Elsevier

World Neurosurgery

Volume 114, June 2018, Pages e247-e253
World Neurosurgery

Original Article
Effect of Riluzole on Spinal Cord Regeneration with Hemisection Method Before Injury

https://doi.org/10.1016/j.wneu.2018.02.171Get rights and content

Highlights

  • Riluzole treatment is more effective before injury.

  • Positive clinical results were obtained in groups given riluzole before injury.

  • Recurrent riluzole application increases neuroregeneration.

Objective

The pathophysiology of spinal cord injury (SCI) with the information obtained to date has not been elucidated fully. A safe drug or treatment protocol that results in cell regeneration for SCI remains unknown. Neuroprotective and neuroregenerative effects of riluzole, administered after a SCI, have been shown in experimental studies. This study aimed to investigate the effect of riluzole on neural regeneration in a rat SCI model.

Methods

Thirty-two rats were divided into 8 groups, with 4 rats in each group. Hemisection method was performed after T7–T9 laminectomy. Rats were intraperitoneally aministered with riluzole (6 mg/kg). Locomotor recovery of the rats was assessed at 1 day, and 1, 2, 3, and 4 weeks after the 21-point Basso, Beattie, and Bresnahan test. Subsequently, the spinal cords of the rats were scored according to a semiquantitative grading system using a light microscope, and the numbers of myelinated axons, neurons, and glial cells were calculated.

Results

Basso, Beattie, and Bresnahan test changes were statistically significant when groups 4–6 and 8 were compared with the other groups (P < 0.05, P < 0.00625). The results of the numbers of neurons, glial cells, and myelinated axons were statistically significant. Especially group 8, in which riluzole was administered 5 days before injury, more positive clinical and histopathologic results were obtained.

Conclusions

Riluzole treatment is more effective when provided before injury. Riluzole may contribute to functional recovery when used in the preoperative period in patients who are at a high risk for permanent neurologic deficit.

Introduction

Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission, and it has gained popularity because of its safety and efficacy in patients with amyotrophic lateral sclerosis.1, 2, 3, 4, 5 Riluzole blocks voltage-gated sodium channels and calcium ion channels and inhibits glutamate release in the nervous system,5, 6, 7, 8, 9, 10, 11, 12, 13 which has been shown to be potentially protective.1, 14, 15, 16, 17 It also has been studied for use in spinal cord injury (SCI), and experimental studies in animals have underlined the decrease in tissue destruction and increase in functional recovery after riluzole use.18, 19, 20

SCI may be due to traumatic injuries, tumors, infections, and nontraumatic causes such as spondylosis.4 Its pathophysiology is biphasic: the primary acute phase develops concurrently with traumatic injury and consists of necrosis and apoptosis, whereas secondary damage is a result of primary damage that begins with activation of endogenous cell death pathways.21, 22, 23 Those in the primary phase present with mechanical tissue damage immediately after trauma, so no intervention may help. However, secondary damage begins with a tissue damage response, which is revealed especially by glutamate-mediated excitotoxicity, and it can be interrupted by suspension of these pathways.24

The North American Clinical Trials Network Consortium (NACT) conducted systematic studies of reports published between 1966 and 2011 regarding pharmacologic therapies for SCI. The NACT Treatment Strategy Selection Committee has suggested that 5 drugs are effective for treating SCI: riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline.24

We studied the effect of riluzole in the treatment of SCI. According to our knowledge, riluzole has not been administered in SCI prior to injury. Additionally, the effect of Riluzole onneural degeneration was firstly investigated using spinal cord hemisectionmodel which imitates the neural degeneration mechanisms in a most realistic way. We questioned whether riluzole may be beneficial and may contribute to functional recovery when used in the preoperative period in patients who are at high risk for permanent neurologic deficit.

Section snippets

Experimental Groups

All experimental procedures used in this investigation were reviewed and approved by the ethical committee of the Ankara University and conformed to the National Institutes of Health Guidelines for Care and Use of Experimental Animals. Riluzole was administered intraperitoneally at a dose of 6 mg/kg. A total of 32 adult male Wistar albino rats weighing 210–250 g were assigned randomly to 8 groups with 4 rats per group: group 1, riluzole solvent (HCl + NaOH + saline; riluzole solution is needed

Results

We studied 32 albino Wistar rats, with each group containing four animals. Two rats (groups 7 and 8) died at the end of the week. The average weight of the remaining 30 rats was 228.13 ± 10 g (minimum 210 g, maximum 246 g). There was no significant difference in the average weights of the group (P > 0.05, Kruskal–Wallis χ2 tests).

Investigation of the Effectiveness of Riluzole

In a current meta-analysis of SCI, riluzole was demonstrated to have significant clinical effects in experimental animal models.22, 23 In these studies, riluzole was given after SCI, which was performed via ischemia,26 weight reduction,27 clipping,18 and balloon compression.19 Two situations make our study important. First, in our study, the hemisection method was used for the first time to investigate the effectiveness of riluzole on neural regeneration in a rat SCI model. Second, for the

Conclusions

The pathophysiology of SCI with the information obtained to date has not been fully elucidated. Specific treatment has not been found in SCI to prevent local or remote damage (neural protection) and for regeneration. A safe drug or treatment protocol that results in cell regeneration is not known for SCI.

Neuroprotective and neuroregenerative effects of riluzole, which is in a trial phase, given after SCI have been shown in experimental studies. In our study, histopathologic and clinic results

References (45)

  • A. Nogradi et al.

    Delayed Riluzole treatment is able to rescue injured rat spinal motoneurons

    Neuroscience

    (2007)
  • R.G. Miller et al.

    Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)

    Cochrane Database Syst Rev

    (2007)
  • G. Bensimon et al.

    A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group

    N Engl J Med

    (1994)
  • L. Lacomblez et al.

    Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II

    Lancet

    (1996)
  • M.G. Fehlings 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)
  • J. Liu et al.

    The efficacy and safety of riluzole for neurodegenerative movement disorders: a systematic review with meta-analysis

    Drug Deliv

    (2018)
  • M.S. Levi et al.

    A review of neuroprotective agents

    Curr Med Chem

    (2004)
  • B.K. Siesjö et al.

    Neurocytotoxicity: pharmacological implications

    Fundam Clin Pharmacol

    (1991)
  • B.K. Siesjö

    Pathophysiology and treatment of focal cerebral ischemia. Part I: pathophysiology. (1992)

    J Neurosurg

    (2008)
  • E.N. Shimizu et al.

    Prophylactic riluzole attenuates oxidative stress damage in spinal cord distraction

    J Neurotrauma

    (2018)
  • C. Samano et al.

    Mechanism of neuroprotection against experimental spinal cord ınjury by riluzole or methylprednisolone

    Neurochem Res

    (2017)
  • B. Gloviczki et al.

    Delayed spinal cord-brachial plexus reconnection after C7 ventral root avulsion: the effect of reinnervating motoneurons rescued by riluzole treatment

    J Neurotrauma

    (2017)
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    Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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