title: 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.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Venugopal Reddy
authors.initials: VR
authors.lastname: Venna
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Benashski
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Chauhan
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA MC-1840, Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA The Stroke Center at Hartford Hospital, Hartford, Connecticut 06102, USA lmccullough@uchc.edu.
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020244:Infarction, Middle Cerebral Artery; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055372:AMP-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020930:MAP Kinase Kinase Kinases; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7; C534978:Prkaa2 protein, mouse; C000605507:Gsk3b protein, mouse