zearalenone and Brain-Ischemia

TGFβ-activated kinase 1 (TAK1), a MAP3 kinase, is involved in at least five signaling cascades that modulate ischemic brain damage. Inhibition of TAK1 may therefore be an efficient way to interfere with multiple mechanisms in ischemic stroke. Indeed, a recent publication in Experimental Neurology confirmed that TAK1 inhibition by 5Z-7-oxozeaenol is neuroprotective. The beneficial effect of 5Z-7-oxozeaenol was associated with a reduced activation of Jun kinase that leads to inflammation and apoptosis. Recently, other TAK1 inhibitors were developed suggesting that TAK1 may prove as an efficient therapeutic target for neurodegenerative diseases if safety issues are not limiting.

Topics: Animals; Brain Ischemia; Male; MAP Kinase Kinase Kinases; Zearalenone

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.. 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.. 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.. 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.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Protein Kinases; Random Allocation; Signal Transduction; Zearalenone