Detrimental effects of antiapoptotic treatments in spinal cord injury

Diana M. Cittelly, Olivera Nesic, Kathia Johnson, Claire Hulsebosch, J. Regino Perez-Polo

    Research output: Contribution to journalArticle

    22 Scopus citations

    Abstract

    Long-term functional impairments due to spinal cord injury (SCI) in the rat result from secondary apoptotic death regulated, in part, by SCI-induced decreases in protein levels of the antiapoptotic protein Bcl-xL. We have shown that exogenous administration of Bcl-xL spares neurons 24 h after SCI. However, long-term effects of chronic application of Bcl-xL have not been characterized. To counteract SCI-induced decreases in Bcl-xL and resulting apoptosis, we used the TAT protein transduction domain fused to the Bcl-xL protein (Tat-Bcl-xL), or its antiapoptotic domain BH4 (Tat-BH4). We used intrathecal delivery of Tat-Bcl-xL, or Tat-BH4, into injured spinal cords for 24 h or 7 days, and apoptosis, neuronal death and locomotor recovery were assessed up to 2 months after injury. Both, Tat-Bcl-xL and Tat-BH4, significantly decreased SCI-induced apoptosis in thoracic segments containing the site of injury (T10) at 24 h or 7 days after SCI. However, the 7-day delivery of Tat-Bcl-xL, or Tat-BH4, also induced a significant impairment of locomotor recovery that lasted beyond the drug delivery time. We found that the 7-day administration of Tat-Bcl-xL, or Tat-BH4, significantly increased non-apoptotic neuronal loss and robustly augmented microglia/macrophage activation. These results indicate that the antiapoptotic treatment targeting Bcl-xL shifts neuronal apoptosis to necrosis, increases the inflammatory response and impairs locomotor recovery. Our results suggest that a combinatorial treatment consisting of antiapoptotic and anti-inflammatory agents may be necessary to achieve tissue preservation and significant improvement in functional recovery after SCI.

    Original languageEnglish (US)
    Pages (from-to)295-307
    Number of pages13
    JournalExperimental Neurology
    Volume210
    Issue number2
    DOIs
    StatePublished - Apr 1 2008

    Keywords

    • Apoptosis
    • Cell death
    • Inflammation
    • Microglia
    • Spinal cord injury
    • Tat-BH4
    • Tat-Bcl-x

    ASJC Scopus subject areas

    • Neurology
    • Developmental Neuroscience

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  • Cite this

    Cittelly, D. M., Nesic, O., Johnson, K., Hulsebosch, C., & Perez-Polo, J. R. (2008). Detrimental effects of antiapoptotic treatments in spinal cord injury. Experimental Neurology, 210(2), 295-307. https://doi.org/10.1016/j.expneurol.2007.03.001