Protection from cerebral ischemia by inhibition of TGFβ-activated kinase

Abstract

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.

Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

“…We speculate that this TAK1/pGSK-3b interaction restrains deleterious pro-apoptotic signaling during stroke, and is consistent with our results showing that the inhibition TAK1 or GSK3b is neuroprotective. The downstream effects and targets of this TAK1/pGSK-3b interaction are not yet known but likely include JNK/c-Jun signaling as seen in prior studies (White et al 2012). While these findings are encouraging, this work has several limitations.…”

“…GSK has been recently demonstrated to increase the stabilization of TAK1's interaction with its binding partner, TAB (TAK1-binding protein) (Bang et al 2013), but no studies have investigated the direct interaction of GSK-3b and TAK1. Acute inhibition of TAK1 is neuroprotective and stroke-induced memory deficits can be ameliorated by TAK1 inhibition (White et al 2012). Activation of TAK1 enhances caspase activity via downstream JNK signaling (Sanna et al 2002).…”

“…Dose volumes were 100 mL/10 g body weight. Inhibitors and their doses were carefully selected from the literature and from our previous study using TAK1 inhibitor (Koh et al 2008;White et al 2012). All control animals were treated with equal volume of vehicle.…”

“…Cerebral ischemia was induced by 90 min of reversible middle cerebral artery occlusion (MCAO) under Isoflurane anesthesia, as described previously (Venna et al 2012b;White et al 2012). In brief, a midline ventral neck incision was made, and unilateral right MCAO was performed by advancing a 6.0 silicone-coated nylon monofilament into the internal carotid artery 6 mm from the internal carotid-pterygopalatine artery bifurcation via an external carotid artery stump.…”

“…TAK is also an upstream kinase of 5 ′ adenosine monophosphate-activated protein kinase (AMPK), a key energy sensing kinase involved in stroke. We have recently found that inhibition of TAK1 is neuroprotective after focal ischemia (White et al 2012). Our previous work demonstrated that neuroprotective effects of TAK1 inhibition are independent of its activation of AMPK (White et al 2012).…”