Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation.
BACKGROUND
Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.


METHODS
Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed.


RESULTS
Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning.


CONCLUSIONS
Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration.
Cippitelli
Andrea
A
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-1108, USA.
Damadzic
Ruslan
R
Frankola
Kate
K
Goldstein
Andrea
A
Thorsell
Annika
A
Singley
Erick
E
Eskay
Robert L
RL
Heilig
Markus
M
D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D009930:Organic Chemicals / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012193:Reversal Learning / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005452:Fluoresceins; C118218:LY 379268; D009930:Organic Chemicals; D018094:Receptors, Metabotropic Glutamate; D016212:Transforming Growth Factor beta; C435731:fluoro jade; C108822:metabotropic glutamate receptor 2; D000431:Ethanol