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Aims  Alcohol abuse has attracted public attention and chronic alcohol exposure can result in irreversible structural changes in the brain. The molecular mechanisms underlying alcohol neurotoxicity are complex, mandating comprehensive mining of spatial protein expression profile.    Methods  In this study, mice models of chronic alcohol intoxication were established after 95% alcohol vapor administration for 30 consecutive days. On Day 30, striatum (the dorsal and ventral striatum) and hippocampus, the two major brain regions responsible for learning and memorizing while being sensitive to alcohol toxicity, were collected. After that, isobaric tags for relative and absolute quantitation -based quantitative proteomic analysis were carried out for further exploration of the novel mechanisms underlying alcohol neurotoxicity.    Results  Proteomic results showed that in the striatum, 29 proteins were significantly up-regulated and 17 proteins were significantly down-regulated. In the hippocampus, 72 proteins were significantly up-regulated, while 2 proteins were significantly down-regulated. Analysis of the overlay proteins revealed that a total of 102 proteins were consistently altered (P &amp;lt; 0.05) in both hippocampus and striatum regions, including multiple keratins such as Krt6a, Krt17 and Krt5. Ingenuity pathway analysis revealed that previously reported diseases/biofunctions such as dermatological diseases and developmental disorders were enriched in those proteins. Interestingly, the glucocorticoid receptor (GR) signaling was among the top enriched pathways in both brain regions, while multiple keratins from the GR signaling such as Krt1 and Krt17 exhibited significantly opposite expression patterns in the two brain nuclei. Moreover, there are several other involved pathways significantly differed between the hippocampus and striatum.    Conclusions  Our data revealed brain regional differences upon alcohol consumption and indicated the critical involvement of keratins from GR signaling in alcohol neurotoxicity. The differences in proteomic results between the striatum and hippocampus suggested a necessity of taking into consideration brain regional differences and intertwined signaling pathways rather than merely focusing on single nuclei or molecule during the study of drug-induced neurotoxicity in the future.

Proteomic Analysis of Brain Regions Reveals Brain Regional Differences and the Involvement of Multiple Keratins in Chronic Alcohol Neurotoxicity