Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzole.
OBJECTIVE
Recent studies confirmed the deleterious role of glutamate in the pathophysiology of spinal cord ischemia induced by aortic cross-clamping. We investigated the effect of riluzole, an anti-glutamate drug, in a rat model of spinal cord ischemia.


METHODS
Spinal cord ischemia was induced in normothermia for 14 min in Sprague-Dawley rats using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy. Experimental groups were as follows: sham-operation (n=15), control (n=15) receiving only vehicle, riluzole (n=15) receiving riluzole (4 mg/kg) before clamping and at the onset of reperfusion. Separate animals were used for monitoring physiologic parameters in the sham-operation (n=3), control (n=5), and riluzole (n=5) groups. Neurologic status was assessed at 6, 24 h, and then daily up to 96 h. Rats were randomly killed at 24, 48, or 96 h (n=5 for each time). Spinal cords were harvested for histopathology, immunohistochemistry for microtubule-associated protein 2 (MAP-2), TUNEL staining, and analysis of DNA fragmentation by agarose gel electrophoresis.


RESULTS
All sham-operated rats had a normal neurologic outcome, whereas all control rats suffered severe and definitive paraplegia. Riluzole-treated rats had significantly better neurologic function compared to the control. Histopathology disclosed severe neuronal necrosis in the lumbar gray matter of control rats, whereas riluzole-treated rats suffered usually mild to moderate injury. Riluzole particularly prevented motor neurons injury. MAP-2 immunoreactivity was completely lost in control rats, whereas it was preserved either completely or partly in riluzole-treated rats. TUNEL staining revealed numerous apoptotic neurons scattered within the whole gray matter of control rats. Riluzole prevented or dramatically attenuated apoptotic neuronal death in treated rats. DNA extracted from lumbar spinal cords of sham-operated and riluzole-treated rats exhibited no laddering, whereas spinal cords from control rats showed DNA laddering with fragmentation into approximately 180 multiples of base pairs.


CONCLUSIONS
Riluzole may protect the spinal cord in a setting of severe ischemia by preventing neuronal necrosis and apoptosis. This drug may therefore be considered for clinical use during 'high risk' surgical procedures on the thoracoabdominal aorta.
Department of Cardiovascular Surgery, Hopital Bichat and Xavier Bichat Medical University, Paris, France. loic.lang@wanadoo.fr
L
L
Lang-Lazdunski
C
C
Heurteaux
A
A
Mignon
J
J
Mantz
C
C
Widmann
J
J
Desmonts
M
M
Lazdunski
D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D004587:Electrophoresis, Agar Gel; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008026:Ligation / Q000009:adverse effects; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000627:therapeutic use*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D020760:Spinal Cord Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D008869:Microtubule-Associated Proteins; D019782:Riluzole