Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat.
OBJECTIVE
Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI.


METHODS
Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function was evaluated in the Morris Water Maze (MWM) followed by evaluation of regional cerebral edema at 48 h post-injury. In Study 2, animals were evaluated for neurological motor function and post-injury learning in the MWM at one week post-injury.


RESULTS
FP brain injury caused significant cognitive (p < 0.05) and neurological motor (p < 0.05) deficits and increased regional brain water content in the injured hemisphere. Treatment with either TNF- or IL-6-mAB had no effect on neurological motor, cognitive function or brain edema during the first post-injury week.


CONCLUSIONS
Evaluation of anti-inflammatory mABs on more chronic behavioral deficits appears warranted.
Marklund
Niklas
N
Traumatic Brain Injury Labraty, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Keck
Carrie
C
Hoover
Rachel
R
Soltesz
Kristie
K
Millard
Marie
M
LeBold
David
D
Spangler
Zachary
Z
Banning
Adrian
A
Benson
Jacqueline
J
McIntosh
Tracy K
TK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D001929:Brain Edema / Q000188:drug therapy / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D003072:Cognition Disorders / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors