Abstract T P223: Role of GSK-3ß and Transforming Growth Factor-ß-activated Kinase in Ischemic Neuroprotection
Objectives: Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular signaling pathways involved in both cell survival and cell death. GSK-3β activation promotes inflammation and apoptosis which are detrimental in stroke. GSK-3β inhibition enhances cognition in many animal models; however the role of GSK-3β in stroke and the mechanism by which activation is detrimental remains to be elucidated. It was recently found that GSK inhibits the function of the master energy sensor AMP-activated kinase (AMPK). We have also recently shown that TAK1, an upstream kinase that activates AMPK, is also involved in regulating ischemic injury. Inhibition of TAK leads to dramatic protection, even when treatment is delayed, and this effect is independent of AMPK signaling. We hypothesize that TAK1 regulates GSK-3β. The aim of this study was to determine whether GSK-3β inhibition confers ischemic neuroprotection via TAK1 signaling.
Methods: C57BL/6 male mice were randomly assigned to treatment groups and subjected to right middle cerebral artery occlusion The GSK-3β inhibitor VIII (4 mg/kg); and/or the TAK1 inhibitor, 5Z-7-oxozeaenol (5 mg/kg) were administered i.p. either immediately or 2h after stroke. Control mice were treated vehicle. Western blotting was performed for on brains obtained 6h after stroke. Data were presented as mean ± SEM.
Results: GSK-3β inhibition was protective when delivered immediately after stroke (Total hemisphere: 44.2±3.2 vs 36.2±3.1; n=8, p<0.05) or if treatment was delayed for 2h (Total: 46.2±3.0 vs 32.2±4.3; n=7, p<0.05). Beneficial effects of GSK-3β inhibition in NDS (p<0.05) was also seen. TAK inhibitor reduced pTAK1 in parallel to GSK-3β inhibition. But, GSK-3β inhibitor treated brains has no effect on pTAK1 levels p>0.05. Finally, compared to GSK-3β inhibition alone, simultaneous GSK-3β+TAK1 inhibition did not offer any additional neuroprotection in stroke (Total: 33.6±2.8 vs 30.7±3.9; p>0.05).
Conclusion: Our findings indicate that GSK-3β inhibition is protective even with delayed administration after stroke. In this study, we identified TAK1 as a potential upstream regulator of GSK-3β. Directly targeting TAK1 and GSK-3β inhibition may develop into a novel and powerful neuroprotective strategy.
Author Disclosures: V.R. Venna: None. S.E. Benashski: None. L.D. McCullough: None.
This research has received full or partial funding support from the American Heart Association, Founders - Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont.
- © 2014 by American Heart Association, Inc.