title: Riluzole, a novel neuroprotective agent, attenuates both neurologic motor and cognitive dysfunction following experimental brain injury in the rat.
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 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, 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 post-traumatic 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.
authors.affiliation: Division of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: McIntosh
authors.forename: D H
authors.initials: DH
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Voddi
authors.forename: B R
authors.initials: BR
authors.lastname: Perri
authors.forename: J M
authors.initials: JM
authors.lastname: Stutzmann
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism; D001929:Brain Edema / Q000378:metabolism; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D003072:Cognition Disorders / Q000523:psychology*; D008297:Male; D009069:Movement Disorders / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D013844:Thiazoles; D019782:Riluzole