title: Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice.
abstract: Interleukin-1beta (IL-1beta) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1beta neutralizing antibody IgG2a/k (1.5 microg/mL) or control antibody was infused at a rate of 0.25 microL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1-7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1betain vitro. IL-1beta neutralization attenuated the CCI-induced cortical and hippocampal microglial activation (P < 0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils (P < 0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1beta neutralization (P < 0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue (P < 0.05). In brain-injured animals, IL-1beta neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P < 0.05) without influencing neurological motor function. Our results indicate that IL-1beta is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.
authors.affiliation: Department of Neuroscience, Section for Neurosurgery, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Clausen
authors.forename: Anders
authors.initials: A
authors.lastname: Hånell
authors.forename: Maria
authors.initials: M
authors.lastname: Björk
authors.forename: Lars
authors.initials: L
authors.lastname: Hillered
authors.forename: Anis K
authors.initials: AK
authors.lastname: Mir
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D003071:Cognition / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology; D045442:Rotarod Performance Test; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D053583:Interleukin-1beta