The present study evaluated behavioral and histopathological outcome after controlled cortical impact (CCI) brain injury in mice deficient in tumor necrosis factor [TNF(؊/؊)] and their wild-type (wt) littermates. Mice were subjected to CCI brain injury [TNF(؊/؊), n ‫؍‬ 10; wt, n ‫؍‬ 10] or served as uninjured controls [TNF(؊/؊), n ‫؍‬ 10; wt, n ‫؍‬ 10] and were evaluated for deficits in memory retention at 7 days postinjury. Although both brain-injured wt and TNF(؊/؊) mice exhibited significant memory dysfunction compared to uninjured controls (P < 0.02), the deficits in memory retention in injured TNF(؊/؊) mice were significantly less severe than in injured wt mice (P < 0.02). A second group of mice was subjected to CCI brain injury [TNF(؊/؊), n ‫؍‬ 20; wt, n ‫؍‬ 20] or served as uninjured controls [TNF(؊/؊), n ‫؍‬ 15; wt, n ‫؍‬ 15] and were evaluated over a 4-week period for neurological motor function. In the acute posttraumatic period (48 h postinjury), braininjured TNF(؊/؊) mice were significantly less impaired than injured wt mice on composite neuroscore (P < 0.001), rotarod (P < 0.05), and beam balance (P < 0.02) tests. However, wt mice recovered from brain injury by 2-3 weeks postinjury, whereas TNF(؊/؊) mice continued to demonstrate persistent motor deficits up to 4 weeks postinjury. Histopathological analysis at 2 and 4 weeks postinjury revealed that brain-injured TNF(؊/؊) mice had significantly more cortical tissue loss than wt mice (P < 0.02). Our results suggest that although the presence of TNF in the acute posttraumatic period may be deleterious, this cytokine may play a role in facilitating long-term behavioral recovery and histological repair after brain injury.

The cell death regulatory protein, Bcl‐2, has been suggested to participate in the pathophysiology of various neurological disorders, including traumatic brain injury (TBI). The cognitive function and histopathologic sequelae after controlled cortical impact brain injury were evaluated in transgenic (TG) mice that overexpress human Bcl‐2 protein (n = 13) and their wild type (WT) controls (n = 9). Although brain‐injured Bcl‐2 TG mice exhibited similar posttraumatic deficits in a Morris water maze (MWM) test of spatial memory as their WT counterparts at 1 week postinjury, the preinjury learning ability of Bcl‐2 TG mice was impaired significantly compared with their WT littermates (P < 0.05). In contrast, histopathologic analysis revealed significantly attenuated tissue loss in the ipsilateral hemisphere (p < 0.01) and decreased tissue loss in ipsilateral hippocampal area CA3 (P < 0.001) and the dentate gyrus (P < 0.01) in brain‐injured Bcl‐2 TG mice compared with brain‐injured WT mice. Immunohistochemical evaluation of glial fibrillary acidic protein also revealed a significant decrease in reactive astrocytosis in the ipsilateral dorsal thalamus (P < 0.05) and the ventral thalamus (P < 0.01) in brain‐injured Bcl‐2 TG mice. These results suggest that overexpression of Bcl‐2 protein may play a protective role in neuropathologic sequelae after TBI. J. Comp. Neurol. 412:681–692, 1999. © 1999 Wiley‐Liss, Inc.