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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.
J Neurochem. 2010 Jul; 114(1):237-46.JN

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.

Authors+Show Affiliations

Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung 824, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20403072

Citation

Lu, Kang, et al. "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." Journal of Neurochemistry, vol. 114, no. 1, 2010, pp. 237-46.
Lu K, Liang CL, Liliang PC, et al. 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. J Neurochem. 2010;114(1):237-46.
Lu, K., Liang, C. L., Liliang, P. C., Yang, C. H., Cho, C. L., Weng, H. C., Tsai, Y. D., Wang, K. W., & Chen, H. J. (2010). 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. Journal of Neurochemistry, 114(1), 237-46. https://doi.org/10.1111/j.1471-4159.2010.06747.x
Lu K, et al. 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. J Neurochem. 2010;114(1):237-46. PubMed PMID: 20403072.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lu,Kang, AU - Liang,Cheng-Loong, AU - Liliang,Po-Chou, AU - Yang,Chih-Hui, AU - Cho,Chung-Lung, AU - Weng,Hui-Ching, AU - Tsai,Yu-Duan, AU - Wang,Kuo-Wei, AU - Chen,Han-Jung, Y1 - 2010/04/09/ PY - 2010/4/21/entrez PY - 2010/4/21/pubmed PY - 2010/7/20/medline SP - 237 EP - 46 JF - Journal of neurochemistry JO - J Neurochem VL - 114 IS - 1 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/20403072/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_ L2 - https://doi.org/10.1111/j.1471-4159.2010.06747.x DB - PRIME DP - Unbound Medicine ER -