title: 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.
authors.affiliation: Department of Neuroscience, Section for Neurosurgery, Uppsala University, Entrance 85, 2nd floor, Uppsala University Hospital, S-75185 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Clausen
authors.forename: Anders
authors.initials: A
authors.lastname: Hånell
authors.forename: Charlotte
authors.initials: C
authors.lastname: Israelsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Hedin
authors.forename: Ted
authors.initials: T
authors.lastname: Ebendal
authors.forename: Anis K
authors.initials: AK
authors.lastname: Mir
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001522:Behavior, Animal / Q000502:physiology; D001929:Brain Edema / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009483:Neuropsychological Tests; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D018925:Chemokines; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D015850:Interleukin-6