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

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-κB phosphorylation and enhanced nuclear factor (NF)-κB/DNA binding activity, leading to expression of cellular inhibitors of apoptosis protein 2 (c-IAP2), a known nuclear factor-κB (NF-κB)-regulated endogenous anti-apoptotic molecule. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, by blocking I-κB phosphorylation, NF-κB 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-κB-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-κB transcriptional cascade.