 mg/kg in 7 in vivo studies in rats with predominantly intraperitoneal administration, with a few exceptions instead involving intrathecal and intracerebroventricular24 or intravenous administration33 and rabbits.31–33,39 For behavioral studies, locomotion was evaluated with the rotarod, grid walk, open field, and pellet-reaching tasks; strength was evaluated with the inclined plane test; and sensory function was evaluated with the hind paw withdrawal test. A plethora of behavioral studies demonstrated positive effects of riluzole on motor function including locomotion,21,27,34,38,48,58,57 strength,1,47,48 and stance and stride length.47,49 With regard to sensory function, behavioral studies have suggested that riluzole decreases nociception24 and spastic reflexes,30 which is both encouraging for reduction of neuropathic behaviors and concerning for decreased response to noxious stimuli. Histopathological experiments have shown that after SCI, riluzole increased rostrocaudal and epicenter tissue sparing with decreased lesion volume, increased axonal sparing, and increased serotonergic fibers.38,48,55 Other studies have shown an increase in glial cell and neuronal survival,6,34,44,58 decrease in reactive oxygen species,49 increase in synaptophysin expression in the ventral horn,47 decrease in capillary fragmentation,50 decrease in pyknosis and hypoplasia of ventral motor neurons,49 decrease in lymphocytes and granulocytes,7 increase in choline acetylcholine transferase staining in motor neurons,21 decrease in lactate dehydrogenase,23 decrease in TUNEL staining apoptotic neurons,32,58,57 decrease in macrophages and microglia,58 and decrease in lipid peroxidation and water content.1 Electrophysiological experiments have suggested a decrease in muscle spasm,5 attenuation of altered reflex mechanisms,47 and increase in amplitude of somatosensory evoked potentials.58 Key findings within the animal data demonstrate spinal cord tissue sparing with cell survival after SCI,1,6,33,31–34,38,39,41,44,46,48,55,57,58 reduced inflammatory mediators and sequelae,7,49 improved locomotion,1,7,21,27,30,31–34,38,44,49,55 and decreased aberrant sensory responses.5,24 A full description of animal studies and the results from these investigations can be found in Table 2.

TABLE 2.

Impact of riluzole on SCI in in vitro and in vivo animal experiments

Authors & YearTitleStudy DesignSubject TypeInjury ModelExperimental GrpControl GrpDoseTimingRouteMain Findings
Caglar et al., 2018Effect of riluzole on spinal cord regeneration with hemisection method before injuryIn vivoRatHemisection after T7–9 lamniectomyGrps 1–6 & 8 (n = 28): riluzoleGrp 7 (n = 4): vehicle6 mg/kgGrps 1 & 6: 12 hrs pre-SCI & BID post-SCI until 7 DPI; grps 2 & 5: 1 hr pre-SCI & BID post-SCI until 7 DPI; grps 3 & 4: BID post-SCI until 7 DPI; grp 8: BID for 5 days pre-SCI but not post-SCIIPHistopathology: early riluzole Tx causes lower histopathological spinal cord tissue damage & ↑ no. of surviving glial cells & neurons
Shimizu et al., 2018Prophylactic riluzole attenuates oxidative stress damage in spinal cord distractionIn vivoRatBidirectional spinal distractor deviceGrp 1 (n = 54): riluzoleGrp 2 (n = 54): vehicle8 mg/kg initial dose, then 6 mg/kgBIDIPHistopathology: riluzole Tx ↓ reactive oxygen species formation & attenuates pyknosis & hypoplasia of ventral motor neurons post-SCI

Behavior: riluzole Tx maintains normal gait post-SCI as measured by ↑ stance duration & ↓ stride length
Martins et al., 2018Association of riluzole and dantrolene improves significant recovery after acute spinal cord injury in ratsIn vivoRatExtradural compression of dorsal surface of spinal cord using weightGrp 1 (n = 5): laminectomy + SCI + riluzole + placebo (15 mins & 1 hr postlaminectomy); grp 2 (n = 6): laminectomy + SCI + riluzole + dantrolene (15 mins/1 hr postlaminectomy) (total: 11)Grp 3 (n = 6): laminectomy + placebo; grp 4 (n = 6): laminectomy + SCI; grp 5 (n = 6): laminectomy + SCI + placebo + dantrolene (15 mins/1 hr postlaminectomy) (total: 18)4 mg/kg15 mins & 1 hr postlaminectomyIPImmunohistochemistry: when combined w/ dantrolene, riluzole significantly ↑ neuron survival in epicenter of injury & caudal regions as well

Behavior: when combined w/ dantrolene, riluzole improves hindlimb performance on BBB scale; riluzole alone does not improve hindlimb performance
Can et al., 2017Combined and individual use of pancaspase inhibitor Q-VD-OPh and NMDA receptor antagonist riluzole in experimental spinal cord injuryIn vivoRatClip compression via T7–9 laminectomiesGrp 1 (n = 9): SCI + riluzole only; grp 2 (n = 9): SCI + both riluzole & Q-VD-OPh (total: 18)Grp 3 (n = 9): SCI only; grp 4 (n = 9): SCI + vehicle; grp 5 (n = 9) SCI + Q-VD-OPh (pancaspase inhibitor) only (total: 27)5 mg/kg1 hr postinjuryIPHistopathology: riluzole Tx significantly ↓ lymphocyte count & polymorphonuclear leukocytes/granulocytes post-SCI; riluzole Tx does not significantly attenuate no. of apoptotic cells post-SCI

Behavior: riluzole significantly improves clinical motor score & inclined plane score post-SCI
Gloviczki et al., 2017Delayed spinal cord-brachial plexus reconnection after C7 ventral root avulsion: the effect of reinnervating motoneurons rescued by riluzole treatmentIn vivoRatC7 ventral root avulsion + C7 autologous nerve graftGrp 1 (n = 5): avulsion + immediate reconnection + riluzole; grp 2 (n = 5): avulsion + 1-wk delay to reconnection + riluzole; grp 3 (n = 5): avulsion + 3-wk delay to reconnection + riluzole (total: 15)Grp 4 (n = 5): avulsion + immediate reconnection; grp 5 (n = 5): avulsion + 1-wk delay to reconnection; grp 6 (n = 5): avulsion + 3-wk delay to reconnection (total: 15)5 mg/kgDaily for 1st wk & every 2nd day for 2nd wkIPHistopathology: riluzole Tx significantly improves motor neuron survival independent of timing of reconnection procedure relative to injury

Behavior: riluzole significantly improves pellet reaching & dorsiflexion after reconnection after ventral root avulsion
Brocard et al., 2016Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injuryIn vivoRatSpinal cord transection at T9Grp 1 (n = 8): 8 mg/kg once; grp 2 (n = 8): 4 mg/kg BID for 2 wks; grp 3 (n = 7): 1 mg/kg BID for 2 wks (total: 23)NA8 , 4, & 1 mg/kg8 mg/kg once, 4 mg/kg BID for 2 wks, or 1 mg/kg BID for 2 wksIPElectrophysiology: as measured by EMG, riluzole Tx at moderate dose (8 or 4 mg/kg) significantly ↓ muscle spasm & augments muscle spasm reduction when voltage-gated sodium channels are spared post-SCI; riluzole does not attenuate monosynaptic reflexes associated w/ glutamatergic currents
Vasconcelos et al., 2016Combining neuroprotective agents: effect of riluzole and magnesium in a rat model of thoracic spinal cord injuryIn vivoRatThoracic spinal cord contusion w/ weight dropGrp 1 (n = 4): riluzole; grp 2 (n = 5): riluzole + MgCl (total: 9)Grp 3 (n = 5): saline; grp 4 (n = 5): MgCl (total: 10)2.50 mg/kg1 hr postinjuryIPHistopathology: riluzole ↓ lesion vol, ↑ axonal preservation, & ↑ glutamatergic & serotonergic fiber sparing caudal but not rostral to epicenter of injury; riluzole does not significantly ↑ motor neuron survival

Behavior: riluzole significantly improves locomotor score as measured on BBB scale; riluzole significantly ↑ distance traveled in activity box
Satkunendrarajah et al., 2016Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisectionIn vivoRatComplete lt hemisection from midline below C2 dorsal rootGrp 1 (n = 18): riluzoleGrp 2 (n = 17): vehicle8 mg/kg1 hr postinjury, then BID for 7 daysIPHistopathology: riluzole Tx ↑ synaptophisin expression in caudal cervical ventral horn; riluzole Tx attenuates loss of NR2A subunit of NMDA receptor & GluR1 subunit of AMPA receptor; riluzole attenuates motor neuron loss as measured by ChAT positivity on ipsilesional & contralesional sides of injury

Electrophysiology: riluzole Tx attenuates injury-mediated alteration in Hmax/Mmax ratio

Behavior: riluzole Tx improves ipsilat forelimb grip strength as early as 3 DPI & contralat forelimb grip strength as early as 19 DPI; riluzole Tx ↑ stride length, swing speed, & forepaw width on catwalk test from 2 to 6 wks postinjury; riluzole Tx ↑ peak amplitude of inspiratory bursts of ipsilat diaphragm 2 wks postinjury
Hachem et al., 2015Evaluation of the effects of riluzole on adult spinal cord-derived neural stem/progenitor cells in vitro and in vivoIn vivo + in vitroRatRodent clip compression + injection of neural progenitor cells in proximal rostral & caudal regions to injury epicenterGrp 1 (n = 4): riluzoleGrp 2 (n = 4): vehicle8 mg/kgImmediately post-transplant, 6 mg/kg BID for 3 days, then once daily for 10 daysIPHistopathology

In vitro: exposure to high doses of riluzole ↓ neural progenitor stem cell survival & membrane integrity; riluzole does not affect no. of living or proliferating neural progenitor stem cells after glutamate exposure.

In vivo: riluzole does not affect survival or phenotype of cells in neural progenitor stem cell graft
Hosier et al., 2015A direct comparison of three clinically relevant treatments in a rat model of cervical spinal cord injuryIn vivoRatLower cervical hemicord contusion at C7Grp 1 (n = 10): riluzoleGrp 1 (n = 10): glibenclamide; grp 2 (n = 10): hypothermia; grp 3 (n = 10): vehicle (total: 30)5 mg/kgBID for 7 daysIPBehavior: riluzole significantly improves locomotor score on mBBB scale 3 wks postinjury & accelerating rotarod 5 wks postinjury
Wu et al., 2014Riluzole improves outcome following ischemia-reperfusion injury to the spinal cord by preventing delayed paraplegiaIn vivoRatHigh thoracic aortic balloon occlusionGrp 1 (n = 7): riluzoleGrp 2 (n = 7): vehicle8 mg/kg4 hrs postinjuryIPHistopathology: riluzole Tx ↑ neuron survival & ↓ no. of reactive astrocytes in laminae 7 & 9 but not 2; riluzole Tx ↓ macrophages & microglia in laminae 7, 8, & 9; riluzole Tx attenuates ischemia-related apoptosis as measured by TUNEL staining
Wu et al., 2013Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injuryIn vivoRatC7–T1 extradural spinal cord compression for 1 min w/ modified aneurysm clipGrp 1 (n = 6): 8 mg/kg 1 hr postinjury, then 8 mg/kg BID for 7 days; grp 2 (n = 10): 6 mg/kg 1 hr postinjury, then 6 mg/kg BID for 7 days; grp 3 (n = 6): 4 mg/kg 1 hr postinjury, then 4 mg/kg BID for 7 days; grp 4 (p1) (n = 12): 8 mg/kg at 1 hr postinjury, then 6 mg/kg BID for 7 days; grp 5 (p3) (n = 12): 8 mg/kg at 3 hrs postinjury, then 6 mg/kg BID for 7 days (total: 46)Grp 6 (n = 12): no injury + vehicle8, 6, 4 mg/kg1 or 3 hrs postinjury, then BID for 7 daysIPHistopathology: early riluzole Tx ↑ tissue sparing caudal to injury epicenter & cytoskeletal integrity of axons while ↓ apoptosis; delayed riluzole Tx does not significantly reduce apoptosis; both early & delayed riluzole Tx improve axonal connections & reduce inflammation
Sámano et al., 2012A study of the potential neuroprotective effect of riluzole on locomotor networks of the neonatal rat spinal cord in vitro damaged by excitotoxicityIn vitroRatTransient kainate (glutamate agonist) at 0.05–0.1 mM to produce excitotoxicityGrp 1 (n = 3): riluzole alone for 3 hrs in vitro postkainate washout; grp 2 (n = 3): riluzole alone for 24 hrs in vitro postkainate wash out (total: 6)Grp 3 (n = 6): sham; grp 4 (n = 3): 0.05 mM kainate alone (1 hr); grp 5 (n = 6): 0.01 mM kainate alone (1 hr) (total: 15)5 μM3 or 24 hrs postinjuryIn vitroHistopathology: continuous but not short duration of riluzole attenuates pyknosis in dorsal, central, & ventral horns of spinal cord; continuous duration of riluzole ↑ dorsal & central neuron survival w/ no significant effect on ventral neuron survival; short duration of riluzole had opposite effect

Electrophysiology: riluzole does not significantly improve peak amplitude of polysynaptic response to dorsal root stimulation or reflex area
Simard et al., 2012Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injuryIn vivoRatUnilat cervical impactor on dura mater near lt C8 nerve rootGrp 1 (n = 3): riluzole; grp 2 (n = 13): riluzole (total: 16)Grp 3 (n = 3): vehicle; grp 4 (n = 13): glibenclamide; grp 5 (n = 15): vehicle (total: 31)2.5 mg/kgGrp 1: once postinjury; grp 2: 3 hrs postinjury, then BID for 7 daysGrp 1: IP; grp 2: osmotic pump injuryHistopathology: riluzole Tx ↓ capillary fragmentation in penumbral microvessels & ↑ NeuN+ neurons in ventral gray matter contralat to injury site; compared w/ glibenclamide, riluzole Tx had significantly larger lesion vol 6 wks post-SCI

Behavior: compared w/ glibenclamide, riluzole-treated rats had significantly worse grip strength, performance on rotarod, & lower mBBB scores
Hama & Sagen, 2011Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury painIn vivoRatCompressive injury to midthoracic (T6/T7) spinal cord w/ microvascular clampGrp 1 (n = 18): ICV delivery post-SCI; grp 2 (n = 18): IT delivery post-SCI; grp 3 (n = 11): 8 mg/kg IP (total: 47)Grp 4 (n = 10): ICV vehicle; grp 5 (n = 12): IT vehicle; grp 6 (n = 11): IP vehicle (total: 33)IT/ICV: 5 μl; IP: 8 mg/kg4 wks postinjuryIT, ICV, & IPBehavior: IP riluzole Tx ↓ nociception in healthy controls & experimental animals undergoing SCI; ICV but not IT riluzole ↓ nociception post-SCI
Pintér et al., 2010Increased survival and reinnervation of cervical motoneurons by riluzole after avulsion of the C7 ventral rootIn vivoRatC7 ventral root avulsion + reimplantationGrp 1 (n = 5): ventral root avulsion + reimplantation + riluzole; grp 2 (n = 5): ventral root avulsion + riluzole (total: 10)Grp 3 (n = 5): ventral root avulsion; grp 4 (n = 5): ventral root avulsion + reimplantation; grp 5 (n = 5): ventral root avulsion + sural nerve graft implantation (total: 15)4 mg/kgPostop, daily for wk 1, then BID for wks 2 & 3IPHistopathology: riluzole ↑ motor neuron survival after ventral root avulsion & augments motor neuronal survival & axonal growth after reinnervation

Behavior: riluzole augments functional recovery in forelimb after reinnervation in a time-delayed manner
Kitzman, 2009Effectiveness of riluzole in suppressing spasticity in the spinal cord injured ratIn vivo cross-overRatS2 spinal transectionGrp 1 (n = 10): riluzole 8 mg/kg; grp 2 (n = 9): saline 10 mg/kg (total: 19)Grp 1 (n = 10): saline 8 mg/kg; grp 2 (n = 9): saline 10 mg/kg (total: 19)8 or 10 mg/kgOnce daily for 3 DPIIPHistopathology: riluzole ↑ motor neuron survival after ventral root avulsion & augments motor neuronal survival & axonal growth after reinnervation

Behavior: Tx w/ both 8 & 10 mg/kg riluzole ↓ response to noxious (pinch) & nonnoxious (light touch) stimuli, w/ 10 mg/kg also attenuating quick stretch reflex
Ates et al., 2007Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injuryIn vivoRatWeight-drop trauma at T7–10 (50 g/cm)Grp 1 (n = 18): riluzoleGrp 1 (n = 18): sham; grp 2 (n = 18): vehicle; grp 3 (n = 18): mexiletine; grp 4 (n = 18): phenytoin (total: 72)8 mg/kgSingle dose postinjuryIPHistopathology: riluzole reduces spinal cord lesion area, lipid peroxidation, & spinal cord water content

Behavior: riluzole improves motor function & inclined plane score
Nógrádi et al., 2007Delayed riluzole treatment is able to rescue injured rat spinal motoneuronsIn vivoRatL4 ventral root avulsion + reimplantation dorsolaterallyGrp 1 (n = 5): injury + riluzole immediately; grp 2 (n = 5): injury + riluzole 5 DPI; grp 3 (n = 5): injury + riluzole 10 DPI; grp 4 (n = 5): injury + riluzole 14 DPI; grp 5 (n = 5): injury + riluzole 16 DPI (total: 25)Grp 6 (n = 3): sham; grp 7 (n = 4): injury + no Tx (total: 7)4 mg/kgImmediately, 5, 10, 14, or 16 DPI 1st dose + daily 1 wk + BID for next 2 wksIPHistopathology: early (10 DPI & before) riluzole Tx ↑ motor neuron survival compared w/ delayed (14 DPI & after) riluzole Tx
Springer et al., 1997Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatmentIn vivoRatContusion injury (impactor probe at T10)Grp 1 (n = 6): SCI + riluzoleGrp 2 (n = 6): SCI + vehicle8 mg/kg15 mins pre- & 2 hrs postinjuryIPHistopathology: riluzole Tx significantly ↑ MAP2 levels, a marker of structural neuronal integrity
Schwartz & Fehlings, 2001Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzoleIn vivoRatCompressive SCI at C7–T1Grp 1 (n = 15): riluzoleGrp 2 (n = 15): vehicle5 mg/kg15 mins postopIPHistopathology: riluzole attenuates gray matter loss rostrocaudal to ↑ injury epicenter; riluzole attenuates normalized epicenter cavity area; riluzole ↑ red nuclei neurons caudal to injury

Behavior: riluzole significantly ↑ hindlimb function on BBB scale & strength on inclined plane scale
Mu et al., 200039Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injuryIn vivoRatNYU impactorGrp 1 (n = 9): riluzole; grp 2 (n = 9): riluzole + methylprednisolone (total: 18)Grp 3 (n = 9): vehicle8 mg/kg2 & 4 hrs postinjuryIPHistopathology: riluzole w/ methylprednisolone & not alone causes significant tissue sparing at lesion epicenter

Behavior: riluzole w/ methylprednisolone ↑ locomotor function in open field test
Lips et al., 2000Neuroprotective effects of riluzole and ketamine during transient spinal cord ischemia in the rabbitIn vivoRabbitAortic occlusion w/ balloon catheterGrp 1 (n = 15): injury + riluzole; grp 2 (n = 15): injury + riluzole + ketamine (total: 30)Grp 3 (n = 15): injury + control8 mg/kg15 mins IV preinjury & BID IP for 3 DPIIV & IPHistopathology: riluzole Tx ↑ motor neurons in ventral horn

Behavior: riluzole Tx reduces overall neurological deficits & paraplegia incidence, & improves Tarlov score
Lang-Lazdunski et al., 200032Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzoleIn vivoRabbitDirect aortic arch + lt subclavian artery cross-clampingGrp 1 (n = 15): injury + riluzoleGrp 2 (n = 15): no injury; grp 3 (n = 15): injury + control (total: 30)4 mg/kg30 mins preinjury & at onset of reperfusionIVHistopathology: riluzole Tx attenuates reduction of MAP2 levels in dorsal horn & intermediate zone, reduces apoptosis in gray matter & completely prevents apoptosis in ventral horns as measured by TUNEL staining, & reduces fragmenting of DNA

Behavior: riluzole Tx ↑ neurological outcomes on MSDI as early as 24 hrs after reperfusion
Lang-Lazdunski et al., 200031Prevention of ischemic spinal cord injury: comparative effects of magnesium sulfate and riluzoleIn vivoRabbitInfrarenal aorta occlusion for 40 minsGrp 1 (n = 17): riluzole before clamping; grp 2 (n = 17): MgSO4 + riluzole before clamping (total: 34)Grp 3 (n = 17): vehicle; grp 4 (n = 15): MgSO4 before clamping (total: 32)8 mg/kgBefore clampingIVHistopathology: riluzole Tx attenuates neuronal damage & preserves Map2 expression

Behavior: riluzole Tx ↑ Tarlov score as early as 24 hrs after reperfusion
Mu et al., 200039Riluzole improves measures of oxidative stress following traumatic spinal cord injuryIn vivoRabbitContusion injury (impactor rod at T10)Grp 1 (n = 9): riluzole; grp 2 (n = 9): riluzole + methylprednisolone (total: 18)Grp 3 (n = 9): vehicle; grp 4 (n = 9): methylprednisolone (total: 18)8 mg/kg15 mins & 2 hrs postinjuryIPHistopathology: riluzole Tx alone significantly ↑ mitochondrial function in synaptosomes; riluzole Tx alone does not significantly ↓ reactive oxygen species; riluzole Tx w/ methylprednisolone but not alone significantly reduces lipid peroxidation

BBB = Basso-Beattie-Bresnahan; EMG = electromyography; ICV = intracerebroventricular; IT = intrathecal; IV = intravenous; mBBB = modified BBB; MSDI = motor sensory deficit index; NYU = New York University.

Twenty-six studies with 24 in vivo studies, 1 in vitro study, and 1 combined study; 520 animals were in the riluzole treatment arm and 515 animals were in comparative control groups.

Human Clinical Studies

Three clinical studies were included in this systematic review. The average age of the patients was 39.1 years (range 18–70 years). In total, the percentage of patients included by AIS grade was 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Most patients in the clinical studies included were severely impaired at baseline. The major findings from clinical studies included decreased pain,37 increased motor functionality,22 and decreased spastic reflexes54 after administration of riluzole for SCI. Specifically, with regard to motor function, Meshkini et al.37 and Grossman et al.22 demonstrated statistically significant general motor improvement with riluzole at 6 and 3 months after acute SCI, respectively, while Theiss et al.54 showed strong correlation of riluzole use with lower-limb volitional strength for patients with chronic, incomplete SCI. Of the 3 clinical studies included, only Meshkini et al.37 evaluated reduction in pain after riluzole use, and only Theiss et al.54 evaluated attenuation of spastic reflexes. Clinical studies consistently demonstrated incomplete recovery after SCI despite the use of riluzole as manifested by low motor10,37 and sensory37 scores as well as debilitated voluntary contraction.54 All patients in clinical studies were administered 50 mg of riluzole enterally. However, while Meshkini et al.37 and Grossman et al.22 included a longitudinal dose of 50 mg BID (twice daily) for 8 and 4 weeks, respectively, Theiss et al.54 only included a one-time dose of 50 mg before testing. Overall, riluzole showed promising results with a decrease in neuropathic pain and severity of SCI,37 increase in motor function22 for cervical injury, and decrease in spasticity with preservation of normal voluntary movement.54 However, these benefits were not without risk for complications, as 14%–70% of patients in the Grossman study had elevated liver enzymes and bilirubin levels, implying potentially hepatotoxic effects of riluzole in humans.22 A full description of clinical studies included within this analysis can be found in Table 3.

TABLE 3.

Impact of riluzole on SCI in humans

Authors & YearTitleStudy DesignNo. of Pts Receiving RiluzoleNo. of Pts Receiving PlaceboSCI LevelAIS GradeAverage Age, yrsDoseTimingRouteAdverse EffectsMain Findings
Meshkini et al., 2018Riluzole can improve sensory and motor function in patients with acute spinal cord injuryParallel grp, placebo controlled3030NA40% A; 30% B; 30% C36.950 mgBID for 8 wksPONAPts on riluzole had ↓ pain on VAS system & significantly less severe SCI as determined by Frankel class 6 mos postop
Grossman et al., 2014A prospective, multicenter, phase I matched-comparison grp trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord InjuryParallel grp, placebo controlled363677.8% C4–8; 13.9% T1–6; 8.3% T7–1252.8% A; 25% B; 22.2% C4050 mgBID for 28 daysPO, nasogastric tube14–70% had elevation of liver enzymes & bilirubin levelsPts on riluzole w/ cervical SCI had significantly higher motor scores (ISNCSCI) than controls 90 days postop
Theiss et al., 2011Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injuryw/in grp, placebo controlled77 (same pts)14.3% C1–4; 57.1% C4–8; 14.3% T1–6; 14.3% T7–1235.7% C; 64.3% D4450 mgOncePONoneRiluzole significantly ↑ threshold stimulation intensity & average sustained torque while ↓ peak amplitude of ankle dorsiflexion torque for flexion withdrawal response; riluzole does not significantly change mean peak torque during max voluntary contraction

ISNCSCI = International Standards for Neurological Classification of Spinal Cord Injury; VAS = visual analog scale.

Three studies with corresponding baseline AIS grade distributions of 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D.

Discussion

This systematic review describes the potential use of riluzole for efficacy after SCI in humans and animals in improving functional and neurological outcomes after SCI, including positive neuroprotective results.18 Primary and secondary damage in SCI is mediated primarily by excitotoxicity16 and thus riluzole, a prominent antiglutamatergic agent,56 has been a treatment of interest for SCI. Increased expression of glutamate transporters (EAAC1, GLST, and GLT-1) has been implicated in SCI with riluzole treatment increasing uptake activity of glutamate and attenuating any neuropathic pain sequelae from SCI.53 Moreover, riluzole blocks persistent inward sodium currents and fast sodium spikes, which are particularly important in chronic SCI.25 There is now a consensus that in neurodegenerative disorders, riluzole works predominantly through increasing glutamate uptake in astrocytes and presynaptic neurons, blocking presynaptic release of glutamate, and blocking persistent sodium currents.11 Of significance, in contrast to ALS where a high bioavailability (> 90%) is reported,9 riluzole in SCI in humans exhibited a lower maximum concentration and systemic exposure 0–12 hours after dosing.10 Even more importantly, in SCI, there is inflammation, which increases the spinal cord expression of PgP, a drug efflux transporter, which decreases the bioavailability of riluzole in the spinal cord compared to plasma, so antiinflammatory medications such as COX or LOX-5 inhibitors decrease PgP expression and increase bioavailability of riluzole in the spinal cord.15 However, other studies have suggested that the half-life of riluzole increases with SCI and remains substantially higher in the spinal cord than in the plasma.58 The effects of riluzole seem dose-dependent, with glutamatergic uptake activity of 0.1 and 1.0 μM riluzole in spinal cord synaptosomes that are not replicated at higher doses.2 Careful dose management is likely required for effective treatment of riluzole in humans. Moreover, in one pharmacological study, there was a 30% treatment-associated mortality with riluzole,15 suggesting that despite therapeutic benefits, conservative administration of riluzole in SCI is required for most optimal results.

Within the animal studies, there were significant therapeutic benefits of riluzole manifested by increased tissue sparing,1,6,21,30,32,33,38,39,41,44,46–49,55,57,58 decreased neuropathy,5,24 improved motor function,1,7,21,27,32–34,38,44,47–49,55 and reduction of aberrant electrophysiology.5,47 Histological benefits of riluzole were often localized caudal to the injury epicenter.34,47,48,55,58 Specifically, riluzole decreased molecular markers of injury such as reactive oxygen species49 and immune cells,7,58 while preserving markers of plasticity and structural integrity such as MAP2,32,51 synaptophysin, and subunits of the NMDA receptor and AMPA receptor.47 This neuroprotective effect of riluzole was often augmented by other pharmacological agents, such as methylprednisolone38,39 and dantrolene.34 Moreover, several studies demonstrated dose-dependent,5 time-dependent,41,46 and route-dependent24 efficacy of riluzole in SCI, suggesting that dose, timing, and route are important factors to consider in clinical SCI. While studies demonstrate poor efficacy of riluzole in select experiments—behaviorally,34 histologically,7,23,39,50,55 or via electrophysiological measurements46,50—no study exclusively reported negative results. Rather, the efficacy of riluzole can be subtherapeutic or inferior to other neuroprotective agents contingent on a variety of aforementioned factors.

Many studies produced negative results, with riluzole having little effect on outcomes. For example, one study showed that riluzole alone without methylprednisolone does not improve locomotion or tissue sparing.38 Likewise, another study showed that riluzole does not reduce apoptosis or increase motor function or strength after SCI.7 A similar study showed that riluzole does not affect survival or the phenotype of cells after a neural stem and progenitor cell graft.23 Sámano et al.46 suggested that there is no change in peak amplitude of polysynaptic response to dorsal root stimulation or reflex area in vivo, and no change in ventral motor neuron cell survival in vitro with riluzole. However, a variety of studies found the opposite with regard to ventral motor neuron cell survival.33,41,44 Mu et al.39 suggested that riluzole does not reduce reactive oxygen species or lipid deoxidation, but the opposite was found by Shimizu et al.49 and Ates et al.,1 respectively. Given the discrepancy in outcomes between animal studies, riluzole may be neuroprotective in SCI on a selective basis. For example, studies have shown that with higher doses, riluzole had longer-lasting and more effective outcomes.5,23 However, also with high doses of riluzole, adverse outcomes such as death and respiratory distress have been reported.58

Of encouragement, early clinical studies suggested that riluzole is efficacious in decreasing neuropathic pain,37 increasing motor recovery,22 and decreasing aberrant reflexes.54 However, given the relatively sparse number of patients (n = 73) and potential hepatotoxic effects of riluzole22 in SCI, there remains a need for more robust clinical data on safety and therapeutic benefit from the phase 2 and 3 clinical trials.18 This is especially true considering the wide range of adverse effects reported with riluzole use in ALS, including hypertension, peripheral edema, pancreatitis,17 neutropenia, renal disease, interstitial lung disease, and hepatotoxicity. The use of riluzole in SCI is documented far more extensively in animal models than in humans. Given this disparity in total subjects, animal studies have greater power, and the neuroprotective effects of riluzole after SCI in animals are well known. As more patients are enrolled in the ongoing phase 2 clinical trial, the effects of riluzole on motor, sensory, and neurological function will become better understood.18 Thus, the primary limitation of this review includes extrapolation of animal data to the clinical efficacy of riluzole. Moreover, the most common adverse effects of riluzole are described more extensively in ALS than in SCI. According to the National Spinal Cord Injury Center, life expectancy for patients with SCI remains significantly lower than for those without SCI, and this disparity has not been improving since the 1980s.40 Given the astronomical inpatient and outpatient costs associated with SCI,20 improving patient outcomes with neuroprotective agents can decrease cost and improve quality of life.

Conclusions

The neuroprotective effects of riluzole in SCI are promising, but the therapeutic benefit of riluzole in SCI must be appreciated in the appropriate clinical context. Success in animal models does not always translate to success in humans. While preliminary human studies suggest that riluzole may have a role in decreasing neuropathic pain and improving motor recovery for patients with SCI, there remains a need to substantiate these data with consistently reported clinical studies. However, other studies have demonstrated adverse effects, including pancreatitis, lung disease, and neutropenia, without conferring much clinical benefit. As the drug advances through the subsequent clinical trial stages, it will be important to titer the dose and timing to maximize benefits in appropriately selected patients to minimize adverse or ineffective outcomes. Nevertheless, these efforts provide the opportunity to expand the existing, limited pharmacological treatment options to mitigate the devastating effects of SCI and to offer patients the possibility of medical options to improve long-term function and pain control.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: all authors. Acquisition of data: Srinivas. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Pham. Statistical analysis: all authors. Administrative/technical/material support: Pham. Study supervision: Pham.

References

  • 1

    Ates OCayli SRGurses ITurkoz YTarim OCakir CO: Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J Clin Neurosci 14:6586652007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Azbill RDMu XSpringer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 871:1751802000

  • 3

    Bartholdi DSchwab ME: Methylprednisolone inhibits early inflammatory processes but not ischemic cell death after experimental spinal cord lesion in the rat. Brain Res 672:1771861995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Bellingham MC: A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 17:4312011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Brocard CPlantier VBoulenguez PLiabeuf SBouhadfane MViallat-Lieutaud A: Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury. Nat Med 22:4044112016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Caglar YSDemirel ADogan IHuseynov REroglu UOzgural O: Effect of riluzole on spinal cord regeneration with hemisection method before injury. World Neurosurg 114:e247e2532018

    • Search Google Scholar
    • Export Citation
  • 7

    Can HAydoseli AGömleksiz CGöker BAltunrende MEDolgun M: Combined and individual use of pancaspase inhibitor Q-VD-OPh and NMDA receptor antagonist riluzole in experimental spinal cord injury. Ulus Travma Acil Cerrahi Derg 23:4524582017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cardenas DDHoffman JMKirshblum SMcKinley W: Etiology and incidence of rehospitalization after traumatic spinal cord injury: a multicenter analysis. Arch Phys Med Rehabil 85:175717632004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Cheah BCVucic SKrishnan AVKiernan MC: Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem 17:19421992010

  • 10

    Chow DSTeng YToups EGAarabi BHarrop JSShaffrey CI: Pharmacology of riluzole in acute spinal cord injury. J Neurosurg Spine 17 (1 Suppl):1291402012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Cifra AMazzone GLNistri A: Riluzole: what it does to spinal and brainstem neurons and how it does it. Neuroscientist 19:1371442013

  • 12

    David SKroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:3883992011

  • 13

    DeVivo MJChen YMennemeyer STDeutsch A: Costs of care following spinal cord injury. Top Spinal Cord Inj Rehabil 16:192011

  • 14

    Doble A: The pharmacology and mechanism of action of riluzole. Neurology 47 (6 Suppl 4):S233S2411996

  • 15

    Dulin JNMoore MLGrill RJ: The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cord. J Neurotrauma 30:2112262013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Dumont RJOkonkwo DOVerma SHurlbert RJBoulos PTEllegala DB: Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24:2542642001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Falcão de Campos Cde Carvalho M: Riluzole-induced recurrent pancreatitis. J Clin Neurosci 45:1531542017

  • 18

    Fehlings MGNakashima HNagoshi NChow DSLGrossman RGKopjar B: Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord 54:8152016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Fehlings MGWilson JRFrankowski RFToups EGAarabi BHarrop JS: Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine 17 (1 Suppl):1511562012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    French DDCampbell RRSabharwal SNelson ALPalacios PAGavin-Dreschnack D: Health care costs for patients with chronic spinal cord injury in the Veterans Health Administration. J Spinal Cord Med 30:4774812007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Gloviczki BTörök DGMárton GGál LBodzay TPintér S: Delayed spinal cord-brachial plexus reconnection after C7 ventral root avulsion: the effect of reinnervating motoneurons rescued by riluzole treatment. J Neurotrauma 34:236423742017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Grossman RGFehlings MGFrankowski RFBurau KDChow DSTator C: A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 31:2392552014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Hachem LDMothe AJTator CH: Evaluation of the effects of riluzole on adult spinal cord-derived neural stem/progenitor cells in vitro and in vivo. Int J Dev Neurosci 47 (Pt B):1401462015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hama ASagen J: Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain. J Neurotrauma 28:1271342011

  • 25

    Harvey PJLi YLi XBennett DJ: Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult rats. J Neurophysiol 96:114111572006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Hinchcliffe MSmith A: Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis. Degener Neurol Neuromuscul Dis 7:61702017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Hosier HPeterson DTsymbalyuk OKeledjian KSmith BRIvanova S: A direct comparison of three clinically relevant treatments in a rat model of cervical spinal cord injury. J Neurotrauma 32:163316442015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Kakulas BA: Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord 42:5495632004

  • 29

    Katoh-Semba RAsano TUeda HMorishita RTakeuchi IKInaguma Y: Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J 16:132813302002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Kitzman PH: Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat. Neurosci Lett 455:1501532009

  • 31

    Lang-Lazdunski LHeurteaux CDupont HWidmann CLazdunski M: Prevention of ischemic spinal cord injury: comparative effects of magnesium sulfate and riluzole. J Vasc Surg 32:1791892000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lang-Lazdunski LHeurteaux CMignon AMantz JWidmann CDesmonts J: Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzole. Eur J Cardiothorac Surg 18:1741812000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Lips Jde Haan PBodewits PVanicky IDzoljic MJacobs MJ: Neuroprotective effects of riluzole and ketamine during transient spinal cord ischemia in the rabbit. Anesthesiology 93:130313112000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Martins BCTorres BBJde Oliveira KMLavor MSOsório CMFukushima FB: Association of riluzole and dantrolene improves significant recovery after acute spinal cord injury in rats. Spine J 18:5325392018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    McAdoo DJHughes MGNie LShah BClifton CFullwood S: The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage → glutamate release → damage → glutamate release → etc. Brain Res 1038:92992005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    McDonald JWSadowsky C: Spinal-cord injury. Lancet 359:4174252002

  • 37

    Meshkini ASalehpour FAghazadeh JMirzaei FNaseri Alavi SA: Riluzole can improve sensory and motor function in patients with acute spinal cord injury. Asian J Neurosurg 13:6566592018

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Mu XAzbill RDSpringer JE: Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injury. J Neurotrauma 17:7737802000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Mu XAzbill RDSpringer JE: Riluzole improves measures of oxidative stress following traumatic spinal cord injury. Brain Res 870:66722000

  • 40

    National Spinal Cord Injury Statistical Center: Spinal cord injury facts and figures at a glance. J Spinal Cord Med 35:1971982012

  • 41

    Nógrádi ASzabó APintér SVrbová G: Delayed riluzole treatment is able to rescue injured rat spinal motoneurons. Neuroscience 144:4314382007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Noh KMHwang JYShin HCKoh JY: A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol Dis 7:3753832000

  • 43

    Park EVelumian AAFehlings MG: The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21:7547742004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Pintér SGloviczki BSzabó AMárton GNógrádi A: Increased survival and reinnervation of cervical motoneurons by riluzole after avulsion of the C7 ventral root. J Neurotrauma 27:227322822010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Rowland JWHawryluk GWKwon BFehlings MG: Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 25(5):E22008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Sámano CNasrabady SENistri A: A study of the potential neuroprotective effect of riluzole on locomotor networks of the neonatal rat spinal cord in vitro damaged by excitotoxicity. Neuroscience 222:3563652012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Satkunendrarajah KNassiri FKaradimas SKLip AYao GFehlings MG: Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Exp Neurol 276:59712016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Schwartz GFehlings MG: Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg 94 (2 Suppl):2452562001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Shimizu ENSeifert JLJohnson KJRomero-Ortega MI: Prophylactic riluzole attenuates oxidative stress damage in spinal cord distraction. J Neurotrauma 35:131913282018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Simard JMTsymbalyuk OKeledjian KIvanov AIvanova SGerzanich V: Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury. Exp Neurol 233:5665742012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    Springer JEAzbill RDKennedy SEGeorge JGeddes JW: Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem 69:159216001997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Stratman RCWiesner AMSmith KMCook AM: Hemodynamic management after spinal cord injury. Orthopedics 31:2522552008

  • 53

    Sung BLim GMao J: Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23:289929102003

    • Crossref
    • PubMed
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  • 54

    Theiss RDHornby TGRymer WZSchmit BD: Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injury. J Neurophysiol 105:278127902011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Vasconcelos NLGomes EDOliveira EPSilva CJLima RSousa N: Combining neuroprotective agents: effect of riluzole and magnesium in a rat model of thoracic spinal cord injury. Spine J 16:101510242016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56

    Wokke J: Riluzole. Lancet 348:7957991996

  • 57

    Wu YSatkunendrarajah KFehlings MG: Riluzole improves outcome following ischemia-reperfusion injury to the spinal cord by preventing delayed paraplegia. Neuroscience 265:3023122014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Wu YSatkunendrarajah KTeng YChow DSButtigieg JFehlings MG: Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injury. J Neurotrauma 30:4414522013

    • Crossref
    • Search Google Scholar
    • Export Citation

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Article Information

Correspondence Martin H. Pham: University of California San Diego School of Medicine, San Diego, CA. mhpham@ucsd.edu.

INCLUDE WHEN CITING DOI: 10.3171/2019.1.FOCUS18596.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

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    Ninety-nine clinical studies regarding the use of riluzole in spinal cord injury were initially identified. Twenty-seven articles were removed for inadequate access to the full article. Seventy-two papers were fully reviewed. After applying inclusion and exclusion criteria, 37 articles were selected for review and analysis.

References

  • 1

    Ates OCayli SRGurses ITurkoz YTarim OCakir CO: Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J Clin Neurosci 14:6586652007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Azbill RDMu XSpringer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 871:1751802000

  • 3

    Bartholdi DSchwab ME: Methylprednisolone inhibits early inflammatory processes but not ischemic cell death after experimental spinal cord lesion in the rat. Brain Res 672:1771861995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Bellingham MC: A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 17:4312011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Brocard CPlantier VBoulenguez PLiabeuf SBouhadfane MViallat-Lieutaud A: Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury. Nat Med 22:4044112016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Caglar YSDemirel ADogan IHuseynov REroglu UOzgural O: Effect of riluzole on spinal cord regeneration with hemisection method before injury. World Neurosurg 114:e247e2532018

    • Search Google Scholar
    • Export Citation
  • 7

    Can HAydoseli AGömleksiz CGöker BAltunrende MEDolgun M: Combined and individual use of pancaspase inhibitor Q-VD-OPh and NMDA receptor antagonist riluzole in experimental spinal cord injury. Ulus Travma Acil Cerrahi Derg 23:4524582017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cardenas DDHoffman JMKirshblum SMcKinley W: Etiology and incidence of rehospitalization after traumatic spinal cord injury: a multicenter analysis. Arch Phys Med Rehabil 85:175717632004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Cheah BCVucic SKrishnan AVKiernan MC: Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem 17:19421992010

  • 10

    Chow DSTeng YToups EGAarabi BHarrop JSShaffrey CI: Pharmacology of riluzole in acute spinal cord injury. J Neurosurg Spine 17 (1 Suppl):1291402012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Cifra AMazzone GLNistri A: Riluzole: what it does to spinal and brainstem neurons and how it does it. Neuroscientist 19:1371442013

  • 12

    David SKroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:3883992011

  • 13

    DeVivo MJChen YMennemeyer STDeutsch A: Costs of care following spinal cord injury. Top Spinal Cord Inj Rehabil 16:192011

  • 14

    Doble A: The pharmacology and mechanism of action of riluzole. Neurology 47 (6 Suppl 4):S233S2411996

  • 15

    Dulin JNMoore MLGrill RJ: The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cord. J Neurotrauma 30:2112262013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Dumont RJOkonkwo DOVerma SHurlbert RJBoulos PTEllegala DB: Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24:2542642001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Falcão de Campos Cde Carvalho M: Riluzole-induced recurrent pancreatitis. J Clin Neurosci 45:1531542017

  • 18

    Fehlings MGNakashima HNagoshi NChow DSLGrossman RGKopjar B: Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord 54:8152016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Fehlings MGWilson JRFrankowski RFToups EGAarabi BHarrop JS: Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine 17 (1 Suppl):1511562012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    French DDCampbell RRSabharwal SNelson ALPalacios PAGavin-Dreschnack D: Health care costs for patients with chronic spinal cord injury in the Veterans Health Administration. J Spinal Cord Med 30:4774812007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Gloviczki BTörök DGMárton GGál LBodzay TPintér S: Delayed spinal cord-brachial plexus reconnection after C7 ventral root avulsion: the effect of reinnervating motoneurons rescued by riluzole treatment. J Neurotrauma 34:236423742017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Grossman RGFehlings MGFrankowski RFBurau KDChow DSTator C: A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma 31:2392552014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Hachem LDMothe AJTator CH: Evaluation of the effects of riluzole on adult spinal cord-derived neural stem/progenitor cells in vitro and in vivo. Int J Dev Neurosci 47 (Pt B):1401462015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hama ASagen J: Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain. J Neurotrauma 28:1271342011

  • 25

    Harvey PJLi YLi XBennett DJ: Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult rats. J Neurophysiol 96:114111572006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Hinchcliffe MSmith A: Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis. Degener Neurol Neuromuscul Dis 7:61702017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Hosier HPeterson DTsymbalyuk OKeledjian KSmith BRIvanova S: A direct comparison of three clinically relevant treatments in a rat model of cervical spinal cord injury. J Neurotrauma 32:163316442015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Kakulas BA: Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord 42:5495632004

  • 29

    Katoh-Semba RAsano TUeda HMorishita RTakeuchi IKInaguma Y: Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J 16:132813302002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Kitzman PH: Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat. Neurosci Lett 455:1501532009

  • 31

    Lang-Lazdunski LHeurteaux CDupont HWidmann CLazdunski M: Prevention of ischemic spinal cord injury: comparative effects of magnesium sulfate and riluzole. J Vasc Surg 32:1791892000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lang-Lazdunski LHeurteaux CMignon AMantz JWidmann CDesmonts J: Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzole. Eur J Cardiothorac Surg 18:1741812000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Lips Jde Haan PBodewits PVanicky IDzoljic MJacobs MJ: Neuroprotective effects of riluzole and ketamine during transient spinal cord ischemia in the rabbit. Anesthesiology 93:130313112000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Martins BCTorres BBJde Oliveira KMLavor MSOsório CMFukushima FB: Association of riluzole and dantrolene improves significant recovery after acute spinal cord injury in rats. Spine J 18:5325392018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    McAdoo DJHughes MGNie LShah BClifton CFullwood S: The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage → glutamate release → damage → glutamate release → etc. Brain Res 1038:92992005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    McDonald JWSadowsky C: Spinal-cord injury. Lancet 359:4174252002

  • 37

    Meshkini ASalehpour FAghazadeh JMirzaei FNaseri Alavi SA: Riluzole can improve sensory and motor function in patients with acute spinal cord injury. Asian J Neurosurg 13:6566592018

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Mu XAzbill RDSpringer JE: Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injury. J Neurotrauma 17:7737802000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Mu XAzbill RDSpringer JE: Riluzole improves measures of oxidative stress following traumatic spinal cord injury. Brain Res 870:66722000

  • 40

    National Spinal Cord Injury Statistical Center: Spinal cord injury facts and figures at a glance. J Spinal Cord Med 35:1971982012

  • 41

    Nógrádi ASzabó APintér SVrbová G: Delayed riluzole treatment is able to rescue injured rat spinal motoneurons. Neuroscience 144:4314382007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Noh KMHwang JYShin HCKoh JY: A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol Dis 7:3753832000

  • 43

    Park EVelumian AAFehlings MG: The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21:7547742004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Pintér SGloviczki BSzabó AMárton GNógrádi A: Increased survival and reinnervation of cervical motoneurons by riluzole after avulsion of the C7 ventral root. J Neurotrauma 27:227322822010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Rowland JWHawryluk GWKwon BFehlings MG: Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 25(5):E22008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Sámano CNasrabady SENistri A: A study of the potential neuroprotective effect of riluzole on locomotor networks of the neonatal rat spinal cord in vitro damaged by excitotoxicity. Neuroscience 222:3563652012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Satkunendrarajah KNassiri FKaradimas SKLip AYao GFehlings MG: Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Exp Neurol 276:59712016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Schwartz GFehlings MG: Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg 94 (2 Suppl):2452562001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Shimizu ENSeifert JLJohnson KJRomero-Ortega MI: Prophylactic riluzole attenuates oxidative stress damage in spinal cord distraction. J Neurotrauma 35:131913282018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Simard JMTsymbalyuk OKeledjian KIvanov AIvanova SGerzanich V: Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury. Exp Neurol 233:5665742012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    Springer JEAzbill RDKennedy SEGeorge JGeddes JW: Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem 69:159216001997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Stratman RCWiesner AMSmith KMCook AM: Hemodynamic management after spinal cord injury. Orthopedics 31:2522552008

  • 53

    Sung BLim GMao J: Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23:289929102003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Theiss RDHornby TGRymer WZSchmit BD: Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injury. J Neurophysiol 105:278127902011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Vasconcelos NLGomes EDOliveira EPSilva CJLima RSousa N: Combining neuroprotective agents: effect of riluzole and magnesium in a rat model of thoracic spinal cord injury. Spine J 16:101510242016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56

    Wokke J: Riluzole. Lancet 348:7957991996

  • 57

    Wu YSatkunendrarajah KFehlings MG: Riluzole improves outcome following ischemia-reperfusion injury to the spinal cord by preventing delayed paraplegia. Neuroscience 265:3023122014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Wu YSatkunendrarajah KTeng YChow DSButtigieg JFehlings MG: Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injury. J Neurotrauma 30:4414522013

    • Crossref
    • Search Google Scholar
    • Export Citation

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