Blockade of the translocation and activation of mitogen‐activated protein kinase kinase 4 (MKK4) signaling attenuates neuronal damage during later ischemia–reperfusion

• Published in: Journal of neurochemistry Vol. 98; no. 1; pp. 170 - 179
• Main Authors: Zhang, Qing‐Xiu, Pei, Dong‐Sheng, Guan, Qiu‐Hua, Sun, Ya‐Feng, Liu, Xiao‐Mei, Zhang, Guang‐Yi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2006; Blackwell
• Subjects: Analysis of Variance; Animals; Antioxidants - pharmacology; Biological and medical sciences; Blotting, Western - methods; brain ischemia–reperfusion; Cell physiology; Cystine - analogs & derivatives; Cystine - pharmacology; c‐Jun NH2‐terminal kinase interacting protein 3; Disease Models, Animal; Drug Interactions; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzymes; Fundamental and applied biological sciences. Psychology; Immunohistochemistry - methods; Immunoprecipitation - methods; Male; MAP Kinase Kinase 4 - metabolism; Medical sciences; mitogen‐activated protein kinase kinase 4; Molecular and cellular biology; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; neuroprotection; N‐acetylcysteine; Protein Transport - drug effects; Protein Transport - physiology; Proteins; Rats; Rats, Sprague-Dawley; Reperfusion Injury - pathology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; Time Factors; translocation; Vascular diseases and vascular malformations of the nervous system; Rat; Central nervous system; Cardiovascular disease; brain ischemia-reperfusion; Activation; terminal kinase; mitogen-activated protein kinase kinase 4; N-acetylcysteine; Vascular disease; Signal transduction; Reperfusion; c-Jun NH2-terminal kinase interacting protein 3; Localization; Cerebrovascular disease; Nervous system diseases; translocation; Enzyme; Stress-activated kinase; Transferases; Interaction; Ischemia reperfusion; Rodentia; Cytokine; Mitogen-activated protein kinase; Antioxidant; Protein; Stress; Cerebral disorder; Vertebrata; Mammalia; Kinase; neuroprotection; Central nervous system disease; c-Jun NH; Brain ischemia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03848.x

Mitogen‐activated protein kinase kinase 4 (MKK4), as an upstream activator of c‐Jun NH2‐terminal kinase (JNK), plays a critical role in response to cellular stresses and pro‐inflammatory cytokines. In this study, we investigated the subcellular localization and activation of MKK4 in response to global cerebral ischemia. Our results indicated that MKK4 had two activation peaks in both the cytosol and the nucleus, and translocated from the cytosol to the nucleus at 30 min and 6 h of reperfusion. We also detected the interaction of JNK‐interacting protein 3 (JIP3) and MKK4, which reached a maximum at 6 h of reperfusion. To elucidate the mechanism of translocation and activation, we administered N‐acetylcysteine, an antioxidant reagent, and a glutamate receptor 6 C‐terminus‐containing peptide (Tat‐GluR6‐9c) to rats. The data showed that N‐acetylcysteine limited the translocation and activation at 30 min of reperfusion; however, the peptide perturbed the subcellular localization and activation at 6 h of reperfusion, and subsequently provided a protective role against delayed neuronal cell death. Taken together, these results demonstrate that the translocation and activation of MKK4 during early reperfusion are closely associated with reactive oxygen species, whereas, at late reperfusion, MKK4 activation may be involved in brain ischemic injury.