RESUMO
Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Canabidiol , Ratos , Masculino , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Canabidiol/farmacologia , Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Corticosterona , Glucocorticoides , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Etanol , HipotálamoRESUMO
Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.
Assuntos
Acetilcisteína , Alcoolismo , Humanos , Adolescente , Feminino , Masculino , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Alcoolismo/diagnóstico por imagem , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Etanol , Método Duplo-Cego , Glutationa , Ácido gama-Aminobutírico , Ácido Glutâmico/metabolismoRESUMO
Probiotics are known to protect against liver damage induced by the alcohol and acetaldehyde accumulation associated with alcohol intake. However, there have been few studies of the direct effect of probiotics on alcohol metabolism, and the types of probiotics that were previously analyzed were few in number. Here, we investigated the effects of 19 probiotic species on alcohol and acetaldehyde metabolism. Four probiotic species that had a relatively high tolerance to alcohol and metabolized alcohol and acetaldehyde effectively were identified: Lactobacillus gasseri CBT LGA1, Lactobacillus casei CBT LC5, Bifidobacterium lactis CBT BL3, and Bifidobacterium breve CBT BR3. These species also demonstrated high mRNA expression of alcohol and acetaldehyde dehydrogenases. ProAP4, a mixture of these four probiotics species and excipient, was then administered to rats for 2 weeks in advance of acute alcohol administration. The serum alcohol and acetaldehyde concentrations were significantly lower in the ProAP4-administered group than in the control and excipient groups. Thus, the administration of ProAP4, containing four probiotic species, quickly lowers blood alcohol and acetaldehyde concentrations in an alcohol and acetaldehyde dehydrogenasedependent manner. Furthermore, the serum alanine aminotransferase activity, which is indicative of liver damage, was significantly lower in the ProAP4 group than in the control group. The present findings suggest that ProAP4 may be an effective means of limiting alcohol-induced liver damage.
Assuntos
Acetaldeído/sangue , Álcool Desidrogenase/metabolismo , Aldeído Oxirredutases/metabolismo , Etanol/sangue , Probióticos/administração & dosagem , Alanina Transaminase/sangue , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído Oxirredutases/genética , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bifidobacterium animalis/genética , Bifidobacterium animalis/metabolismo , Bifidobacterium breve/genética , Bifidobacterium breve/metabolismo , Suplementos Nutricionais , Lacticaseibacillus casei/genética , Lacticaseibacillus casei/metabolismo , Lactobacillus gasseri/genética , Lactobacillus gasseri/metabolismo , Masculino , RNA Bacteriano , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
AIMS: Lifestyle interventions are an important and viable approach for preventing cognitive deficits. However, the results of studies on alcohol, coffee and tea consumption in relation to cognitive decline have been divergent, likely due to confounds from dose-response effects. This meta-analysis aimed to find the dose-response relationship between alcohol, coffee or tea consumption and cognitive deficits. METHODS: Prospective cohort studies or nested case-control studies in a cohort investigating the risk factors of cognitive deficits were searched in PubMed, Embase, the Cochrane and Web of Science up to 4th June 2020. Two authors searched the databases and extracted the data independently. We also assessed the quality of the studies with the Newcastle-Ottawa scale. Stata 15.0 software was used to perform model estimation and plot the linear or nonlinear dose-response relationship graphs. RESULTS: The search identified 29 prospective studies from America, Japan, China and some European countries. The dose-response relationships showed that compared to non-drinkers, low consumption (<11 g/day) of alcohol could reduce the risk of cognitive deficits or only dementias, but there was no significant effect of heavier drinking (>11 g/day). Low consumption of coffee reduced the risk of any cognitive deficit (<2.8 cups/day) or dementia (<2.3 cups/day). Green tea consumption was a significant protective factor for cognitive health (relative risk, 0.94; 95% confidence intervals, 0.92-0.97), with one cup of tea per day brings a 6% reduction in risk of cognitive deficits. CONCLUSIONS: Light consumption of alcohol (<11 g/day) and coffee (<2.8 cups/day) was associated with reduced risk of cognitive deficits. Cognitive benefits of green tea consumption increased with the daily consumption.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Café/efeitos adversos , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/etiologia , Consumo de Bebidas Alcoólicas/metabolismo , Café/metabolismo , Cognição , Transtornos Cognitivos/epidemiologia , Disfunção Cognitiva/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores de Risco , Chá/efeitos adversos , Chá/metabolismoRESUMO
OBJECTIVES: This study aimed at determining the synergistic effects of Yuanhu Zhitong tablets (YHZTP) on alcohol-induced conditioned place preference (CPP) in mice, in addition, the intervention mechanism was preliminarily explored based on traditional Chinese Medicine (TCM) network pharmacology on alcohol addiction. METHODS: Alcohol-induced CPP mice were used to evaluate the effects of either YHZTP or levo-tetrahydropalmatine (l-THP) plus imperatorin (IMP) administration on animal behavior. The network pharmacological strategy was used to establish the "compound-target" and "disease-drug-target" network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the shared targets between the compound and the disease. Twelve algorithms on CytoHubba were used to find the hub genes that were verified by qPCR. RESULTS: Systemic administration (2 g/kg, i.p.) of ethanol (EtOH) to mice was used to induce CPP. YHZTP On its own did not induce CPP or conditioned place aversion (CPA) at the doses of 0.3 g/kg or 0.6 g/kg (i.g.), but attenuated the acquisition and expression of EtOH-induce CPP in mice. In addition, YHZTP (0.3 or 0.6 g/kg) did not exhibit any effect on the motor activity of mice. Acquisition of alcohol-induced CPP was blocked by a combination of l-THP (5 mg/kg, i.g.) + IMP (2.5 mg/kg, i.g.) or l-THP (10 mg/kg, i.g.) + IMP (5 mg/kg, i.g.). However, the combination of l-THP (2.5 mg/kg, i.g.) + IMP (1.25 mg/kg, i.g.) or mono-administration of l-THP and IMP did not exhibit any effect on alcohol-induced CPP. YHZTP was also shown to reverse the up-regulation of Gabra1, Ptgs2, Mapk1, Mapk8, Mapk14, Nr3c, Prkca and Sirt1 genes and the down-regulation of Hhtr2a and Drd2 genes in the prefrontal cortex of EtOH induced CPP mice. These genes were associated with neuroactive ligand-receptor interactions, activation of the sphingolipid, calcium, cAMP, ErbB, NF-kappa B and MAPK signaling pathways. CONCLUSION: YHZTP inhibits EtOH-induced CPP behavior in mice while a combination of l-THP and IMP exerts a synergistic effect on the reduction of EtOH-induced CPP. Possible pharmacological mechanisms include inhibition of the expression of inflammatory factors and regulation of neurotransmitter receptor levels. Therefore, YHZTP is a novel candidate for the treatment of alcohol addiction.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Etanol/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Alcaloides de Berberina/farmacologia , Sinergismo Farmacológico , Furocumarinas/farmacologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Mapas de Interação de Proteínas , Transdução de Sinais , Biologia de Sistemas , ComprimidosRESUMO
There are some studies that suggest that moderate consumption of wine, as part of a healthy and balanced diet, has a favourable effect on intestinal health. This study evaluates the effect of moderate wine consumption on faecal water (FW) cytotoxicity as a parameter of gut health. To that end, faecal samples before and after a red wine intervention study (250 mL of wine/day, 4 weeks) in healthy volunteers (n = 8) and in a parallel control group (n = 3) were collected and assayed for in vitro FW cytotoxicity. Two reference compounds, phenol and p-cresol, were used for assessing the cytotoxicity assays using two colon epithelial cell lines (HT-29 and HCT 116) and different assay conditions (FW dilution and incubation time). For the two cell lines and all assay conditions, the means of percentage cell viability were higher (lower cytotoxicity) for samples collected after the red wine intervention than for those collected before, although significant (p < 0.05) differences were only found in certain assay conditions for both cell lines. Significant positive correlations between the percentage cell viability and the contents of some faecal metabolites (short-chain fatty acids (SCFA) and phenolic acids (PA)) were found for the more resistant cell line (HCT 116), suggesting that the reduction in FW cytotoxicity observed after moderate red wine consumption was related to the production of microbial-derived metabolites such as SCFA and PA, whose faecal contents have been shown to increase after wine consumption. FW cytotoxicity can be deemed as a holistic biomarker that involves diet, gut microbiota and host.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Fezes/química , Água/análise , Vinho/análise , Adulto , Linhagem Celular , Colo/citologia , Colo/microbiologia , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Hidroxibenzoatos/metabolismo , MasculinoRESUMO
This study investigated the protective effects of pu-erh tea extract (PTE) on alcohol-induced microbiomic and metabolomic disorders. In chronic alcohol-exposed mice, PTE ameliorated chronic alcoholic consumption-induced oxidative stress, inflammation, lipid accumulation, and liver and colon damage through modulating microbiomic and metabolomic responses. PTE restored the alcohol-induced fecal microbiota dysbiosis by elevating the relative abundance of potentially beneficial bacteria, for example, Bifidobacterium and Allobaculum, and decreasing the relative abundance of potentially harmful bacteria, for example, Helicobacter and Bacteroides. The alcohol-induced metabolomic disorder was modulated by PTE, which was characterized by regulations of lipid metabolism (sphingolipid, glycerophospholipid, and linoleic acid metabolism), amino acid metabolism (phenylalanine and tryptophan metabolism), and purine metabolism. Besides, the bacterial metabolites of phytochemicals in PTE might contribute to the protective effects of PTE. Overall, PTE could be a functional beverage to treat chronic alcohol consumption-induced microbiomic and metabolomic disorders.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Álcoois/efeitos adversos , Camellia sinensis/metabolismo , Microbioma Gastrointestinal , Metaboloma/efeitos dos fármacos , Chá/metabolismo , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Fetal ethanol experience generates learning and memories capable to increase ethanol consummatory behaviors during infancy. Opioid system seems to be involved in mediating those alcohol-related behaviors. In this work, we proposed to study the impact of prenatal exposure to a moderate ethanol dose, upon ingestion of the drug and possible ethanol-induced molecular changes on opioid precursor peptides (POMC, Pro-enk and Pro-DYN) and receptors (MOR, DOR and KOR) mRNA expression, in hypothalamus. Pregnant rats received during gestational days (GDs) 17-20, a daily intragastric (i.g.) administration with 2g/kg ethanol or water. A third group of dams was left undisturbed during pregnancy (Unmanipulated group). Intake test was conducted at postnatal days (PDs) 14-15. Three groups of pups were performed: control (no intake test), water (vehicle) and 5% ethanol. At the end of intake test blood samples were taken to quantify blood ethanol concentrations (BECs) and hypothalamus sections were obtained to perform qRT-PRC assessment of opioid precursor peptides and receptors. The analysis of the consummatory responses (% of consumption) and pharmacokinetic profiles (BECs) suggested that maternal manipulation induced by i.g. intubations, during the last four days of gestation (whenever ethanol or water), are sufficient to induce infantile ethanol intake during infancy. Gene expression from the hypothalamus of unmanipulated group revealed that infantile ingestive experiences with ethanol can down-regulate expression of mRNA Pro-Dyn and up-regulate mRNA expression of MOR and KOR. Finally, MOR mRNA expression was attenuated by prenatal i.g. manipulation in pups exposed to 5% ethanol.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Opioides/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Animais , Animais Recém-Nascidos , Etanol/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Peptídeos Opioides , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Opioides/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genéticaRESUMO
Evidence has revealed a high degree of comorbidity of excessive alcohol intake and abstinence anxiety-like behavior. The ethanolic extracts of Bacopa monnieri (BME) are used in Indian traditional medicines for the management of alcoholic disorders. However, the underlying mechanism(s) associated with the influence of BME on alcohol abstinence-induced anxiety-like behavior have not been adequately addressed. Therefore, the present study was planned to examine the beneficial effects of BME in alcohol abstinence-induced anxiety-like behavior and the underlying mechanism of action subsequent to long-term voluntary drinking of alcohol. For the assessment of the effects of BME, Wistar rats were exposed to voluntary ingestion of 4.5%, 7.5% and 9% v/v alcohol for 15 days. The doses (100, 200, and 500 mg/kg) of BME and diazepam (2 mg/kg) were administered via gavage for three consecutive days in the alcohol abstinence period on the days 16, 17, and 18. The behavioral studies were conducted employing the elevated plus maze test (EPM), and light-dark test on day 18 to determine the effects of BME and diazepam in the ethanol abstinence-induced anxiety-like behavior. Alcohol biomarkers like ALT, AST, ALP, GGT, and MCV were estimated using commercially available kits. The expression of Gabra1, Gabra2, Gabra3, Gabra4, Gabra5 genes of the GABAA receptors subunits in the hippocampus as well as amygdala were also examined by reverse-transcription quantitative polymerase chain reaction. The HPLC analysis demonstrated that BME contained 9.9% bacoside-A as a major component. The results revealed that alcohol abstinence group depicted a reduction in the time spent on the open arms, numbers of entries in the open as well as closed arms in EPM test and similarly decrease in latency to the dark chamber, time spent in light chamber and numbers of transitions in LDT. Further, BME at the doses of 200 mg/kg and 500 mg/kg alleviated anxiety-like behavior which was escalated during alcohol abstinence. However, BME (100 mg/kg) exhibited insignificant protection against alcohol abstinence-induced syndrome. The escalated levels of alcohol-intake biomarkers were also reversed by BME at the dose of 200 mg/kg and 500 mg/kg. The down-regulation of Gabra1, Gabra4, and Gabra5 gene expression following alcohol abstinence were also reversed with a higher dose of BME (200 and 500 mg/kg) treatment. These results show that BME abrogates anxiety-like behavior by modulating alcohol markers and Gabra1, Gabra4, Gabra5 gene expression of GABAA receptor signaling pathway in rats.
Assuntos
Ansiedade/tratamento farmacológico , Bacopa/química , Etanol/efeitos adversos , Extratos Vegetais/farmacologia , Receptores de GABA-A/metabolismo , Abstinência de Álcool , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Biomarcadores/metabolismo , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Epigenetic modifications of a gene have been shown to play a role in maintaining a long-lasting change in gene expression. We hypothesize that alcohol's modulating effect on DNA methylation on certain genes in blood is evident in binge and heavy alcohol drinkers and is associated with alcohol motivation. METHODS: Methylation-specific polymerase chain reaction (PCR) assays were used to measure changes in gene methylation of period 2 (PER2) and proopiomelanocortin (POMC) genes in peripheral blood samples collected from nonsmoking moderate, nonbinging, binge, and heavy social drinkers who participated in a 3-day behavioral alcohol motivation experiment of imagery exposure to either stress, neutral, or alcohol-related cues, 1 per day, presented on consecutive days in counterbalanced order. Following imagery exposure on each day, subjects were exposed to discrete alcoholic beer cues followed by an alcohol taste test (ATT) to assess behavioral motivation. Quantitative real-time PCR was used to measure gene expression of PER2 and POMC gene levels in blood samples across samples. RESULTS: In the sample of moderate, binge, and heavy drinkers, we found increased methylation of the PER2 and POMC DNA, reduced expression of these genes in the blood samples of the binge and heavy drinkers relative to the moderate, nonbinge drinkers. Increased PER2 and POMC DNA methylation was also significantly predictive of both increased levels of subjective alcohol craving immediately following imagery (p < 0.0001), and with presentation of the alcohol (2 beers) (p < 0.0001) prior to the ATT, as well as with alcohol amount consumed during the ATT (p < 0.003). CONCLUSIONS: These data establish significant association between binge or heavy levels of alcohol drinking and elevated levels of methylation and reduced levels of expression of POMC and PER2 genes. Furthermore, elevated methylation of POMC and PER2 genes is associated with greater subjective and behavioral motivation for alcohol.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Metilação de DNA/efeitos dos fármacos , Motivação , Proteínas Circadianas Period/metabolismo , Pró-Opiomelanocortina/metabolismo , Adulto , Fissura/efeitos dos fármacos , Sinais (Psicologia) , Epigênese Genética , Etanol/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas Circadianas Period/sangue , Estimulação Luminosa , Pró-Opiomelanocortina/sangue , Adulto JovemRESUMO
BACKGROUND: It is estimated that 1 billion people in the world have a point mutation in the gene encoding the aldehyde dehydrogenase 2 (ALDH2) enzyme, the primary enzyme responsible for the metabolism of acetaldehyde. The presence of this mutation is called ALDH2 deficiency. Because of limited ability to metabolize acetaldehyde, individuals with ALDH2 deficiency experience elevated levels of blood acetaldehyde after exposure to various common sources such as recreational alcohol. Because of higher levels of acetaldehyde, individuals with ALDH2 deficiency are at higher risk for numerous diseases, including liver cirrhosis, esophageal and gastric cancer, osteoporosis, and Alzheimer disease. STUDY QUESTION: The present trial was designed to study the effectiveness, safety, and tolerability of a nutritional supplement (Essential AD2). MEASURES AND OUTCOMES: The primary outcome was change in acetaldehyde levels in the blood after exposure to alcohol in individuals with ALDH2 deficiency before and after the use of study nutritional supplement. STUDY DESIGN: This was a 28-day open-label trial, comparing initial acetaldehyde levels after alcohol ingestion to levels after 28 days of a nutritional supplement (Essential AD2). The study consisted of 12 subjects genotyped to be heterozygous for the ALDH2 gene mutation. RESULTS AND CONCLUSIONS: ALDH2 deficient subjects showed a significant decrease in average blood acetaldehyde level 20 minutes after alcohol consumption (from 0.91 mg/dL to 0.71 mg/dL, P value = 0.02) after receiving 28 days of the nutritional supplement. Acetaldehyde levels taken at 10 minutes and 40 minutes also showed a decrease, although they were not statistically significant. In addition, safety tests looking at liver function tests showed a decrease in aspartate transaminase and alanine transaminase liver proteins from 27.3 to 15.2 and 20.9 to 13.2, respectively, over the 28 days. The treatment was well tolerated and no significant side effects were noted.
Assuntos
Acetaldeído/sangue , Consumo de Bebidas Alcoólicas/sangue , Aldeído-Desidrogenase Mitocondrial/deficiência , Suplementos Nutricionais/efeitos adversos , Etanol/metabolismo , Acetaldeído/metabolismo , Adulto , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Povo Asiático/genética , Etanol/administração & dosagem , Etanol/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos/administração & dosagem , Placebos/efeitos adversos , Mutação Puntual , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE: Alcohol use disorder (AUD) is a chronically relapsing condition, which affects nearly 11% of population worldwide. Currently, there are only three FDA-approved medications for treatment of AUD, and normally, satisfactory effects are hard to be achieved. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling has been implicated in regulation of ethanol intake. Phosphodiesterase 2 (PDE), a dual substrate PDE that hydrolyzes both cAMP and cGMP, may play a crucial role in regulating ethanol consumption. METHODS: The present study determined whether PDE2 was involved in the regulation of ethanol intake and preference. The two-bottle choice procedure was used to examine the effects of the selective PDE2 inhibitor Bay 60-7550 on ethanol intake. The sucrose and quinine intake (taste preference) and locomotor activity (sedative effects) were also measured to exclude the false positive effects of Bay 60-7550. RESULTS: Treatment with Bay 60-7550 (1 and 3 mg/kg, i.p.) decreased ethanol intake and preference, without changing total fluid intake. In addition, Bay 60-7550 at doses that reduced ethanol intake did not affect sucrose and quinine intake and preference, which excluded the potential influence of taste preference and sedative effects on ethanol drinking behavior. Moreover, Bay 60-7550 at 3 mg/kg did not alter locomotor activity or ethanol metabolism, further supporting the specific effect of Bay 60-7550 on ethanol drinking behavior. CONCLUSIONS: The results suggest that PDE2 plays a role in the regulation of ethanol consumption and that PDE2 inhibitors may be a novel class of drugs for treatment of alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Imidazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Triazinas/uso terapêutico , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Fosfodiesterase/farmacologia , Triazinas/farmacologiaRESUMO
Metabolomics studies of disease conditions related to chronic alcohol consumption provide compelling evidence of several perturbed metabolic pathways underlying the pathophysiology of alcoholism. The objective of the present study was to utilize proton nuclear magnetic resonance (1H-NMR) spectroscopy metabolomics to study the holistic metabolic consequences of acute alcohol consumption in humans. The experimental design was a cross-over intervention study which included a number of substances to be consumed-alcohol, a nicotinamide adenine dinucleotide (NAD) supplement, and a benzoic acid-containing flavoured water vehicle. The experimental subjects-24 healthy, moderate-drinking young men-each provided six hourly-collected urine samples for analysis. Complete data sets were obtained from 20 of the subjects and used for data generation, analysis and interpretation. The results from the NMR approach produced complex spectral data, which could be resolved sufficiently through the application of a combination of univariate and multivariate methods of statistical analysis. The metabolite profiles resulting from acute alcohol consumption indicated that alcohol-induced NAD+ depletion, and the production of an excessive amount of reducing equivalents, greatly perturbed the hepatocyte redox homeostasis, resulting in essentially three major metabolic disturbances-up-regulated lactic acid metabolism, down-regulated purine catabolism and osmoregulation. Of these, the urinary excretion of the osmolyte sorbitol proved to be novel, and suggests hepatocyte swelling due to ethanol influx following acute alcohol consumption. Time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment, thereby also giving methodological significance to this study. The outcomes of this approach have the potential to significantly advance our understanding of the serious impact of the pathophysiological perturbations which arise from the consumption of a single, large dose of alcohol-a simulation of a widespread, and mostly naive, social practice.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Etanol/administração & dosagem , Redes e Vias Metabólicas/fisiologia , Adulto , Ácido Benzoico/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Adulto JovemRESUMO
BACKGROUND: Because alcohol (ALC) delays signs of pubertal development, we assessed the time course of events associated with the synthesis of critical hypothalamic peptides that regulate secretion of luteinizing hormone-releasing hormone (LHRH), the peptide that drives the pubertal process. METHODS: Immature female rats were administered either laboratory chow or BioServe isocaloric control or ALC-liquid diets from 27 through 33 days of age. On days 28, 29, 31, and 33, animals were killed by decapitation and tissue blocks containing the medial basal hypothalamus (MBH) and the rostral hypothalamic area (RHA) were isolated and stored frozen until assessed by Western blot analysis. RESULTS: Synthesis of dynorphin (DYN), a prepubertal inhibitor of LHRH secretion, was increased (p < 0.05) in the MBH of ALC-treated animals by day 29. DYN was further elevated (p < 0.01) on day 33 and was associated with an increase (p < 0.01) in DYN receptor expression. ALC did not affect synthesis of neurokinin B (NKB), a prepubertal stimulator of LHRH; however, it did suppress (p < 0.05) NKB receptor expression in the MBH by day 31. The most potent stimulator of prepubertal LHRH secretion, kisspeptin (Kp), was also decreased (p < 0.05) in the MBH as early as day 29, with continued suppression (p < 0.01) through day 33. Similar timely suppressions of mammalian target of rapamycin (mTOR), an immediate upstream regulator of Kp, were also noted. These decreases in mTOR and Kp were consistent with ALC stimulating (p < 0.05) the p-AMP-activated protein kinase/Raptor inhibitory pathway to mTOR on day 29, then later suppressing (p < 0.001) an Akt-mediated induction pathway to mTOR by day 31. In the RHA, ALC affected the pathways regulating Kp in a manner similar to that described in the MBH; however, these effects were not noted until day 33. CONCLUSIONS: ALC acts within the MBH as early as 29 days to induce inhibitor and repressor inputs to LHRH, while depressing stimulatory inputs to the peptide. Collectively, these events lead to delayed signs of pubertal development.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Etanol/toxicidade , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Maturidade Sexual/efeitos dos fármacos , Fatores Etários , Animais , Etanol/administração & dosagem , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologiaRESUMO
Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aminoácidos de Cadeia Ramificada , Fígado Gorduroso , Mitocôndrias , Doenças Mitocondriais , Consumo de Bebidas Alcoólicas/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos de Cadeia Ramificada/farmacologia , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/prevenção & controle , NAD/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ethanol is the most important teratogen agent in humans. Prenatal alcohol exposure can lead to a wide range of adverse effects, which are broadly termed as fetal alcohol spectrum disorder (FASD). The most severe consequence of maternal alcohol abuse is the development of fetal alcohol syndrome, defined by growth retardation, facial malformations, and central nervous system impairment expressed as microcephaly and neurodevelopment abnormalities. These alterations generate a broad range of cognitive abnormalities such as learning disabilities and hyperactivity and behavioural problems. Socioeconomic status, ethnicity, differences in genetic susceptibility related to ethanol metabolism, alcohol consumption patterns, obstetric problems, and environmental influences like maternal nutrition, stress, and other co-administered drugs are all factors that may influence FASD manifestations. Recently, much attention has been paid to the role of nutrition as a protective factor against alcohol teratogenicity. There are a great number of papers related to nutritional treatment of nutritional deficits due to several factors associated with maternal consumption of alcohol and with eating and social disorders in FASD children. Although research showed the clinical benefits of nutritional interventions, most of work was in animal models, in a preclinical phase, or in the prenatal period. However, a minimum number of studies refer to postnatal nutrition treatment of neurodevelopmental deficits. Nutritional supplementation in children with FASD has a dual objective: to overcome nutritional deficiencies and to reverse or improve the cognitive deleterious effects of prenatal alcohol exposure. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of simultaneous multiple-nutrient supplementation.
Assuntos
Transtornos do Espectro Alcoólico Fetal/dietoterapia , Transtornos Neurocognitivos/dietoterapia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Etanol/efeitos adversos , Etanol/metabolismo , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/patologia , Predisposição Genética para Doença , Humanos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/patologiaRESUMO
Alcohol and nutrition have the potential to interact at multiple levels. For example, heavy alcohol consumption can interfere with normal nutrition, resulting in overall malnutrition or in deficiencies of important micronutrients, such as zinc, by reducing their absorption or increasing their loss. Interactions between alcohol consumption and nutrition also can affect epigenetic regulation of gene expression by influencing multiple regulatory mechanisms, including methylation and acetylation of histone proteins and DNA. These effects may contribute to alcohol-related organ or tissue injury. The impact of alcohol-nutrition interactions has been assessed for several organs and tissues, including the intestine, where heavy alcohol use can increase intestinal permeability, and the liver, where the degree of malnutrition can be associated with the severity of liver injury and liver disease. Alcohol-nutrition interactions also play a role in alcohol-related lung injury, brain injury, and immune dysfunction. Therefore, treatment involving nutrient supplementation (e.g., with zinc or S-adenosylmethionine) may help prevent or attenuate some types of alcohol-induced organ damage.
Assuntos
Consumo de Bebidas Alcoólicas , Transtornos Relacionados ao Uso de Álcool , Deficiências Nutricionais , Fenômenos Fisiológicos da Nutrição/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/prevenção & controle , Animais , Deficiências Nutricionais/induzido quimicamente , Deficiências Nutricionais/complicações , Deficiências Nutricionais/metabolismo , HumanosRESUMO
The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily through the hypothalamus itself, OX homeostatically regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, through extrahypothalamic limbic brain regions, OX promotes seeking and intake of rewarding substances of abuse, like palatable food, alcohol, nicotine, and cocaine. This neuropeptide, in turn, is stimulated by the intake of or early life exposure to these substances, forming a nonhomeostatic, positive feedback loop. The specific OX receptor involved in these behaviors, whether adaptive behavior or substance seeking and intake, is dependent on the particular brain region that contributes to them. Thus, we propose that, while the primary function of OX is to maintain arousal for the performance of adaptive behaviors, this neuropeptide system is readily co-opted by rewarding substances that involve positive feedback, ultimately promoting their abuse.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Homeostase/fisiologia , Hipotálamo/metabolismo , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , HumanosRESUMO
BACKGROUND: The principal aim of this study was to investigate the oxidative effects of acute alcohol consumption on the functions of the heart and the liver and the possible modification of this effect by phenolic compounds from n-butanol extract of Camellia sinensis supplementation. METHOD: Three experimental groups of rats were used: control, ethanol-exposed (40% v/v, 5 g/kg per oral every 12 hours for 3 doses, binge model), and ethanol-exposed plus n-butanol extract of Camellia sinensis (100 mg/kg once a day for three days before and simultaneously with ethanol administration). Serum transaminases, cholesterol, triglycerides, lipid peroxidation (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were estimated to assess organs damage. RESULTS: n-butanol extract of Camellia sinensis at a dose of 100 mg/kg body weight exhibited a significant reversal effect in all biochemical parameters measured such as extent of lipid peroxidation, GSH, lipid profile, and serum aminotransferase activities. CONCLUSION: These results suggest that n-butanol extract of Camellia sinensis protected the heart and the liver from binge ethanol induced injury through attenuating oxidative stress.
Assuntos
Antioxidantes/uso terapêutico , Camellia sinensis/química , Cardiotoxicidade/tratamento farmacológico , Etanol/toxicidade , Hepatopatias Alcoólicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , 1-Butanol/química , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Antioxidantes/química , Cardiotoxicidade/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Hepatopatias Alcoólicas/sangue , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Extratos Vegetais/química , Ratos , Chá/químicaRESUMO
Opioid receptor antagonist naltrexone reduces alcohol consumption and relapse in both humans and rodents. This study investigated whether hypothalamic proopiomelanocortin (POMC) neurons (producing beta-endorphin and melanocortins) play a role in alcohol drinking behaviors. Both male and female mice with targeted deletion of two neuronal Pomc enhancers nPE1 and nPE2 (nPE-/-), resulting in hypothalamic-specific POMC deficiency, were studied in short-access (4-h/day) drinking-in-the-dark (DID, alcohol in one bottle, intermittent access (IA, 24-h cycles of alcohol access every other day, alcohol vs. water in a two-bottle choice) and alcohol deprivation effect (ADE) models. Wild-type nPE+/+ exposed to 1-week DID rapidly established stable alcohol drinking behavior with more intake in females, whereas nPE-/- mice of both sexes had less intake and less preference. Although nPE-/- showed less saccharin intake and preference than nPE+/+, there was no genotype difference in sucrose intake or preference in the DID paradigm. After 3-week IA, nPE+/+ gradually escalated to high alcohol intake and preference, with more intake in females, whereas nPE-/- showed less escalation. Pharmacological blockade of mu-opioid receptors with naltrexone reduced intake in nPE+/+ in a dose-dependent manner, but had blunted effects in nPE-/- of both sexes. When alcohol was presented again after 1-week abstinence from IA, nPE+/+ of both sexes displayed significant increases in alcohol intake (ADE or relapse-like drinking), with more pronounced ADE in females, whereas nPE-/- did not show ADE in either sex. Our results suggest that neuronal POMC is involved in modulation of alcohol 'binge' drinking, escalation and 'relapse', probably via hypothalamic-mediated mechanisms, with sex differences.