Acetaminophen prevents aging-associated hyperglycemia in aged rats: effect of aging-associated hyperactivation of p38-MAPK and ERK1/2

Background Aging‐related hyperglycemia is associated with increased oxidative stress and diminished muscle glucose transporter‐4 (Glut4) that may be regulated, at least in part, by the mitogen‐activated protein kinases (MAPK). Methods To test the possibility that aging‐related hyperglycemia can be prevented by pharmacological manipulation of MAPK hyperactivation, aged (27‐month old) Fischer 344/NNiaHSD × Brown Norway/BiNia F1 (F344BN) rats were administered acetaminophen (30 mg/kg body weight/day) for 6 months in drinking water. Results Hepatic histopathology, serum aspartate aminotransferase and alanine aminotransferase analyses suggested that chronic acetaminophen did not cause hepatotoxicity. Compared with adult (6‐month) and aged (27‐month) rats, very aged rats (33‐month) had higher levels of blood glucose, phosphorylation of soleus p38‐MAPK and extracellular‐regulated kinase 1/2 (ERK1/2), superoxide and oxidatively modified proteins (p < 0.05), and these changes were associated with decreased soleus Glut4 protein abundance (p < 0.05). Chronic acetaminophen treatment attenuated age‐associated increase in blood glucose by 61.3% (p < 0.05) and increased soleus Glut4 protein by 157.2% (p < 0.05). These changes were accompanied by diminished superoxide levels, decrease in oxidatively modified proteins (−60.8%; p < 0.05) and reduced p38‐MAPK and ERK1/2 hyperactivation (−50.4% and − 35.4%, respectively; p < 0.05). Conclusions These results suggest that acetaminophen may be useful for the treatment of age‐associated hyperglycemia. Copyright © 2009 John Wiley & Sons, Ltd.