Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression.
OBJECTIVE
Central nervous system axons regenerate poorly after traumatic brain injury (TBI), partly due to inhibitors such as the protein Nogo-A present in myelin. The authors evaluated the efficacy of anti-Nogo-A monoclonal antibody (mAb) 7B12 administration on the neurobehavioral and cognitive outcome of rats following lateral fluid-percussion brain injury, characterized the penetration of the 7B12 or control antibodies into target brain regions, and evaluated the effects of Nogo-A inhibition on hemispheric tissue loss and sprouting of uninjured motor tracts in the cervical cord. To elucidate a potential molecular response to Nogo-A inhibition, we evaluated the effects of 7B12 on hippocampal GAP-43 expression.


METHODS
Beginning 24 hours after lateral fluid-percussion brain injury or sham injury in rats, the mAb 7B12 or control antibody was infused intracerebroventricularly over 14 days, and behavior was assessed over 4 weeks.


RESULTS
Immunoreactivity for 7B12 or immunoglobulin G was detected in widespread brain regions at 1 and 3 weeks postinjury. The brain-injured animals treated with 7B12 showed improvement in cognitive function (p < 0.05) at 4 weeks but no improvement in neurological motor function from 1 to 4 weeks postinjury compared with brain-injured, vehicle-treated controls. The enhanced cognitive function following inhibition of Nogo-A was correlated with an attenuated postinjury downregulation of hippocampal GAP-43 expression (p < 0.05).


CONCLUSIONS
Increased GAP-43 expression may be a novel molecular mechanism of the enhanced cognitive recovery mediated by Nogo-A inhibition after TBI in rats.
Marklund
Niklas
N
Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, USA. niklas.marklund@neurokir.uu.se
Bareyre
Florence M
FM
Royo
Nicolas C
NC
Thompson
Hilaire J
HJ
Mir
Anis K
AK
Grady
M Sean
MS
Schwab
Martin E
ME
McIntosh
Tracy K
TK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001522:Behavior, Animal; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D003071:Cognition; D015536:Down-Regulation / Q000502:physiology; D019922:GAP-43 Protein / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D009185:Myelin Proteins / Q000037:antagonists & inhibitors*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects; D000070798:Nogo Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D019922:GAP-43 Protein; D007074:Immunoglobulin G; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat