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.