IMPROVEMENT OF COGNITIVE DEFICITS AND DECREASED CHOLINERGIC NEURONAL CELL LOSS AND APOPTOTIC CELL-DEATH FOLLOWING NEUROTROPHIN INFUSION AFTER EXPERIMENTAL TRAUMATIC BRAIN INJURY

This study explores the effects of infusion of nerve growth factor (NG F) 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 fun ction 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 r egion using choline acetyltransferase immunohistochemistry demonstrate d significant cell loss after injury. infusion of NGF significantly at tenuated loss of these cholinergic neurons. A second group of animals was subjected to fluid-percussion brain injury alone (23 rats) or inju ry followed by NGF infusion(18 rats). These animals were killed betwee n 24 hours and 2 weeks postinjury and the septal region was examined f or the presence of apoptotic cells using the terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end l abeling technique. Apoptotic cells were identified as early as 24 hour s 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 sign ificant motor differences were observed between the NCF- and vehicle t reated groups. These data indicate that NGF administration beginning 2 4 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 benef icial effects of NGF may be related to its ability to attenuate trauma tically induced apoptotic cell death.