Dataset Information

Blood vessel remodeling in the cerebral cortex induced by binge alcohol intake in mice.

ABSTRACT: Ethanol is toxic to the brain and causes various neurological disorders. Although ethanol can directly exert toxicity on neurons, it also acts on other cell types in the central nervous system. Blood vessel endothelial cells interact with, and are affected by blood ethanol. However, the effects of ethanol on the vascular structures of the brain have not been well documented. In this study, we examined the effects of binge levels of ethanol on brain vasculature. Immunostaining analysis indicated structural alterations of blood vessels in the cerebral cortex, which became more tortuous than those in the control mice after ethanol administration. The interaction between the blood vessels and astrocytes decreased, especially in the upper layers of the cerebral cortex. Messenger RNA expression analysis revealed a unique downregulation of Vegfa mRNA encoding vascular endothelial growth factor (VEGF)-A among VEGF, angiopoietin, endothelin family angiogenic and blood vessel remodeling factors. The expression of three proteoglycan core proteins, glypican-5, neurocan, and serglycin, was also altered after ethanol administration. Thus, binge levels of ethanol affect the expression of VEGF-A and blood vessel-supporting proteoglycans, resulting in changes in the vascular structure of the cerebral cortex.

Supplementary information

The online version contains supplementary material available at 10.1007/s43188-022-00164-y.

SUBMITTER: Hasegawa H

PROVIDER: S-EPMC9839917 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Blood vessel remodeling in the cerebral cortex induced by binge alcohol intake in mice.

Hasegawa Hiroshi H Tanaka Toshiya T Kondo Mari M Teramoto Koji K Nakayama Kei K Hwang Gi-Wook GW

Toxicological research 20221221 1

Ethanol is toxic to the brain and causes various neurological disorders. Although ethanol can directly exert toxicity on neurons, it also acts on other cell types in the central nervous system. Blood vessel endothelial cells interact with, and are affected by blood ethanol. However, the effects of ethanol on the vascular structures of the brain have not been well documented. In this study, we examined the effects of binge levels of ethanol on brain vasculature. Immunostaining analysis indicated ...[more]

PMID: 36726835

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Project description:BackgroundAlcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α2-containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking.MethodsMale wild-type (Wt) C57BL/6J and point-mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α2-containing GABAA receptors were assessed for their binge-like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH-naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.).ResultsMice with BZD-insensitive α2-containing GABAA receptors (H101R) escalated their binge-like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild-types, they did not show forced abstinence-induced social deficits.ConclusionsThese findings suggest a role for: (i) H101 in species-typical binge-like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence-associated social deficits. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive α2-containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic EtOH intake.

Project description:ObjectiveExcessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain.MethodsWe recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice.ResultsWe show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice.ConclusionsFGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.

Dataset Information

Blood vessel remodeling in the cerebral cortex induced by binge alcohol intake in mice.

Supplementary information

Publications

Blood vessel remodeling in the cerebral cortex induced by binge alcohol intake in mice.

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