Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole.
OBJECTIVE
Persistent activation of voltage-sensitive Na+ channels is associated with cellular toxicity and may contribute to the degeneration of neural tissue following traumatic brain and spinal cord injury (SCI). Pharmacological blockade of these channels can attenuate secondary pathophysiology and reduce functional deficits acutely.


METHODS
To determine the therapeutic effects of Na+ channel blockers on long-term tissue sparing and functional neurological recovery after traumatic SCI, the authors injected Wistar rats intraperitoneally with riluzole (5 mg/kg), phenytoin (30 mg/kg), CNS5546A, a novel Na+ channel blocker (15 mg/kg), or vehicle (2-HP3CD; 5 mg/kg) 15 minutes after induction of compressive SCI at C7-T1. Functional neurological recovery of coordinated hindlimb function and strength, assessed 1 week postinjury and weekly thereafter for 6 weeks, was significantly enhanced in animals treated with riluzole compared with the other treatment groups. Seven weeks postinjury the preservation of residual tissue and integrity of descending axons were determined with digital morphometrical and fluorescent histochemical analysis. All three Na+ channel blockers significantly enhanced residual tissue area at the injury epicenter compared with control. Riluzole significantly reduced tissue loss in rostrocaudal regions surrounding the epicenter, with overall sparing of gray matter and selective sparing of white matter. Also, counts of red nuclei neurons retrogradely labeled with fluorogold introduced caudal to the injury site were significantly increased in the riluzole group.


CONCLUSIONS
Systemic Na+ channel blockers, in particular riluzole, can confer significant neuroprotection after in vivo SCI and result in behavioral recovery and sparing of both gray and white matter.
Schwartz
G
G
Division of Cell and Molecular Biology, The Toronto Western Research Institute, Ontario, Canada.
Fehlings
M G
MG
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D004525:Efferent Pathways / Q000187:drug effects / Q000473:pathology; D005260:Female; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D019782:Riluzole / Q000627:therapeutic use*; D026941:Sodium Channel Blockers; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013117:Spinal Cord Compression / Q000209:etiology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology
D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D019782:Riluzole