Detrimental effects of antiapoptotic treatments in spinal cord injury

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-x(L). We have shown that exogenous administration of Bcl-x(L) spares neurons 24 It after SCI. However, long-term effects of chronic application of Bcl-x(L) have not been characterized. To counteract SCI-induced decreases in BcI-XL and resulting apoptosis, we used the TAT protein transduction domain fused to the Bcl-x(L) protein (Tat-Bcl-x(L)), or its antiapoptotic domain BH4 (Tat-BH4). We used intrathecal delivery of Tat-Bcl-X-L, 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-x(L) 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-x(L), or Tat-BH4, significantly increased non-apoptotic neuronal loss and robustly augmented microglia/macrophage activation. These results indicate that the antiapoplotic treatment targeting Bcl-x(L) 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. (c) 2007 Elsevier Inc. All rights reserved.