Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Abstract

Neuronal apoptosis contributes to ischemic brain damage and neurodegenerative disorders. Key regulators of neuronal apoptosis are the transcription factor NF-jB and the MAP kinases p38/MAPK and JNK, which share a common upstream activator, the mitogen-activated protein kinase kinase kinase (MAP3K) TGFb-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.

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

“…Combining tissue-specific and inducible deletion systems, we found that both acute and sustained loss of TAK1 resulted in an extensive apoptotic death of DCs. This result contrasted with the observations in neuronal cells in which short-term inhibition of TAK1 protects neurons from apoptosis, whereas prolonged inhibition is not protective (61). Therefore, our findings indicate a direct effect of TAK1 to actively maintain DC survival.…”

TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

“…The activated TAK1 in turn activates the NF-B and MAPK pathways (13,14). Recent investigations also demonstrate that inhibition of TAK1 provides neuroprotection in ischemia and traumatic brain injury (15)(16)(17). Taking into account this background, the present study aimed to evaluate whether TAK1 is activated after SAH.…”

“…Several studies have reported that TAK1 is a critical regulator of apoptosis, which is mainly mediated by the downstream pathways of p38 MAPKK, JNK, ERK-1/2, and NF-B p65 (15,16,37). Evidence shows that activation of MAPK and NF-B pathways contributes to EBI after SAH, and inhibition of these pathways offer neuroprotective effects against SAH (5, 24, 26).…”

Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells

“…Consistent with this study, TAK1 blockage formed more ROS in response to LPS stimulation in neutrophils, indicating that TAK1 is a negative regulator of ROS production (Omori et al 2008). However, recent studies have shown that pharmacological blockade or genetic ablation of TAK1 causes a drastic reduction in ROS production such as superoxide formation in vascular smooth muscle cells and neurons (Song et al 2014;Neubert et al 2011). Herein, the enhancement of superoxide formation by 5Z-7-oxozeaenol might be essential for the apoptotic enhancement after HT treatment.…”