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

J Biol Chem. 2015 Aug 7;290(32):19900-9. doi: 10.1074/jbc.M115.636795. Epub 2015 Jun 22.

Abstract

Accumulating evidence suggests that activation of mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking proapoptotic and proinflammatory cellular signaling. Here we evaluate the role of TGFβ-activated kinase 1 (TAK1), a critical regulator of the NF-κB and MAPK pathways, in early brain injury following SAH. Although the expression level of TAK1 did not present significant alternation in the basal temporal lobe after SAH, the expression of phosphorylated TAK1 (Thr-187, p-TAK1) showed a substantial increase 24 h post-SAH. Intracerebroventricular injection of a selective TAK1 inhibitor (10 min post-SAH), 5Z-7-oxozeaenol (OZ), significantly reduced the levels of TAK1 and p-TAK1 at 24 h post-SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that OZ inhibited SAH-induced phosphorylation of p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Furthermore, OZ administration diminished the SAH-induced apoptosis and EBI. As a result, neurological deficits caused by SAH were reversed. Our findings suggest that TAK1 inhibition confers marked neuroprotection against EBI following SAH. Therefore, TAK1 might be a promising new molecular target for the treatment of SAH.

Keywords: 5Z-7-oxozeaenol; NF-κB (NF-KB); TAK1; apoptosis; brain; mitogen-activated protein kinase (MAPK); neuroprotection; subarachnoid hemorrhage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis / drug effects
  • Cerebrovascular Trauma / genetics
  • Cerebrovascular Trauma / metabolism
  • Cerebrovascular Trauma / pathology
  • Cerebrovascular Trauma / prevention & control*
  • Disease Models, Animal
  • Gene Expression Regulation
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Injections, Intraventricular
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • NF-KappaB Inhibitor alpha
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Stereotaxic Techniques
  • Subarachnoid Hemorrhage / drug therapy*
  • Subarachnoid Hemorrhage / genetics
  • Subarachnoid Hemorrhage / metabolism
  • Subarachnoid Hemorrhage / pathology
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Zearalenone / analogs & derivatives*
  • Zearalenone / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 7-oxozeanol
  • Anti-Inflammatory Agents, Non-Steroidal
  • I-kappa B Proteins
  • Neuroprotective Agents
  • Nfkbia protein, rat
  • Protein Kinase Inhibitors
  • Rela protein, rat
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Zearalenone
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 4