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

• Published in: Journal of neurochemistry Vol. 114; no. 1; pp. 237 - 246
• Main Authors: Lu, Kang, Liang, Cheng‐Loong, Liliang, Po‐Chou, Yang, Chih‐Hui, Cho, Chung‐Lung, Weng, Hui‐Ching, Tsai, Yu‐Duan, Wang, Kuo‐Wei, Chen, Han‐Jung
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2010; Wiley-Blackwell
• Subjects: apoptosis; Biological and medical sciences; Cardiology. Vascular system; cellular inhibitor of apoptosis protein 2; Cerebrospinal fluid. Meninges. Spinal cord; extracellular signal‐regulated kinases 1/2; ischemia‐reperfusion injury; Medical sciences; Nervous system (semeiology, syndromes); Neurology; nuclear factor‐κB; spinal cord; Phosphorylation; cellular inhibitor of apoptosis protein 2; Extracellular signal-regulated protein kinase; Rat; Central nervous system; Cardiovascular disease; Vascular disease; Signal transduction; Reperfusion; Spinal cord trauma; Transcription factor NFκB; spinal cord; Nervous system diseases; Enzyme; Transferases; Rodentia; Caspase; Mitogen-activated protein kinase; Survival; Protein; extracellular signal-regulated kinases 1/2; Spinal cord ischemia; ischemia-reperfusion injury; nuclear factor-κB; Peptidases; Vertebrata; Mammalia; Treatment; Cell death; Central nervous system disease; Hydrolases; Spinal cord disease; Apoptosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06747.x

J. Neurochem. (2010) 114, 237–246. 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.