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Mechanism of Neuroprotection Against Experimental Spinal Cord Injury by Riluzole or Methylprednisolone

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Abstract

Any spinal cord injury carries the potential for persistent disability affecting motor, sensory and autonomic functions. To prevent this outcome, it is highly desirable to block a chain of deleterious reactions developing in the spinal areas immediately around the primary lesion. Thus, early timing of pharmacological neuroprotection should be one major strategy whose impact may be first studied with preclinical models. Using a simple in vitro model of the rat spinal cord it is possible to mimic pathological processes like excitotoxicity that damages neurons because of excessive glutamate receptor activation due to injury, or hypoxic/dysmetabolic insult that preferentially affects glia following vascular dysfunction. While ongoing research is exploring the various components of pathways leading to cell death, current treatment principally relies on the off-label use of riluzole (RLZ) or methylprednisolone sodium succinate (MPSS). The mechanism of action of these drugs is diverse as RLZ targets mainly neurons and MPSS targets glia. Even when applied after a transient excitotoxic stimulus, RLZ can provide effective prevention of secondary excitotoxic damage to premotoneurons, although not to motoneurons that remain very vulnerable. This observation indicates persistent inability to express locomotor activity despite pharmacological treatment conferring some histological protection. MPSS can protect glia from dysmetabolic insult, yet it remains poorly effective to prevent neuronal death. In summary, it appears that these pharmacological agents can produce delayed protection for certain cell types only, and that their combined administration does not provide additional benefit. The search should continue for better, mechanism-based neuroprotective agents.

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Fig. 1
Fig. 2

Figures c, d are reprinted from Sámano et al. [46]. A study of the potential neuroprotective effect of riluzole on locomotor networks of the neonatal rat spinal cord in vitro damaged by excitotoxicity. Copyright (2012), with permission from Elsevier

Fig. 3

Figures d, e are reprinted from Sámano et al. [56]. A study of methylprednisolone neuroprotection against acute injury to the rat spinal cord in vitro. Copyright (2016), with permission from Elsevier. (Color figure online)

Fig. 4

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

ASIA:

American Spinal Injury Association

AU:

Arbitrary units

bcl-xL :

Anti-apoptotic regulator, and splicing isoform of bcl-x gene

BCSFB:

Blood-cerebrospinal fluid barrier

BLMB:

Blood-leptomeningeal barrier

BSB:

Blood-spinal barrier

CD200L:

CD200 ligand

CD200R:

CD200 receptor

CNS:

Central nervous system

CPG:

Central pattern generators

SCI:

Spinal cord injury

DAPI:

4′,6-Diamidino-2-phenylindole

EAAT:

Excitatory amino acid transporters

EPO:

Cytokine erythropoietin

FDA:

Food and Drug Administration

GFAP:

Glial fibrillary acidic protein

GR:

Glucocorticoid receptor

HIF1α:

Hypoxic inducing factor 1α

hCNS-SCns:

Human central nervous system-derived neural stem cell

i.v.:

Intravenous

IL:

Interleukin

KA:

Kainate

LWM:

Lateral white matter

MBP:

Mature myelin basic protein

MPSS:

Methylprednisolone sodium succinate

NASCIS:

National Acute Spinal Cord Injury Study Trials

NMDA:

N-methyl-d-aspartic acid

nNOS:

Neuronal nitric oxide synthase

OLs:

Oligodendrocytes

PM:

Pathological medium

RISCIS:

Riluzole in Acute Spinal Cord Injury Study

RLZ:

Riluzole or rilutek

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SMI-32:

Neurofilament H non-phosphorylated antibody

SOD-1:

Superoxide dismutase

STAT5:

Activator transcription factor STAT

TBOA:

Threo-β-benzyloxyaspartate

TNF-α:

Tumor necrosis factor alpha

TRPM:

Transient receptor potential cation channel, subfamily M

VWM:

Ventral white matter

WM:

White matter

Wsh:

Washout

5-HT:

5-Hydroxytryptamine

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Authors and Affiliations

  1. División de Ciencias Naturales e Ingeniería, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, Mexico City, Mexico

    Cynthia Sámano

  2. Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy

    Andrea Nistri

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  1. Cynthia Sámano
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  2. Andrea Nistri
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Correspondence to Andrea Nistri.

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Sámano, C., Nistri, A. Mechanism of Neuroprotection Against Experimental Spinal Cord Injury by Riluzole or Methylprednisolone. Neurochem Res 44, 200–213 (2019). https://doi.org/10.1007/s11064-017-2459-6

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  • DOI: https://doi.org/10.1007/s11064-017-2459-6

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