RILUZOLE, A NOVEL NEUROPROTECTIVE AGENT, ATTENUATES BOTH NEUROLOGIC MOTOR AND COGNITIVE DYSFUNCTION FOLLOWING EXPERIMENTAL BRAIN INJURY IN THE RAT

Several potential mechanisms are involved in mediating the pathophysio logy of traumatic brain injury (TBI), including inflammatory processes and excitotoxicity. In the present study, we evaluated the ability of the use-dependent sodium channel inhibitor Riluzole to attenuate cogn itive and neurologic motor deficits and reduce regional cerebral edema and histologic cell damage following lateral fluid-percussion (FP) br ain injury in rats (n = 109). In study 1, 58 anesthetized male Sprague -Dawley rats (350-400 g) were subjected to FP brain injury of moderate severity (2.3-2.5 atm). Fifteen minutes following brain injury, anima ls randomly received an i.v. bolus of either Riluzole (4 mg/kg, n = 11 ), Riluzole (8 mg/kg, n = 11), or glycol vehicle (n = 20), followed by 6 h and 24 h s.c. injections (identical dose). Surgically prepared bu t uninjured animals received vehicle (n = 16) and served as controls. Animals were evaluated for cognitive deficits at 48 h postinjury and k illed for assessment of regional brain edema. Administration of vehicl e or Riluzole (4 mg/kg x 3) had no significant effect on memory or ede ma, whereas Riluzole (8 mg/kg x 3) significantly attenuated posttrauma tic cognitive dysfunction (p < 0.05). In study 2, a second group of an imals (n = 25) was injured, treated with Riluzole (8 mg/kg x 3 doses, n = 13) or vehicle (n = 12), and evaluated for neurologic motor functi on over 2 weeks. Animals treated with Riluzole demonstrated significan tly improved motor scores beginning 1 week postinjury (p < 0.05). In s tudy 3, brain-injured animals were treated with Riluzole (8 mg/kg x 3 doses, n = 10) or vehicle (n = 10), and posttraumatic Iesion volume wa s assessed at 48 h postinjury using 2,3,5-triphenyltetrazolium chlorid e (TTC) staining. Treatment with Riluzole had no significant effect on posttraumatic lesion volume. The present study demonstrates that use- dependent sodium channel inhibitors, such as Riluzole, can attenuate b oth cognitive and neuromotor dysfunction associated with brain trauma.