Riluzole, a Novel Neuroprotective Agent, Attenuates Both Neurologic Motor and Cognitive Dysfunction Following Experimental Brain Injury in the Rat

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Abstract
Several potential mechanisms are involved in mediating the pathophysiology 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 cognitive and neurologic motor deficits and reduce regional cerebral edema and histologic cell damage following lateral fluid-percussion (FP) brain injury in rats (n = 109). In study 1, 58 anesthetized male SpragueDawley rats (350–400 g) were subjected to FP brain injury of moderate severity (2.3–2.5 atm). Fifteen minutes following brain injury, animals 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 but uninjured animals received vehicle (n = 16) and served as controls. Animals were evaluated for cognitive deficits at 48 h postinjury and killed for assessment of regional brain edema. Administration of vehicle or Riluzole (4 mg/kg x 3) had no significant effect on memory or edema, whereas Riluzole (8 mg/kg x 3) significantly attenuated posttraumatic cognitive dysfunction (p < 0.05). In study 2, a second group of animals (n = 25) was injured, treated with Riluzole (8 mg/kg x 3 doses, n = 13) or vehicle (n = 12), and evaluated for neurologic motor function over 2 weeks. Animals treated with Riluzole demonstrated significantly improved motor scores beginning 1 week postinjury (p < 0.05). In study 3, brain-injured animals were treated with Riluzole (8 mg/kg x 3 doses, n = 10) or vehicle (n = 10), and posttraumatic lesion volume was assessed at 48 h postinjury using 2,3,5-triphenyltetrazolium chloride (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 both cognitive and neuromotor dysfunction associated with brain trauma.