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.
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.
Lu
Kang
K
Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung 824, Taiwan.
Liang
Cheng-Loong
CL
Liliang
Po-Chou
PC
Yang
Chih-Hui
CH
Cho
Chung-Lung
CL
Weng
Hui-Ching
HC
Tsai
Yu-Duan
YD
Wang
Kuo-Wei
KW
Chen
Han-Jung
HJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002070:Butadienes; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009570:Nitriles; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3