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 x 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.
Wu
Miaozong
M
Department of Biological Sciences, Marshall University, Huntington, WV 25755-1090, USA.
Desai
Devashish H
DH
Kakarla
Sunil K
SK
Katta
Anjaiah
A
Paturi
Satyanarayana
S
Gutta
Anil K
AK
Rice
Kevin M
KM
Walker
Ernest M
EM
Blough
Eric R
ER
D000082:Acetaminophen / Q000494:pharmacology*; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D013481:Superoxides; D000082:Acetaminophen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases