Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside

Narihito Nagoshi, Hiroaki Nakashima, Michael G Fehlings, Narihito Nagoshi, Hiroaki Nakashima, Michael G Fehlings

Abstract

Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.

Trial registration: ClinicalTrials.gov NCT00876889 NCT01597518.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of riluzole.
Figure 2
Figure 2
Ionic imbalance and glutamate excitotoxicity. The excessive influx of sodium and calcium triggers extracellular release of glutamate in presynaptic neurons. In the postsynaptic neuron, sodium and calcium influx through NMDAR and AMPAR lead to cellular death and axonal edema. The neuroprotective effects of riluzole appear to result from a blockade of sodium channels, and prevention of exaggerated calcium influx. In addition, riluzole plays a role as an anti-glutamatergic agent via the inhibition of glutamate release in isoxazolepropionic acid receptors: NMDAR; N-methyl-D-aspartic acid receptor, AMPAR; Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor.
Figure 3
Figure 3
Key pathological events in secondary injury of spinal cord ionic imbalance and excitotoxicity are the targets in riluzole treatment.

References

    1. Fehlings M.G., Vaccaro A., Wilson J.R., Singh A., Cadotte D.W., Harrop J.S., Aarabi B., Shaffrey C., Dvorak M., Fisher C., et al. Early versus delayed decompression for traumatic cervical spinal cord injury: Results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) PLoS ONE. 2012;7:e32037.
    1. Wilson J.R., Singh A., Craven C., Verrier M.C., Drew B., Ahn H., Ford M., Fehlings M.G. Early versus late surgery for traumatic spinal cord injury: The results of a prospective Canadian cohort study. Spinal Cord. 2012;50:840–843. doi: 10.1038/sc.2012.59.
    1. Labruyere R., Agarwala A., Curt A. Rehabilitation in spine and spinal cord trauma. Spine. 2010;35(Suppl. 21):S259–S262. doi: 10.1097/BRS.0b013e3181f1a979.
    1. Bensimon G., Lacomblez L., Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 1994;330:585–591. doi: 10.1056/NEJM199403033300901.
    1. Lacomblez L., Bensimon G., Leigh P.N., Guillet P., Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996;347:1425–1431.
    1. Miller R.G., Jackson C.E., Kasarskis E.J., England J.D., Forshew D., Johnston W., Kalra S., Katz J.S., Mitsumoto H., Rosenfeld J., et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73:1218–1226.
    1. Schwartz G., Fehlings M.G. 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. 2002;137:177–190.
    1. Rosenberg L.J., Teng Y.D., Wrathall J.R. Effects of the sodium channel blocker tetrodotoxin on acute white matter pathology after experimental contusive spinal cord injury. J. Neurosci. 1999;19:6122–6133.
    1. Kretschmer B.D., Kratzer U., Schmidt W.J. Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn Schmiedebergs Arch. Pharmacol. 1998;358:181–190. doi: 10.1007/PL00005241.
    1. Fumagalli E., Funicello M., Rauen T., Gobbi M., Mennini T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur. J. Pharmacol. 2008;578:171–176. doi: 10.1016/j.ejphar.2007.10.023.
    1. Wang S.J., Wang K.Y., Wang W.C. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes) Neuroscience. 2004;125:191–201. doi: 10.1016/j.neuroscience.2004.01.019.
    1. Le Liboux A., Cachia J.P., Kirkesseli S., Gautier J.Y., Guimart C., Montay G., Peeters P.A., Groen E., Jonkman J.H., Wemer J. A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers. J. Clin. Pharmacol. 1999;39:480–486.
    1. Le Liboux A., Lefebvre P., Le Roux Y., Truffinet P., Aubeneau M., Kirkesseli S., Montay G. Single- and multiple-dose pharmacokinetics of riluzole in white subjects. J. Clin. Pharmacol. 1997;37:820–827. doi: 10.1002/j.1552-4604.1997.tb05630.x.
    1. Bruno R., Vivier N., Montay G., Le Liboux A., Powe L.K., Delumeau J.C., Rhodes G.R. Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis. Clin. Pharmacol. Ther. 1997;62:518–526. doi: 10.1016/S0009-9236(97)90047-3.
    1. Groeneveld G.J., van Kan H.J., Kalmijn S., Veldink J.H., Guchelaar H.J., Wokke J.H., van den Berg L.H. Riluzole serum concentrations in patients with ALS: Associations with side effects and symptoms. Neurology. 2003;61:1141–1143. doi: 10.1212/01.WNL.0000090459.76784.49.
    1. Bryson H.M., Fulton B., Benfield P. Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs. 1996;52:549–563.
    1. Tator C.H., Fehlings M.G. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J. Neurosurg. 1991;75:15–26. doi: 10.3171/jns.1991.75.1.0015.
    1. Fehlings M.G., Wilson J.R., Frankowski R.F., Toups E.G., Aarabi B., Harrop J.S., Shaffrey C.I., Harkema S.J., Guest J.D., Tator C.H., et al. Riluzole for the treatment of acute traumatic spinal cord injury: Rationale for and design of the NACTN Phase I clinical trial. J. Neurosurg. Spine. 2012;17(Suppl. 1):151–156.
    1. Agrawal S.K., Fehlings M.G. 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. 1996;16:545–552.
    1. Stys P.K., Waxman S.G., Ransom B.R. Na(+)-Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter. Ann. Neurol. 1991;30:375–380. doi: 10.1002/ana.410300309.
    1. Haigney M.C., Lakatta E.G., Stern M.D., Silverman H.S. Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation. 1994;90:391–399. doi: 10.1161/01.CIR.90.1.391.
    1. Haigney M.C., Miyata H., Lakatta E.G., Stern M.D., Silverman H.S. Dependence of hypoxic cellular calcium loading on Na(+)-Ca2+ exchange. Circ. Res. 1992;71:547–557. doi: 10.1161/01.RES.71.3.547.
    1. Schanne F.A., Kane A.B., Young E.E., Farber J.L. Calcium dependence of toxic cell death: A final common pathway. Science. 1979;206:700–702. doi: 10.1126/science.386513.
    1. Li S., Mealing G.A., Morley P., Stys P.K. Novel injury mechanism in anoxia and trauma of spinal cord white matter: Glutamate release via reverse Na+-dependent glutamate transport. J. Neurosci. 1999;19:RC16.
    1. Lipton S.A., Rosenberg P.A. Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 1994;330:613–622. doi: 10.1056/NEJM199403033300907.
    1. Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996;47(Suppl. 4):S233–S241. doi: 10.1212/WNL.47.6_Suppl_4.233S.
    1. Park E., Velumian A.A., Fehlings M.G. 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. 2004;21:754–774. doi: 10.1089/0897715041269641.
    1. Schnell L., Fearn S., Schwab M.E., Perry V.H., Anthony D.C. Cytokine-induced acute inflammation in the brain and spinal cord. J. Neuropathol. Exp. Neurol. 1999;58:245–254. doi: 10.1097/00005072-199903000-00004.
    1. Kobrine A.I., Evans D.E., LeGrys D.C., Yaffe L.J., Bradley M.E. Effect of intravenous lidocaine on experimental spinal cord injury. J. Neurosurg. 1984;60:595–601. doi: 10.3171/jns.1984.60.3.0595.
    1. Teng Y.D., Wrathall J.R. Local blockade of sodium channels by tetrodotoxin ameliorates tissue loss and long-term functional deficits resulting from experimental spinal cord injury. J. Neurosci. 1997;17:4359–4366.
    1. Schwartz G., Fehlings M.G. Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: Improved behavioral and neuroanatomical recovery with riluzole. J. Neurosurg. 2001;94:245–256.
    1. Kwon B.K., Stammers A.M., Belanger L.M., Bernardo A., Chan D., Bishop C.M., Slobogean G.P., Zhang H., Umedaly H., Giffin M., et al. Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J. Neurotrauma. 2010;27:669–682.
    1. Wu Y., Satkunendrarajah K., Teng Y., Chow D.S., Buttigieg J., Fehlings M.G. Delayed post-injury administration of riluzole is neuroprotective in a preclinical rodent model of cervical spinal cord injury. J. Neurotrauma. 2013;30:441–452. doi: 10.1089/neu.2012.2622.
    1. Wu Y., Satkunendrarajah K., Fehlings M.G. Riluzole improves outcome following ischemia-reperfusion injury to the spinal cord by preventing delayed paraplegia. Neuroscience. 2014;265:302–312. doi: 10.1016/j.neuroscience.2014.01.059.
    1. Ates O., Cayli S.R., Gurses I., Turkoz Y., Tarim O., Cakir C.O., Kocak A. Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J. Clin. Neurosci. 2007;14:658–665. doi: 10.1016/j.jocn.2006.03.023.
    1. Lang-Lazdunski L., Heurteaux C., Vaillant N., Widmann C., Lazdunski M. Riluzole prevents ischemic spinal cord injury caused by aortic crossclamping. J. Thorac. Cardiovasc. Surg. 1999;117:881–889. doi: 10.1016/S0022-5223(99)70367-3.
    1. Lips J., de Haan P., Bodewits P., Vanicky I., Dzoljic M., Jacobs M.J., Kalkman C.J. Neuroprotective effects of riluzole and ketamine during transient spinal cord ischemia in the rabbit. Anesthesiology. 2000;93:1303–1311. doi: 10.1097/00000542-200011000-00025.
    1. Mu X., Azbill R.D., Springer J.E. Riluzole and methylprednisolone combined treatment improves functional recovery in traumatic spinal cord injury. J. Neurotrauma. 2000;17:773–780. doi: 10.1089/neu.2000.17.773.
    1. Stutzmann J.M., Pratt J., Boraud T., Gross C. The effect of riluzole on post-traumatic spinal cord injury in the rat. Neuroreport. 1996;7:387–392. doi: 10.1097/00001756-199601310-00003.
    1. Hama A., Sagen J. Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain. J. Neurotrauma. 2011;28:127–134. doi: 10.1089/neu.2010.1539.
    1. Kitzman P.H. Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat. Neurosci. Lett. 2009;455:150–153. doi: 10.1016/j.neulet.2009.03.016.
    1. Grossman R.G., Fehlings M.G., Frankowski R.F., Burau K.D., Chow D.S., Tator C., Teng A., Toups E.G., Harrop J.S., Aarabi B., et al. 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. 2014;31:239–255.
    1. Grossman R.G., Toups E.G., Frankowski R.F., Burau K.D., Howley S. North American Clinical Trials Network for the Treatment of Spinal Cord Injury: Goals and progress. J. Neurosurg. Spine. 2012;17:6–10.
    1. Maynard F.M., Jr., Bracken M.B., Creasey G., Ditunno J.F., Jr., Donovan W.H., Ducker T.B., Garber S.L., Marino R.J., Stover S.L., Tator C.H., et al. International Standards for Neurological and Functional Classification of Spinal Cord Injury. American Spinal Injury Association. Spinal Cord. 1997;35:266–274.
    1. Chow D.S., Teng Y., Toups E.G., Aarabi B., Harrop J.S., Shaffrey C.I., Johnson M.M., Boakye M., Frankowski R.F., Fehlings M.G., et al. Pharmacology of riluzole in acute spinal cord injury. J. Neurosurg. Spine. 2012;17:129–140.
    1. Grossman R.G., Frankowski R.F., Burau K.D., Toups E.G., Crommett J.W., Johnson M.M., Fehlings M.G., Tator C.H., Shaffrey C.I., Harkema S.J., et al. Incidence and severity of acute complications after spinal cord injury. J. Neurosurg. Spine. 2012;17:119–128.
    1. Mestre H., Alkon T., Salazar S., Ibarra A. Spinal cord injury sequelae alter drug pharmacokinetics: An overview. Spinal Cord. 2011;49:955–960. doi: 10.1038/sc.2011.58.
    1. Vertiz-Hernandez A., Castaneda-Hernandez G., Martinez-Cruz A., Cruz-Antonio L., Grijalva I., Guizar-Sahagun G. l-arginine reverses alterations in drug disposition induced by spinal cord injury by increasing hepatic blood flow. J. Neurotrauma. 2007;24:1855–1862. doi: 10.1089/neu.2007.0375.
    1. Nagoshi N., Fehlings M.G. Investigational drugs for the treatment of spinal cord injury: Review of preclinical studies and evaluation of clinical trials from Phase I to II. Expert Opin. Investig. Drugs. 2015:1–14.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner