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

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 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.

Recombinant Human Interleukin-1 Receptor Antagonist in Severe Traumatic Brain Injury: A Phase II Randomized Control Trial

“…25 Previous rodent models of IL1ra antagonism in TBI have used variations of the controlled cortical impact model. [3][4][5][6] In this study, we have tried to minimize interpatient variability rather than recapitulating these rodent models; however, this does not detract from the core conclusions of the study. It is not possible to select out patients with a 'pure' form of injury for study and therefore human studies are necessarily opportunistic and heterogenous.…”

Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

“…In experimental models of cerebral ischemia/hypoxia or TBI, early and transient profiles of IL-6 elevations have been documented (Woodroofe et al, 1991;Taupin et al, 1993;Maeda et al, 1994;Wang et al, 1995;Hagberg et al, 1996;Bell et al, 1997;Bona et al, 1999;Stover et al, 2000;Clausen et al, 2011;Mukherjee et al, 2011). Commonly, maximum increases in brain IL-6 occur during the first several hours after injury, with normalization by 24 to 48 hours.…”

“…Acute elevations in IL-6 were also seen in plasma and CSF samples. Future studies will be aimed at clarifying the role of IL-6 in the detrimental effects of secondary hypoxia following TBI and the importance of this cytokine as a target for early therapeutic interventions (Beauchamp et al, 2008;Lu et al, 2009;Clausen et al, 2011).…”

The Stress Response and Its Functional Implications in the Immune Response After Surgery in Patients with Chronic Inflammation Undergoing Arthroplasty

“…The interleukin 1 (IL-1) family includes two forms of IL-1 (IL-1 , IL-1 ), IL-1 receptors (RI, RII) and IL-1 receptor antagonist (IL-1Ra). Interestingly, the recent results of studies suggested that the interleukin-1 (IL-1 ) plays the neuroprotective role inside the damaged brain cells (Clausen et al 2011). During the early stages of shock, the IL-1 is secreted from liver cells after the stimulation of noradrenalin, which may be the example of the relationship between neuro-immune systems (Zhou et al, 2005).…”