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Neutralization of interleukin-1β reduces cerebral edema and tissue loss and improves late cognitive outcome following traumatic brain injury in mice

Clausen, Fredrik; Hånell, Anders; Israelsson, Charlotte; Hedin, Johanna; Ebendal, Ted; Mir, Anis K; Gram, Hermann and Marklund, Niklas LU (2011) In European Journal of Neuroscience 34(1). p.23-110
Abstract

Increasing evidence suggests that interleukin-1β (IL-1β) is a key mediator of the inflammatory response following traumatic brain injury (TBI). Recently, we showed that intracerebroventricular administration of an IL-1β-neutralizing antibody was neuroprotective following TBI in mice. In the present study, an anti-IL-1β antibody or control antibody was administered intraperitoneally following controlled cortical injury (CCI) TBI or sham injury in 105 mice and we extended our histological, immunological and behavioral analysis. First, we demonstrated that the treatment antibody reached target brain regions of brain-injured animals in high concentrations (> 11 nm) remaining up to 8 days post-TBI. At 48 h post-injury, the anti-IL-1β... (More)

Increasing evidence suggests that interleukin-1β (IL-1β) is a key mediator of the inflammatory response following traumatic brain injury (TBI). Recently, we showed that intracerebroventricular administration of an IL-1β-neutralizing antibody was neuroprotective following TBI in mice. In the present study, an anti-IL-1β antibody or control antibody was administered intraperitoneally following controlled cortical injury (CCI) TBI or sham injury in 105 mice and we extended our histological, immunological and behavioral analysis. First, we demonstrated that the treatment antibody reached target brain regions of brain-injured animals in high concentrations (> 11 nm) remaining up to 8 days post-TBI. At 48 h post-injury, the anti-IL-1β treatment attenuated the TBI-induced hemispheric edema (P < 0.05) but not the memory deficits evaluated using the Morris water maze (MWM). Neutralization of IL-1β did not influence the TBI-induced increases (P < 0.05) in the gene expression of the Ccl3 and Ccr2 chemokines, IL-6 or Gfap. Up to 20 days post-injury, neutralization of IL-1β was associated with improved visuospatial learning in the MWM, reduced loss of hemispheric tissue and attenuation of the microglial activation caused by TBI (P < 0.05). Motor function using the rotarod and cylinder tests was not affected by the anti-IL-1β treatment. Our results suggest an important negative role for IL-1β in TBI. The improved histological and behavioral outcome following anti-IL-1β treatment also implies that further exploration of IL-1β-neutralizing compounds as a treatment option for TBI patients is warranted.

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published
keywords
Animals, Antibodies, Behavior, Animal, Brain Edema, Brain Injuries, Chemokines, Cognition Disorders, Disease Models, Animal, Glial Fibrillary Acidic Protein, Humans, Interleukin-1beta, Interleukin-6, Learning, Male, Memory, Mice, Mice, Inbred C57BL, Microglia, Neuropsychological Tests, Treatment Outcome, Journal Article, Research Support, Non-U.S. Gov't
in
European Journal of Neuroscience
volume
34
issue
1
pages
14 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:79959969839
ISSN
1460-9568
DOI
10.1111/j.1460-9568.2011.07723.x
language
English
LU publication?
no
id
d2b8cefa-9035-4c7d-bb89-ce706cfd3f80
date added to LUP
2016-12-12 15:53:26
date last changed
2017-11-19 04:35:53
@article{d2b8cefa-9035-4c7d-bb89-ce706cfd3f80,
  abstract     = {<p>Increasing evidence suggests that interleukin-1β (IL-1β) is a key mediator of the inflammatory response following traumatic brain injury (TBI). Recently, we showed that intracerebroventricular administration of an IL-1β-neutralizing antibody was neuroprotective following TBI in mice. In the present study, an anti-IL-1β antibody or control antibody was administered intraperitoneally following controlled cortical injury (CCI) TBI or sham injury in 105 mice and we extended our histological, immunological and behavioral analysis. First, we demonstrated that the treatment antibody reached target brain regions of brain-injured animals in high concentrations (&gt; 11 nm) remaining up to 8 days post-TBI. At 48 h post-injury, the anti-IL-1β treatment attenuated the TBI-induced hemispheric edema (P &lt; 0.05) but not the memory deficits evaluated using the Morris water maze (MWM). Neutralization of IL-1β did not influence the TBI-induced increases (P &lt; 0.05) in the gene expression of the Ccl3 and Ccr2 chemokines, IL-6 or Gfap. Up to 20 days post-injury, neutralization of IL-1β was associated with improved visuospatial learning in the MWM, reduced loss of hemispheric tissue and attenuation of the microglial activation caused by TBI (P &lt; 0.05). Motor function using the rotarod and cylinder tests was not affected by the anti-IL-1β treatment. Our results suggest an important negative role for IL-1β in TBI. The improved histological and behavioral outcome following anti-IL-1β treatment also implies that further exploration of IL-1β-neutralizing compounds as a treatment option for TBI patients is warranted.</p>},
  author       = {Clausen, Fredrik and Hånell, Anders and Israelsson, Charlotte and Hedin, Johanna and Ebendal, Ted and Mir, Anis K and Gram, Hermann and Marklund, Niklas},
  issn         = {1460-9568},
  keyword      = {Animals,Antibodies,Behavior, Animal,Brain Edema,Brain Injuries,Chemokines,Cognition Disorders,Disease Models, Animal,Glial Fibrillary Acidic Protein,Humans,Interleukin-1beta,Interleukin-6,Learning,Male,Memory,Mice,Mice, Inbred C57BL,Microglia,Neuropsychological Tests,Treatment Outcome,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {23--110},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Neutralization of interleukin-1β reduces cerebral edema and tissue loss and improves late cognitive outcome following traumatic brain injury in mice},
  url          = {http://dx.doi.org/10.1111/j.1460-9568.2011.07723.x},
  volume       = {34},
  year         = {2011},
}