Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial

Restricted access

In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.

Abbreviations used in this paper:ALS = amyotrophic lateral sclerosis; ASIA = American Spinal Injury Association; NACTN = North American Clinical Trials Network for Treatment of Spinal Cord Injury; SCI = spinal cord injury.

Article Information

Address correspondence to: Michael G. Fehlings, M.D., Ph.D., F.R.C.S.C., Krembil Neuroscience Center, 399 Bathurst Street, Toronto Western Hospital, Toronto, Ontario M5T2S8, Canada. email: Michael.Fehlings@uhn.on.ca.

Please include this information when citing this paper: DOI: 10.3171/2012.4.AOSPINE1259.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flow diagram summarizing the putative neuroprotective mechanisms of riluzole in SCI.

References

  • 1

    Agrawal SKFehlings MG: The effect of the sodium channel blocker QX-314 on recovery after acute spinal cord injury. J Neurotrauma 14:81881997

    • Search Google Scholar
    • Export Citation
  • 2

    Agrawal SKFehlings MG: Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger. J Neurosci 16:5455521996

    • Search Google Scholar
    • Export Citation
  • 3

    Amar APLevy ML: Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery 44:102710401999

    • Search Google Scholar
    • Export Citation
  • 4

    American Spinal Injury Association International Spinal Cord Society: International Standards for Neurological Classification of Spinal Cord Injury ChicagoAmerican Spinal Injury Association2000

    • Search Google Scholar
    • Export Citation
  • 5

    Baptiste DCFehlings MG: Emerging drugs for spinal cord injury. Expert Opin Emerg Drugs 13:63802008

  • 6

    Bensimon GLacomblez LDelumeau JCBejuit RTruffinet PMeininger V: A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol 249:6096152002

    • Search Google Scholar
    • Export Citation
  • 7

    Bensimon GLacomblez LMeininger V: A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 330:5855911994

  • 8

    Bluvshtein VFront LItzkovich MAidinoff EGelernter IHart J: SCIM III is reliable and valid in a separate analysis for traumatic spinal cord lesions. Spinal Cord 49:2922962011

    • Search Google Scholar
    • Export Citation
  • 9

    Bracken MBCollins WFFreeman DFShepard MJWagner FWSilten RM: Efficacy of methylprednisolone in acute spinal cord injury. JAMA 251:45521984

    • Search Google Scholar
    • Export Citation
  • 10

    Bracken MBShepard MJCollins WFHolford TRYoung WBaskin DS: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322:140514111990

    • Search Google Scholar
    • Export Citation
  • 11

    Bracken MBShepard MJHolford TRLeo-Summers LAldrich EFFazl M: Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial National Acute Spinal Cord Injury Study. JAMA 277:159716041997

    • Search Google Scholar
    • Export Citation
  • 12

    Cleeland CSRyan KM: Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 23:1291381994

  • 13

    Fehlings MGSekhon LSHCellular, ionic and biomolecular mechanisms of the injury process. Tator CHBenzel EC: Contemporary Management of Spinal Cord Injury: From Impact to Rehabilitation Park Ridge, ILAmerican Association of Neurological Surgeons2000. 3350

    • Search Google Scholar
    • Export Citation
  • 14

    Fehlings MGTheodore NHarrop JMaurais GKuntz CShaffrey CI: A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma 28:7877962011

    • Search Google Scholar
    • Export Citation
  • 15

    Geisler FHColeman WPGrieco GPoonian D: The Sygen multicenter acute spinal cord injury study. Spine 26:24 SupplS87S982001

  • 16

    Haigney MCLakatta EGStern MDSilverman HS: Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 90:3913991994

    • Search Google Scholar
    • Export Citation
  • 17

    Haigney MCMiyata HLakatta EGStern MDSilverman HS: Dependence of hypoxic cellular calcium loading on Na(+)-Ca2+ exchange. Circ Res 71:5475571992

    • Search Google Scholar
    • Export Citation
  • 18

    Hawryluk GWRowland JKwon BKFehlings MG: Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury. Neurosurg Focus 25:5E142008

    • Search Google Scholar
    • Export Citation
  • 19

    Lacomblez LBensimon GLeigh PNGuillet PMeininger V: Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 347:142514311996

    • Search Google Scholar
    • Export Citation
  • 20

    Li SMealing GAMorley PStys PK: Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate transport. J Neurosci 19:RC161999

    • Search Google Scholar
    • Export Citation
  • 21

    Miller RGMitchell JDLyon MMoore DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database System Rev 1CD0014472007

    • Search Google Scholar
    • Export Citation
  • 22

    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

    • Search Google Scholar
    • Export Citation
  • 23

    Regan RFChoi DW: Glutamate neurotoxicity in spinal cord cell culture. Neuroscience 43:5855911991

  • 24

    Rosenberg LJTeng YDWrathall JR: Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury. J Neurosci 19:612261331999

    • Search Google Scholar
    • Export Citation
  • 25

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

    • Search Google Scholar
    • Export Citation
  • 26

    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 Suppl2452562001

    • Search Google Scholar
    • Export Citation
  • 27

    Schwartz GFehlings MG: Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole. Prog Brain Res 137:1771902002

    • Search Google Scholar
    • Export Citation
  • 28

    Tator CHFehlings MG: Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75:15261991

    • Search Google Scholar
    • Export Citation
  • 29

    Tator CHKoyanagi I: Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg 86:4834921997

  • 30

    Taylor CPGeer JJBurke SP: Endogenous extracellular glutamate accumulation in rat neocortical cultures by reversal of the transmembrane sodium gradient. Neurosci Lett 145:197 2001992

    • Search Google Scholar
    • Export Citation
  • 31

    Teng YDWrathall JR: Local blockade of sodium channels by tetrodotoxin ameliorates tissue loss and long-term functional deficits resulting from experimental spinal cord injury. J Neurosci 17:435943661997

    • Search Google Scholar
    • Export Citation
  • 32

    Yanagisawa NTashiro KTohgi HMizuno YKowa HKimura J: Efficacy and safety of riluzole in patients with amyotrophic lateral sclerosis: double-blind placebo-controlled study in Japan. Igakuno Ayumi 182:8518661997

    • Search Google Scholar
    • Export Citation
  • 33

    Zhang YLipton P: Cytosolic Ca2+ changes during in vitro ischemia in rat hippocampal slices: major roles for glutamate and Na+-dependent Ca2+ release from mitochondria. J Neurosci 19:330733151999

    • Search Google Scholar
    • Export Citation

TrendMD

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 145 145 10
Full Text Views 107 107 7
PDF Downloads 116 116 7
EPUB Downloads 0 0 0

PubMed

Google Scholar