A-769662, a direct AMPK activator, attenuates lipopolysaccharide-induced acute heart and lung inflammation in rats

Abstract

Activation of AMP-activated protein kinase (AMPK) has been indicated to produce an anti-inflammatory effect through the suppression of toll-like receptor (TLR) activity. In the present study, the investigation was designed to identify the effect of A-769662, a direct activator of AMPK on lipopolysaccharide (LPS)-induced acute lung and heart inflammation in rats. To induce inflammation, an intraperitoneal injection of LPS (0.5 mg/kg) was administered to Wistar rats. The inflammatory parameters and AMPK phosphorylation were then measured 9 h later. For the treatment group, A-769662 (10 mg/kg) was administrated intraperitoneally immediately prior to LPS injection. The results demonstrated that A-769662 attenuated the LPS-induced acute inflammation in the heart and lung tissue, as indicated by the significant reduction in myeloperoxidase activity (P<0.001) and inhibition of tissue damage. This was associated with a significant reduction in tumor necrosis factor-α serum levels (P<0.01) and peripheral neutrophils (P<0.001). Furthermore, A-769662 enhanced AMPK phosphorylation and downregulated the expression of MyD88, a TLR adaptor protein, in the heart tissue. Despite the anti-inflammatory effect of A-769662 on LPS-induced inflammation in the lung tissue, the drug produced no effect on the MyD88 expression levels or AMPK phosphorylation in the tissue. The results of the present study suggested that the administration of A-769662 results in an anti-inflammatory effect in the LPS-induced model of inflammation in rats. The anti-inflammatory activity was demonstrated in the heart and lung tissues and the effect on the cardiac tissue was indicated to be a result of AMPK activation, involving the suppression of TLRs.