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

ABSTRACT: Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3? (GSK-3?) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3? is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3? (pGSK-3?) activity. GSK-3? inhibition has beneficial effects on memory in other disease models. GSK-3? regulates both the 5'AMP-activated kinase (AMPK) and transforming growth factor-?-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3? inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-?2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3? inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3? inhibition were seen in AMPK deficient mice. However, GSK-3? inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3?. Targeting GSK-3? could be a novel therapeutic strategy for post-stroke cognitive deficits.

SUBMITTER: Venna VR 

PROVIDER: S-EPMC4478333 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature