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

Clausen, Fredrik; Hånell, Anders; Björk, Maria; Hillered, Lars; Mir, Anis K; Gram, Hermann and Marklund, Niklas LU (2009) In European Journal of Neuroscience 30(3). p.96-385
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,... (More)

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.

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publishing date
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Contribution to journal
publication status
published
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
in
European Journal of Neuroscience
volume
30
issue
3
pages
96 - 385
publisher
Wiley-Blackwell
external identifiers
  • scopus:68249103676
ISSN
1460-9568
DOI
10.1111/j.1460-9568.2009.06820.x
language
English
LU publication?
no
id
69265970-b1af-4a52-ab60-46774bcb186a
date added to LUP
2018-03-03 14:59:19
date last changed
2018-09-16 04:53:34
@article{69265970-b1af-4a52-ab60-46774bcb186a,
  abstract     = {<p>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 &lt; 0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils (P &lt; 0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1beta neutralization (P &lt; 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 &lt; 0.05). In brain-injured animals, IL-1beta neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P &lt; 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.</p>},
  author       = {Clausen, Fredrik and Hånell, Anders and Björk, Maria and Hillered, Lars and Mir, Anis K and Gram, Hermann and Marklund, Niklas},
  issn         = {1460-9568},
  keyword      = {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},
  language     = {eng},
  number       = {3},
  pages        = {96--385},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice},
  url          = {http://dx.doi.org/10.1111/j.1460-9568.2009.06820.x},
  volume       = {30},
  year         = {2009},
}