title: Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury.
abstract: In rodent models of traumatic brain injury (TBI), both Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/β and TNFα levels. Here we report that blockade of IL-1α/β and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1β binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret.
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: J R
authors.initials: JR
authors.lastname: Perez-Polo
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: H C
authors.initials: HC
authors.lastname: Rea
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: K M
authors.initials: KM
authors.lastname: Johnson
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: M A
authors.initials: MA
authors.lastname: Parsley
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: G C
authors.initials: GC
authors.lastname: Unabia
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Xu
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: D
authors.initials: D
authors.lastname: Prough
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: D S
authors.initials: DS
authors.lastname: DeWitt
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: A A
authors.initials: AA
authors.lastname: Paulucci-Holthauzen
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: K
authors.initials: K
authors.lastname: Werrbach-Perez
authors.affiliation: University of Texas Medical Branch, Galveston, Texas.
authors.forename: C E
authors.initials: CE
authors.lastname: Hulsebosch
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000068800:Etanercept / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D018121:Receptors, Cytokine; D010751:Phosphopyruvate Hydratase; D000068800:Etanercept
keywords: Kineret; cytokines; etanercept; inflammation; mild traumatic brain injury; righting reflex response