Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model.
BACKGROUND
Previous studies linked cerebellar hypoplasia, neuronal loss, and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor signaling mechanisms in experimental models of fetal alcohol syndrome (FAS).


METHODS
To determine the extent to which similar abnormalities occur in mature brains, gene expression, ligand binding, and histopathological studies were performed with temporal lobe, hypothalamus, and cerebellar cortex from adult male Long Evans rats that were pair-fed for 6 weeks with liquid diets containing 0% or 37% ethanol by caloric content.


RESULTS
Real time quantitative RT-PCR analysis demonstrated that the chronic ethanol-fed rats had significantly reduced insulin-like growth factors (IGF)-II receptor expression in all 3 regions and reduced insulin receptor expression in the temporal lobe. However, equilibrium binding assays revealed ethanol-associated impairments in insulin and IGF-I receptor binding in all 3 regions and reduced IGF-II receptor binding in the cerebellum. These abnormalities were associated with decreased expression of Hu (neuronal loss) in the temporal lobe and cerebellum, and choline acetyltransferase (ChAT) in the hypothalamus and cerebellum, and increased expression of NADPH oxidase 3 in all 3 regions examined. Ethanol-associated neuronal loss with increased indices of lipid peroxidation and DNA damage were demonstrated by histopathological, immunohistochemical, and enzyme linked immunosorbant assay studies.


CONCLUSIONS
These results suggest that ethanol-induced neurodegeneration in adults is mediated by insulin/IGF resistance, persistent oxidative stress, and impaired acetylcholine biosynthesis, similar to the findings in FAS. The reductions in ChAT gene expression most likely contribute to the cognitive and motor deficits that occur with chronic alcohol abuse.
Cohen
Ariel C
AC
Department of Medicine, Rhode Island Hospital, Warren Alpert School of Medicine at Brown University, Providence, Rhode Island, USA.
Tong
Ming
M
Wands
Jack R
JR
de la Monte
Suzanne M
SM
D000109:Acetylcholine / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000235:genetics / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D013002:Somatomedins / Q000235:genetics / Q000502:physiology*
D002492:Central Nervous System Depressants; D007328:Insulin; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D013002:Somatomedins; D000431:Ethanol; D011972:Receptor, Insulin; D000109:Acetylcholine