Inhibition of glycogen synthase kinase-3β attenuates organ injury and dysfunction associated with liver ischemia-reperfusion and thermal injury in the rat.
Glycogen synthase kinase 3 (GSK-3) is a serine-threonine kinase discovered decades ago to have an important role in glycogen metabolism. Today, we know that this kinase is involved in the regulation of many cell functions, including insulin signaling, specification of cell fate during embryonic development, and the control of cell division and apoptosis. Insulin and TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) are inhibitors of GSK-3β that have been shown to possess organ-protective effects in inflammatory-mediated organ injury models. We aimed to evaluate the cytoprotective effect of GSK-3β inhibition on rat models of liver ischemia-reperfusion and thermal injury. In the liver ischemia-reperfusion model, TDZD-8 and insulin were administered at 5 mg/kg (i.v.) and 1.4 IU/kg (i.v.), respectively, 30 min before induction of ischemia and led to the significant reduction of the serum concentration of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, and lactate dehydrogenase. Beneficial effects were found to be independent from blood glucose levels. In the thermal injury model, TDZD-8 was administered at 5 mg/kg (i.v.) 5 min before induction of injury and significantly reduced multiple organ dysfunction markers (liver, neuromuscular, and lung). In the lung, TDZD-8 reduced the histological signs of tissue injury, inflammatory markers (cytokines), and neutrophil chemotaxis/infiltration; reduced GSK-3β, nuclear factor-κB, and Akt activation; reduced caspase-3 and metalloproteinase-9 activation. Our study provides a new insight on the beneficial effects of GSK-3β inhibition on systemic inflammation and further elucidates the mechanism and pathway crosstalks by which TDZD-8 reduces the multiple organ injury elicited by thermal injury.
*Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa; and †REQUIMTE, Laboratório de Química Aplicada, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Joao
J
Rocha
Maria-Eduardo
ME
Figueira
Andreia
A
Barateiro
Adelaide
A
Fernandes
Dora
D
Brites
Rui
R
Pinto
Marisa
M
Freitas
Eduarda
E
Fernandes
Helder
H
Mota-Filipe
Bruno
B
Sepodes
D055371:Acute Lung Injury / Q000503:physiopathology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D019070:Cell Lineage; D016207:Cytokines / Q000097:blood; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006358:Hot Temperature; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013830:Thiadiazoles / Q000737:chemistry
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D016207:Cytokines; D007328:Insulin; D013830:Thiadiazoles; D001219:Aspartate Aminotransferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat