title: Tissue sparing and functional recovery following experimental traumatic brain injury is provided by treatment with an anti-myelin-associated glycoprotein antibody.
abstract: Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or control IgG (n=26 injured, n=22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n=14 sham, n=11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P<0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P<0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.
authors.affiliation: Traumatic Brain Injury Laboratory, Department of Neurosurgery, The University of Pennsylvania, Philadelphia, PA, USA, and Department of Neurosurgery, Uppsala University Hospital, Sweden. hilairet@u.washington.edu
authors.forename: Hilaire J
authors.initials: HJ
authors.lastname: Thompson
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
authors.forename: David G
authors.initials: DG
authors.lastname: LeBold
authors.forename: Diego M
authors.initials: DM
authors.lastname: Morales
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Keck
authors.forename: Mary
authors.initials: M
authors.lastname: Vinson
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Royo
authors.forename: Robert
authors.initials: R
authors.lastname: Grundy
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000276:immunology; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D014855:Wallerian Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; D018992:Myelin-Associated Glycoprotein