Inhibition of glycogen synthase kinase-3β 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-3β (GSK-3β) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3β is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition has beneficial effects on memory in other disease models. GSK-3β regulates both the 5′AMP-activated kinase (AMPK) and transforming growth factor-β-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3β inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-α2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3β inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3β inhibition were seen in AMPK deficient mice. However, GSK-3β inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3β. Targeting GSK-3β could be a novel therapeutic strategy for post-stroke cognitive deficits.

Impaired learning and memory in rats induced by a high‐fat diet: Involvement with the imbalance of nesfatin‐1 abundance and copine 6 expression

“…Increasing evidence from animal studies and human research has indicated a role for the Wnt/β‐catenin pathway in the regulation of cognition in the adult brain . The main biological effect of the canonical Wnt/β‐catenin pathway is to regulate the degradation of β‐catenin through GSK‐3β, and regulating the activity and level of GSK‐3β and β‐catenin has been considered as a potential target for improving cognition . In the present study, protein expression of p‐GSK‐3β increased and p‐β‐catenin expression decreased in the hippocampus and PFC of NAFLD rats, which was consistent with the reported findings from studies conducted in chronic intermittent hypoxia mice .…”

Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase‐3β‐mediated activation of autophagy

“…A better understanding of the role of autophagy in cerebral I/R injury is needed. In this respect, glycogen synthase kinase-3 (GSK-3) not only plays an important role in the neuronal cell death caused by cerebral I/R injury but also regulates autophagic cell death (Venna, Benashski, Chauhan, & McCullough, 2015). Thus inhibition of GSK-3β may provide neuroprotective effects against cerebral I/R-induced injury (Chuang, Wang, & Chiu, 2011).…”

Delayed treatment of 6‐Bromoindirubin‐3′‐oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice

“…Although a few papers reported that inhibition of GSK3β enhanced cognitive recovery after stroke mediated by transforming growth factor‐β‐activated kinase (TAK1), and a COX‐2 inhibitor showed neuroprotection by phosphorylation of Akt and GSK3β (Venna et al, 2015; Ye et al, 2012), our study appears the first demonstration of regenerative benefits of delayed inhibition of the GSK3β signaling after ischemic stroke. Most previous neuroprotective investigations administered neuroprotectants before or acutely after the onset of stroke, which may at least partly explain the difficulties of translating these treatments to clinical settings.…”