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PMID:17064355

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Citation

Wang, R, Zhang, QG, Han, D, Xu, J, Lü, Q and Zhang, GY (2006) Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. J. Neurochem. 99:1543-54

Abstract

Numerous studies have demonstrated the neuroprotective effects of estrogen in experimental cerebral ischemia. To investigate molecular mechanisms of estrogen neuroprotection in global ischemia, immunoblotting, immunohistochemistry and Nissel-staining analysis were used. Our results showed that chronic pretreatment with beta-estradiol 3-benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed-lineage kinase 3 (MLK3), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase 1/2 (JNK1/2) in the hippocampal CA1 subfield during reperfusion after 15 min of global ischemia. In addition, E2 reduced downstream JNK nuclear and non-nuclear components, c-Jun and Bcl-2 phosphorylation and Fas ligand protein expression induced by ischemia/reperfusion. Administration of phosphoinositide 3-kinase (PI3K) inhibitor LY 294,002 prevented both activation of Akt1 and inhibition of MLK3, MKK4/7 and JNK1/2. The interaction between ERalpha and the p85 subunit of PI3K was also examined. E2 and antiestrogen ICI 182,780 promoted and prevented this interaction, respectively. Furthermore, ICI 182,780 blocked both the activation of Akt1 and the inhibition of MLK3, MKK4/7 and JNK1/2. Photomicrographs of cresyl violet-stained brain sections showed that E2 reduced CA1 neuron loss after 5 days of reperfusion, which was abolished by ICI 182,780 and LY 294,002. Our data indicate that in response to estrogen, ERalpha interacts with PI3K to activate Akt1, which may inhibit the MLK3-MKK4/7-JNK1/2 pathway to protect hippocampal CA1 neurons against global cerebral ischemia in male rats.

Links

PubMed Online version:10.1111/j.1471-4159.2006.04201.x

Keywords

Animals; Blotting, Western/methods; Chromones/pharmacology; Disease Models, Animal; Drug Interactions; Enzyme Activation/drug effects; Enzyme Inhibitors/pharmacology; Estradiol/analogs & derivatives; Estradiol/pharmacology; Estrogen Antagonists/pharmacology; Estrogens/administration & dosage; Hippocampus/drug effects; Hippocampus/enzymology; Immunohistochemistry/methods; Immunoprecipitation/methods; Ischemic Attack, Transient/pathology; Ischemic Attack, Transient/prevention & control; MAP Kinase Kinase 7/metabolism; MAP Kinase Kinase Kinases/metabolism; Male; Mitogen-Activated Protein Kinase 8/metabolism; Morpholines/pharmacology; Neuroprotective Agents/administration & dosage; Proto-Oncogene Proteins c-akt/physiology; Rats; Rats, Sprague-Dawley; Serine/metabolism; Signal Transduction/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:F1LP57

involved_in

GO:0007254: JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1LP57

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1LP57

enables

GO:0008545: JUN kinase kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MK09

enables

GO:0004705: JUN kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:Q4KSH6

involved_in

GO:0007254: JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q4KSH6

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q4KSH6

enables

GO:0008545: JUN kinase kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:MP2K7

involved_in

GO:0007254: JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MP2K7

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MP2K7

enables

GO:0008545: JUN kinase kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:M3K11

involved_in

GO:0007254: JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:M3K11

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MK08

enables

GO:0004705: JUN kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:AKT1

involved_in

GO:0046329: negative regulation of JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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