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 (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.
Sinson
G
G
Division of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, USA.
Perri
B R
BR
Trojanowski
J Q
JQ
Flamm
E S
ES
McIntosh
T K
TK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy*; D004253:DNA Nucleotidylexotransferase; D003856:Deoxyuracil Nucleotides; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D007260:Infusion Pumps; D008297:Male; D008568:Memory / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010296:Parietal Lobe / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D014677:Pharmaceutical Vehicles; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012686:Septal Nuclei / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D013997:Time Factors
D003856:Deoxyuracil Nucleotides; D009414:Nerve Growth Factors; D014677:Pharmaceutical Vehicles; C027078:deoxyuridine triphosphate; D002795:Choline O-Acetyltransferase; D004253:DNA Nucleotidylexotransferase