Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury

J. R. Perez-Polo, H. C. Rea, K. M. Johnson, M. A. Parsley, G. C. Unabia, G. Y. Xu, D. Prough, D. S. Dewitt, A. A. Paulucci-Holthauzen, K. Werrbach-Perez, C. E. Hulsebosch

    Research output: Contribution to journalArticle

    10 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)27-38
    Number of pages12
    JournalJournal of Neuroscience Research
    Volume94
    Issue number1
    DOIs
    StatePublished - Jan 2016

    Keywords

    • Cytokines
    • Etanercept
    • Inflammation
    • Kineret
    • Mild traumatic brain injury
    • Righting reflex response

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience

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  • Cite this

    Perez-Polo, J. R., Rea, H. C., Johnson, K. M., Parsley, M. A., Unabia, G. C., Xu, G. Y., Prough, D., Dewitt, D. S., Paulucci-Holthauzen, A. A., Werrbach-Perez, K., & Hulsebosch, C. E. (2016). Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury. Journal of Neuroscience Research, 94(1), 27-38. https://doi.org/10.1002/jnr.23617