TY - JOUR
T1 - Detrimental effects of antiapoptotic treatments in spinal cord injury
AU - Cittelly, Diana M.
AU - Nesic, Olivera
AU - Johnson, Kathia
AU - Hulsebosch, Claire
AU - Perez-Polo, J. Regino
N1 - Funding Information:
We would like to thank Dr. Karin High, Dr. Ying Yu, and Linda Muehlberger for their assistance in the neuronal counting and histological preparations. We thank Dr. Ricardo Pastori at the University of Miami for the p-HAT-Tat-Bcl-x L plasmid. This work was supported by grants from NINDS NS39161, Mission Connect of TIRR-Houston, and Sealy Smith Endowment Fund.
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cell death
KW - Inflammation
KW - Microglia
KW - Spinal cord injury
KW - Tat-BH4
KW - Tat-Bcl-x
UR - http://www.scopus.com/inward/record.url?scp=41149152155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41149152155&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2007.03.001
DO - 10.1016/j.expneurol.2007.03.001
M3 - Article
C2 - 18302959
AN - SCOPUS:41149152155
SN - 0014-4886
VL - 210
SP - 295
EP - 307
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -