Inhibition of extracellular signal-regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor-kappaB-regulated anti-apoptotic mechanisms.

Abstract

Previously we demonstrated benefits of inhibiting the extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathway in spinal cord ischemia/reperfusion (I/R) injury. To further identify the underlying mechanisms, we investigated the impact of ERK inhibition on apoptosis and cellular protective mechanisms against cell death. Spinal cord I/R injury induced ERK1/2 phosphorylation, followed by neuronal loss through caspase 3-mediated apoptosis. Pre-treatment with U0126, a specific inhibitor of MAPK/ERK kinases 1/2 (MEK1/2), inhibited ERK1/2 phosphorylation, and significantly attenuated apoptosis and increased neuronal survival. MEK/ERK inhibition also induced I-kappaB phosphorylation and enhanced nuclear factor (NF)-kappaB/DNA binding activity, leading to expression of cellular inhibitors of apoptosis protein 2 (c-IAP2), a known nuclear factor-kappaB (NF-kappaB)-regulated endogenous anti-apoptotic molecule. Pyrrolidine dithiocarbamate, an NF-kappaB inhibitor, by blocking I-kappaB phosphorylation, NF-kappaB activation, and c-IAP2 synthesis, abolished the protective effects of U0126. The MEK/ERK pathway appears to mediate cellular death following I/R injury. The U0126 neuroprotection appears related to NF-kappaB-regulated transcriptional control of c-IAP2. MEK/ERK inhibition at the initial stage of I/R injury may cause changes in c-IAP2 gene expression or c-IAP2/caspase 3 interactions, resulting in long lasting therapeutic effects. Future research should focus on the possible cross-talk between the MEK/ERK pathway and the NF-kappaB transcriptional cascade.

DOI: 10.1111/j.1471-4159.2010.06747.x
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@article{Lu2010InhibitionOE, title={Inhibition of extracellular signal-regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor-kappaB-regulated anti-apoptotic mechanisms.}, author={Kang Shou Lu and Cheng-loong Liang and Po-Chou Liliang and Chih-Hui Yang and Chung-Lung Cho and Hui-Ching Weng and Yu-Duan Tsai and Kuo-Wei Wang and Han-Jung Chen}, journal={Journal of neurochemistry}, year={2010}, volume={114 1}, pages={237-46} }