Combining neuroprotective agents: effect of riluzole and magnesium in a rat model of thoracic spinal cord injury.
Damage to the spinal cord can result in irreversible impairments or complete loss of motor, sensory, and autonomic functions. Riluzole and magnesium have been widely investigated as neuroprotective agents in animal models of spinal cord injury. As these drugs protect the injured spinal cord through different mechanisms, we aimed to investigate if their neuroprotective efficacy could be cumulative.



This study aimed to investigate the neuroprotective efficacy of combined administration of riluzole and magnesium chloride in a contusive model of thoracic spinal cord injury.



An in vivo experiment was set using female Wistar Han rats that underwent a thoracic spinal cord contusion (T8) using a weight drop method. An hour after injury, animals were randomly distributed to receive (1) saline, (2) riluzole (2.50 mg/kg), (3) magnesium chloride (24.18 mg/kg) in a polyethylene glycol formulation, or (4) a combined treatment (riluzole and magnesium). Subsequent treatments were given in four intraperitoneal injections (spaced 12 hours apart).



The Basso, Beattie, and Bresnahan locomotor rating scale, an activity box test, and a swimming test were used to evaluate behavioral recovery over a 4-week period. Histologic analysis of the spinal cords was performed to measure the extent and volume of the lesion, axonal preservation, serotonergic and glutamatergic fiber sparing, motor neuron survival, and inflammation.



Our results show that only the riluzole treatment significantly improved behavioral recovery up to 4 weeks after injury when compared with saline controls (6.2±1.8), with animals achieving weight-supported stepping (9.1±1.2). Riluzole also promoted tissue sparing with significant differences achieved from 200 to 600 µm (caudally to the lesion epicenter), and reduced lesion volume, with animals presenting a significantly smaller lesion (3.23±0.26 mm(3)) when compared with the saline-treated group (4.74±0.80 mm(3)), representing a 32% decrease in lesion volume. Riluzole treatment induced significant axonal preservation, as well as serotonergic fiber sparing, caudally to the injury epicenter.



Our results suggest that the combined treatment, although simultaneously targeting two excitotoxic-related mechanisms, did not further improve behavioral and histologic outcome when compared with riluzole given alone.
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Natália L
NL
Vasconcelos
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Eduardo D
ED
Gomes
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Eduarda P
EP
Oliveira
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Carlos J
CJ
Silva
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Rui
R
Lima
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Nuno
N
Sousa
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
António J
AJ
Salgado
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal. Electronic address: nunosilva@ecsaude.uminho.pt.
Nuno A
NA
Silva
D000818:Animals; D004359:Drug Therapy, Combination; D005260:Female; D008274:Magnesium / Q000008:administration & dosage / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D019782:Riluzole / Q000008:administration & dosage / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
D018696:Neuroprotective Agents; D019782:Riluzole; D008274:Magnesium
Excitotoxicity; Ionic imbalances; Magnesium; Neuroprotection; Riluzole; Spinal cord injury