Thrombopoietin receptor agonist eltrombopag prevents insulin resistance-mediated synaptic pathology via HIF1α/GSK3β/Sirt1 pathway

Background Minimal hepatic encephalopathy (MHE) is characterized by impaired cognitive function and memory loss, which are often the result of synaptic pathology. Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. Methods The effect of thrombopoietin receptor agonist eltrombopag (ELT) on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the phosphorylation of GSK3β (pGSK3 β), upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons. Conclusions These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.