Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Research output: Contribution to journalArticle

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.

Details

Authors
  • Fredrik Clausen
  • Anders Hånell
  • Maria Björk
  • Lars Hillered
  • Anis K Mir
  • Hermann Gram
  • Niklas Marklund
External organisations
  • Uppsala University
Research areas and keywords

Keywords

  • Animals, Brain Injuries, Cognition, Image Processing, Computer-Assisted, Immunohistochemistry, Inflammation, Interleukin-1beta, Male, Maze Learning, Mice, Mice, Inbred C57BL, Microglia, Neutrophil Infiltration, Rotarod Performance Test, T-Lymphocytes, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)385-96
JournalEuropean Journal of Neuroscience
Volume30
Issue number3
Publication statusPublished - 2009 Aug
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes