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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.

This study explores the effects of infusion of nerve growth factor (NGF) on behavioral outcome and cell death in the septal region using the clinically relevant model of fluid-percussion brain injury in the rat. Animals were subjected to fluid-percussion brain injury and 24 hours later a miniosmotic pump was implanted to infuse NGF (12 animals) or vehicle (12 animals) directly into the region of maximum injury for 2 weeks. Four weeks postinjury the animals were tested for cognitive function using a Morris Water Maze paradigm. Neurological motor function was evaluated over a 4-week postinjury period. The rats receiving NGF infusions had significantly higher memory scores than vehicle-treated animals. Examination of the cholinergic neurons in the medial septal region using choline acetyltransferase immunohistochemistry demonstrated significant cell loss after injury. Infusion of NGF significantly attenuated loss of these cholinergic neurons. A second group of animals was subjected to fluid-percussion brain injury alone (23 rats) or injury followed by NGF infusion (18 rats). These animals were killed between 24 hours and 2 weeks postinjury and the septal region was examined for the presence of apoptotic cells using the terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling technique. Apoptotic cells were identified as early as 24 hours postinjury; their numbers peaked at 4 and 7 days, and then declined by 14 days. The NGF-treated animals had some apoptotic cells; however, even at 7 days there were significantly fewer of these cells. No significant motor differences were observed between the NGF- and vehicle-treated groups. These data indicate that NGF administration beginning 24 hours after fluid-percussion brain injury has a beneficial effect on cognition and results in sparing of cholinergic septal neurons. These improvements persist after cessation of NGF administration. The beneficial effects of NGF may be related to its ability to attenuate traumatically induced apoptotic cell death.

A reliable and rapid method for quantifying lesion volume following traumatic brain injury (TBI) has vast potential in brain injury research. Staining with 2, 3, 5-triphenyltetrazolium chloride (TTC) provides for demarcation of damaged or infarcted tissue from normal, viable cerebral tissue, in which a red formazan product is formed by reduction during cellular respiration of mitochondrial dehydrogenase enzymes. The present study evaluated the use of TTC staining to quantify the cortical lesion volume in rats undergoing fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (350-450 g, n = 27) were anesthetized (sodium pentobarbital, 60 mg/kg, ip) and subjected to lateral FP brain injury of mild (1.1-1.3 atm, n = 5), moderate (2.0-2.3 atm, n = 9), or high (2.4-2.6 atm, n = 8) severity, while sham (noninjured) animals (n = 5) were anesthetized and surgically prepared without injury. Forty-eight hours after injury animals were sacrificed, brains were stained with TTC, and lesion volumes were calculated. A highly significant correlation was found between cerebral cortical lesion volume (mm3) and severity of brain injury (r = 0.85; p < 0.0001). The mean (+/-SD) lesion volumes were 12.1 (+/-4.5) mm3 following mild injury, 33.8 (+/-8.6) mm3 following moderate injury, and 45.1 (+/-14.0) mm3 following severe injury. A significant difference was observed between all injury groups using a t test with Bonferroni correction (p < 0.05). These results suggest that the TTC staining technique is a useful, rapid, and reproducible method for quantification of lesion volume following lateral FP brain injury.