Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone.
Binge alcohol drinking has emerged as a typical phenomenon in young people. This pattern of drinking, repeatedly leading to extremely high blood and brain alcohol levels and intoxication is associated with severe risks of neurodegeneration and cognitive damage. Mechanisms involved in excitotoxicity and neuroinflammation are pivotal elements in alcohol-induced neurotoxicity. Evidence has demonstrated that PPARγ receptor activation shows anti-inflammatory and neuroprotective properties. Here we examine whether treatment with the PPARγ agonist pioglitazone is beneficial in counteracting neurodegeneration, neuroinflammation and cognitive damage produced by binge alcohol intoxication. Adult Wistar rats were subjected to a 4-day binge intoxication procedure, which is commonly used to model excessive alcohol consumption in humans. Across the 4-day period, pioglitazone (0, 30, 60mg/kg) was administered orally twice daily at 12-h intervals. Degenerative cells were detected by fluoro-jade B (FJ-B) immunostaining in brain regions where expression of pro-inflammatory cytokines was also determined. The effects of pioglitazone on cognitive function were assessed in an operant reversal learning task and the Morris water maze task. Binge alcohol exposure produced selective neuronal degeneration in the hippocampal dentate gyrus and the adjacent entorhinal cortex. Pioglitazone reduced FJ-B positive cells in both regions and prevented alcohol-induced expression of pro-inflammatory cytokines. Pioglitazone also rescued alcohol-impaired reversal learning in the operant task and spatial learning deficits in the Morris water maze. These findings demonstrate that activation of PPARγ protects against neuronal and cognitive degeneration elicited by binge alcohol exposure. The protective effect of PPARγ agonist appears to be linked to inhibition of pro-inflammatory cytokines.
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy.
Andrea
A
Cippitelli
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy.
Esi
E
Domi
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy.
Massimo
M
Ubaldi
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
James C
JC
Douglas
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy.
Hong Wu
HW
Li
Omeros Corporation, Seattle, WA 98101, USA.
Gregory
G
Demopulos
Omeros Corporation, Seattle, WA 98101, USA.
George
G
Gaitanaris
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
Marisa
M
Roberto
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Paul D
PD
Drew
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cynthia J M
CJM
Kane
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino (MC) 62032, Italy. Electronic address: roberto.ciccocioppo@unicam.it.
Roberto
R
Ciccocioppo
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000067401:Blood Alcohol Content; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D017208:Rats, Wistar; D065853:Spatial Learning / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D045162:Thiazolidinediones / Q000008:administration & dosage*
D000067401:Blood Alcohol Content; D016207:Cytokines; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000431:Ethanol; D000077205:Pioglitazone
Alcohol; Cognitive flexibility; Cytokines; Neurodegeneration; PPARγ; Pioglitazone