RGD Reference Report - Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia. - Rat Genome Database

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Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia.

Authors: Neubert, M  Ridder, D A  Bargiotas, P  Akira, S  Schwaninger, M 
Citation: Neubert M, etal., Cell Death Differ. 2011 Sep;18(9):1521-30. doi: 10.1038/cdd.2011.29. Epub 2011 Apr 8.
RGD ID: 155882442
Pubmed: PMID:21475303   (View Abstract at PubMed)
PMCID: PMC3178433   (View Article at PubMed Central)
DOI: DOI:10.1038/cdd.2011.29   (Journal Full-text)

Neuronal apoptosis contributes to ischemic brain damage and neurodegenerative disorders. Key regulators of neuronal apoptosis are the transcription factor NF-κB and the MAP kinases p38/MAPK and JNK, which share a common upstream activator, the mitogen-activated protein kinase kinase kinase (MAP3K) TGFβ-activated kinase 1 (TAK1). Here we investigate the function of TAK1 in ischemia-induced neuronal apoptosis. In primary cortical neurons, TAK1 was activated by oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia. We found that short-term inhibition of TAK1 protected against OGD in vitro and reduced the infarct volume after middle cerebral artery occlusion in vivo. Prolonged inhibition or deletion of the TAK1 gene in neurons was, however, not protective. Short-term, but not prolonged inhibition of TAK1 interfered with the activation of p38/MAPK and JNK by OGD, the induction of the pro-oxidative genes Cox-2, Nox-2, and p40(phox), and the formation of superoxide. We found that prolonged TAK1 inhibition upregulated another MAP3K, apoptosis signal-regulating kinase-1, which is able to compensate for TAK1 inhibition. Our study demonstrates that TAK1 is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
brain ischemia treatmentISOMap3k7 (Mus musculus)155882442; 155882442 RGD 
brain ischemia treatmentIMP 155882442 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k7  (mitogen activated protein kinase kinase kinase 7)

Genes (Mus musculus)
Map3k7  (mitogen-activated protein kinase kinase kinase 7)

Genes (Homo sapiens)
MAP3K7  (mitogen-activated protein kinase kinase kinase 7)


Additional Information