Neutralization of interleukin‐1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice
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Titel:
Neutralization of interleukin‐1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice
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<jats:title>Abstract</jats:title><jats:p>Interleukin‐1β (IL‐1β) 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‐1β neutralizing antibody IgG2a/k (1.5 μg/mL) or control antibody was infused at a rate of 0.25 μL/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‐1β<jats:italic>in vitro</jats:italic>. IL‐1β neutralization attenuated the CCI‐induced cortical and hippocampal microglial activation (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>0.05 at post‐injury days 3 and 7), and cortical infiltration of neutrophils (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>0.05 at post‐injury day 7). There was only a minimal cortical infiltration of activated T‐cells, attenuated by IL‐1β neutralization (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>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 (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>0.05). In brain‐injured animals, IL‐1β neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (<jats:italic>P </jats:italic><<jats:italic> </jats:italic>0.05) without influencing neurological motor function. Our results indicate that IL‐1β 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.</jats:p>