Protection from cerebral ischemia by inhibition of TGFβ-activated kinase.
OBJECTIVE
Transforming growth factor-β-activated kinase (TAK1) is a member of the mitogen-activated protein kinase family that plays important roles in apoptosis and inflammatory signaling, both of which are critical components of stroke pathology. TAK1 has recently been identified as a major upstream kinase that phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK), a major mediator of neuronal injury after experimental cerebral ischemia. We studied the functional role of TAK1 and its mechanistic link with AMPK after stroke.


METHODS
Male mice were subjected to transient middle cerebral artery occlusion (MCAO). The TAK1 inhibitor 5Z-7-oxozeaenol was injected either intracerebroventricularly or intraperitoneally at various doses and infarct size and functional outcome after long term survival was assessed. Mice with deletion of the AMPK α2 isoform were utilized to assess the contribution of downstream AMPK signaling to stroke outcomes. Levels of pTAK1, pAMPK, and other TAK1 targets including the pro-apoptotic molecule c-Jun-N-terminal kinase (JNK)/c-Jun and the pro-inflammatory protein cyclooxygenase-2 were also examined.


RESULTS
TAK1 is critical in stroke pathology. Delayed treatment with a TAK1 inhibitor reduced infarct size and improved behavioral outcome even when given several hours after stroke onset. This protective effect may be independent of AMPK activation but was associated with a reduction in JNK and c-Jun signaling.


CONCLUSIONS
Enhanced TAK1 signaling, via activation of JNK, contributes to cell death in ischemic stroke. TAK1 inhibition is a novel therapeutic approach for stroke as it is neuroprotective with systemic administration, has a delayed therapeutic window, and demonstrates sustained neuroprotective effects.
University of Connecticut School of Medicine, Farmington, CT, USA.
Benjamin J
BJ
White
Sami
S
Tarabishy
Venugopal Reddy
VR
Venna
Bharti
B
Manwani
Sharon
S
Benashski
Louise D
LD
McCullough
Jun
J
Li
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000502:physiology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
D000091162:AMP-Activated Protein Kinase Kinases; D020930:MAP Kinase Kinase Kinases; D011494:Protein Kinases; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols