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1.
Brain Res ; 1758: 147341, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33548270

RESUMO

Ethanol is associated with oxidative stress. Exposure to ethanol during childhood may lead to neurological disorders. Congenital disorders induced by alcohol are mainly caused by an oxidative-inflammatory cascade due to extensive apoptotic neurodegeneration in the brain, particularly in the hippocampus. Simvastatin, which acts as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), is widely used to manage cardiovascular diseases. Recently, the neuroprotective effects of simvastatin against nervous system disorders have been introduced. In this study, we examined the protective effects of simvastatin on ethanol-related neurotoxicity in the hippocampus of rat pups. Ethanol (5.27 g/kg) in a milk solution (27.8 mL/kg) was administered to male rat pups via intragastric intubation at 2-10 days after birth. Also, 10 and 20 mg/kg of simvastatin were injected to the animals. By using Morris water maze task, the hippocampus-dependent memory and spatial learning was evaluated 36 days after birth. An ELISA assay was performed to investigate the antioxidant and anti-inflammatory effects of simvastatin by measuring the levels of tumor necrosis factor-α (TNF-α), and antioxidant enzymes. To assess the expression levels of Iba1 immunohistochemical staining and caspase-3 immunofluorescence staining was performed. The current study demonstrated that administration of simvastatin significantly attenuates spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also simvastatin could considerably increase the total superoxide dismutaseand glutathione levels (P < 0.01). Moreover, it was associated with a greater reduction in malondialdehyde (P < 0.05) and TNF-α levels, compared to the ethanol group (P < 0.01). Furthermore, in the simvastatin group, the hippocampal level of caspase-3 and the level of Iba1-positive cells, reduced (P < 0.01). This study demonstrated that apoptotic signaling, mediated by the oxidative-inflammatory cascade, could be inhibited by simvastatin in rat pups with ethanol exposure in the postnatal period.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sinvastatina/farmacologia , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Gliose/induzido quimicamente , Hipocampo/patologia , Masculino , Transtornos da Memória/induzido quimicamente , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos
2.
Behav Brain Res ; 396: 112885, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860829

RESUMO

Studies with human subjects indicate that ethanol exposure during fetal development causes long-lasting alterations in motor coordination that are, in part, a consequence of cerebellar damage. Studies with rats exposed to ethanol during the neonatal brain growth spurt have consistently recapitulated these deficits. However, studies with mice have yielded mixed results. We hypothesized that the use of highly sensitive motor function tests, such as the Catwalk test, would reliably detect motor function deficits in mice developmentally exposed to ethanol. Venus-vesicular GABA transporter transgenic mice were ethanol exposed during postnatal days 4-9 using vapor inhalation chambers and then subjected to the Catwalk test during adolescence. Catwalk data were rigorously analyzed using an innovative multistep statistical approach. For comparison, motor coordination and strength were assessed with the triple horizontal bar and rotarod tests. Unexpectedly, we found that out of 186 parameters analyzed in the Catwalk test, only one was affected by ethanol exposure (i.e., reduced coupling between left front paw and the right hind paw). In the triple horizontal bar test, ethanol-exposed mice were able to hold to the bars for less time than controls. Surprisingly, ethanol-exposed mice performed better in the rotarod test than controls. These data indicate that neonatal ethanol exposure of mice causes mixed effects on motor function during adolescence. The Catwalk test suggests that gait is generally preserved in these mice, whereas the triple horizontal bar test revealed deficits on motor strength and the rotarod test an increase in motor coordination.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Atividade Motora/fisiologia , Desempenho Psicomotor/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Depressores do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Etanol/administração & dosagem , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores
3.
Alcohol Alcohol ; 56(1): 89-100, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33089302

RESUMO

AIMS: In patients with a history of chronic alcohol abuse, neurocognitive disorders (NCD) are not uncommon. The current study aimed to explore the course of cognitive performance, as measured by the Montreal Cognitive Assessment (MoCA), and everyday cognitive functioning, as measured by the Patient Competency Rating Scale (PCRS), in a large group of patients with alcohol use disorder (AUD) admitted to the Center of Excellence for Korsakov and Alcohol-related Cognitive Impairments. METHODS: A multiple time-series design was used, in which the MoCA was administered at three time points of assessment, and the PCRS was completed by both the patient and a clinician at two time points, all during clinical treatment. RESULTS: A total of 524 patients were included, 71 of whom were diagnosed with AUD only, 284 with AUD and mild NCD (ARCI) and 169 with AUD, major NCD and fulfilling criteria for Korsakoff's syndrome (KS). CONCLUSIONS: Cognitive performance improved for all three groups during treatment, sustained abstinence and recovery from AUD. A low memory performance on the MoCA without improvement over time was predictive for KS, while improvement on this domain did not differentiate between AUD and ARCI. Changes in overall cognitive performance and orientation in patients with KS were positively related to changes in everyday cognitive functioning.


Assuntos
Síndrome Alcóolica de Korsakoff/psicologia , Alcoolismo/reabilitação , Disfunção Cognitiva/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Transtornos do Sistema Nervoso Induzidos por Álcool/psicologia , Síndrome Alcóolica de Korsakoff/fisiopatologia , Alcoolismo/fisiopatologia , Alcoolismo/psicologia , Disfunção Cognitiva/fisiopatologia , Função Executiva , Feminino , Hospitalização , Humanos , Masculino , Memória , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Transtornos Neurocognitivos/fisiopatologia , Transtornos Neurocognitivos/psicologia
4.
Alcohol Clin Exp Res ; 44(8): 1585-1597, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32524615

RESUMO

BACKGROUND: Alcohol use disorders affect millions of people worldwide, and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals. Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood. Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice. METHODS: For this study, we used an in vivo model to induce alcohol-related neurotoxicity in the hippocampus. Adult male C57BL/6 mice were treated with 95% alcohol vapor either alone or in combination with selective cannabinoid receptor antagonists or agonists, and VX765 (Belnacasan), which is a selective caspase-1 inhibitor. RESULTS: Alcohol-induced in vivo pyroptosis occurs because of an increase in the levels of pyroptotic proteins such as nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), caspase-1, gasdermin D (GSDMD), and amplified inflammatory response. Our results indicated that VX765 suppressed the expression of caspase-1 and inhibited the maturation of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. Additionally, chronic alcohol intake created an imbalance in the endocannabinoid system and regulated 2 cannabinoid receptors (CB1R and CB2R) in the hippocampus. Specific antagonists of CB1R (AM251 and AM281) significantly ameliorated alcohol-induced pyroptosis signaling and inactivated the inflammatory response. CONCLUSIONS: Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity, thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol-induced hippocampal neurotoxicity. Furthermore, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol-induced neurotoxicity through pharmacologic inhibition of CB1R.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Antagonistas de Receptores de Canabinoides/farmacologia , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piroptose/efeitos dos fármacos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Caspase 1/efeitos dos fármacos , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Dipeptídeos/farmacologia , Inflamação , Interleucina-18/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Morfolinas/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndromes Neurotóxicas , Proteínas de Ligação a Fosfato/efeitos dos fármacos , Proteínas de Ligação a Fosfato/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , para-Aminobenzoatos/farmacologia
5.
Nitric Oxide ; 100-101: 50-56, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278831

RESUMO

The cerebellum is widely known as a motor structure because it regulates and controls motor learning, coordination, and balance. However, it is also critical for non-motor functions such as cognitive processing, sensory discrimination, addictive behaviors and mental disorders. The cerebellum has the highest relative abundance of neuronal nitric oxide synthase (nNos) and is sensitive to ethanol. Although it has been demonstrated that the interaction of γ-aminobutyric acid (GABA) and nitric oxide (NO) might play an important role in the regulation of ethanol-induced cerebellar ataxia, the molecular mechanisms through which ethanol regulates nNos function to elicit this behavioral effect have not been studied extensively. Here, we investigated the dose-dependent effects of acute ethanol treatment on motor impairment using the rotarod behavioral paradigm and the alterations of nNos mRNA expression in cerebellum, frontal cortex (FC), hippocampus and striatum. We also examined the link between acute ethanol-induced motor impairment and nNos by pharmacological manipulation of nNos function. We found that acute ethanol induced a dose-dependent elevation of ethanol blood levels which was associated with the impairment of motor coordination performance and decreased expression of cerebellar nNos. In contrast, acute ethanol increased nNos expression in FC but did not to change the expression for this enzyme in striatum and hippocampus. The effects of acute ethanol were attenuated by l-arginine, a precursor for NO and potentiated by 7-nitroindazole (7-NI), a selective inhibitor of nNos. Our data suggests that differential regulation of nNos mRNA expression in cerebellum and frontal cortex might be involved in acute ethanol-induced motor impairment.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Ataxia Cerebelar/metabolismo , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo I/metabolismo , Transtornos Psicomotores/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/induzido quimicamente , Animais , Arginina/farmacologia , Ataxia Cerebelar/induzido quimicamente , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Inibidores Enzimáticos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Indazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Transtornos Psicomotores/induzido quimicamente , Ratos Sprague-Dawley
6.
Pharmacol Rep ; 71(5): 804-810, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377562

RESUMO

BACKGROUND: Excessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice. METHODS: The behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured. RESULTS: Ethanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice. CONCLUSION: The present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lacosamida/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Animais , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Natação
7.
Stem Cell Res Ther ; 10(1): 205, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286996

RESUMO

BACKGROUND: Chronic consumption of most drugs of abuse leads to brain oxidative stress and neuroinflammation, which inhibit the glutamate transporter GLT-1, proposed to perpetuate drug intake. The present study aimed at inhibiting chronic ethanol and nicotine self-administration and relapse by the non-invasive intranasal administration of antioxidant and anti-inflammatory secretome generated by adipose tissue-derived activated mesenchymal stem cells. The anti-addiction mechanism of stem cell secretome is also addressed. METHODS: Rats bred for their alcohol preference ingested alcohol chronically or were trained to self-administer nicotine. Secretome of human adipose tissue-derived activated mesenchymal stem cells was administered intranasally to animals, both (i) chronically consuming alcohol or nicotine and (ii) during a protracted deprivation before a drug re-access leading to relapse intake. RESULTS: The intranasal administration of secretome derived from activated mesenchymal stem cells inhibited chronic self-administration of ethanol or nicotine by 85% and 75%, respectively. Secretome administration further inhibited by 85-90% the relapse "binge" intake that occurs after a protracted drug deprivation followed by a 60-min drug re-access. Secretome administration fully abolished the oxidative stress induced by chronic ethanol or nicotine self-administration, shown by the normalization of the hippocampal oxidized/reduced glutathione ratio, and the neuroinflammation determined by astrocyte and microglial immunofluorescence. Knockdown of the glutamate transporter GLT-1 by the intracerebral administration of an antisense oligonucleotide fully abolished the inhibitory effect of the secretome on ethanol and nicotine intake. CONCLUSIONS: The non-invasive intranasal administration of secretome generated by human adipose tissue-derived activated mesenchymal stem cells markedly inhibits alcohol and nicotine self-administration, an effect mediated by the glutamate GLT-1 transporter. Translational implications are envisioned.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/terapia , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais , Tabagismo/terapia , Administração Intranasal , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Transtornos do Sistema Nervoso Induzidos por Álcool/prevenção & controle , Álcoois/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Células-Tronco Mesenquimais/metabolismo , Tecido Nervoso/patologia , Tecido Nervoso/transplante , Nicotina/efeitos adversos , Estresse Oxidativo/genética , Ratos , Autoadministração , Tabagismo/patologia , Tabagismo/prevenção & controle
8.
Neurochem Int ; 129: 104497, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251945

RESUMO

Chronic alcoholism promotes brain damage that impairs memory and cognition. High binge alcohol levels in adult rats also cause substantial neurodamage to memory-linked regions, notably, the hippocampus (HC) and entorhinal cortex (ECX). Concurrent with neurodegeneration, alcohol elevates poly (ADP-ribose) polymerase-1 (PARP-1) and cytosolic phospholipase A2 (cPLA2) levels. PARP-1 triggers necrosis when excessively activated, while cPLA2 liberates neuroinflammatory ω-6 arachidonic acid. Inhibitors of PARP exert in vitro neuroprotection while suppressing cPLA2 elevations in alcohol-treated HC-ECX slice cultures. Here, we examined in vivo neuroprotection and cPLA2 suppression by the PARP inhibitor, veliparib, in a recognized adult rat model of alcohol-binging. Adult male rats received Vanilla Ensure containing alcohol (ethanol, 7.1 ±â€¯0.3 g/kg/day), or control (dextrose) ±â€¯veliparib (25 mg/kg/day), by gavage 3x daily for 4 days. Rats were sacrificed on the morning after the final binge. HC and ECX neurodegeneration was assessed in fixed sections by Fluoro-Jade B (FJB) staining. Dorsal HC, ventral HC, and ECX cPLA2 levels were quantified by immunoblotting. Like other studies using this model, alcohol binges elevated FJB staining in the HC (dentate gyrus) and ECX, indicating neurodegeneration. Veliparib co-treatment significantly reduced dentate gyrus and ECX neurodegeneration by 79% and 66%, respectively. Alcohol binges increased cPLA2 in the ventral HC by 34% and ECX by 72%, which veliparib co-treatment largely prevented. Dorsal HC cPLA2 levels remained unaffected by alcohol binges, consistent with negligible FJB staining in this brain region. These in vivo results support an emerging key role for PARP in binge alcohol-induced neurodegeneration and cPLA2-related neuroinflammation.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/prevenção & controle , Benzimidazóis/uso terapêutico , Proteínas do Tecido Nervoso/biossíntese , Fosfolipases A2 Citosólicas/biossíntese , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Transtornos do Sistema Nervoso Induzidos por Álcool/tratamento farmacológico , Transtornos do Sistema Nervoso Induzidos por Álcool/enzimologia , Animais , Benzimidazóis/farmacologia , Consumo Excessivo de Bebidas Alcoólicas , Giro Denteado/efeitos dos fármacos , Giro Denteado/enzimologia , Giro Denteado/patologia , Modelos Animais de Doenças , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/enzimologia , Córtex Entorrinal/patologia , Indução Enzimática/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso/genética , Fosfolipases A2 Citosólicas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos , Ratos Sprague-Dawley
9.
Oxid Med Cell Longev ; 2019: 7849876, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210848

RESUMO

An ethyl acetate fraction from Aralia elata (AEEF) was investigated to confirm its neuronal cell protective effect on ethanol-induced cytotoxicity in MC-IXC cells and its ameliorating effect on neurodegeneration in chronic alcohol-induced mice. The neuroprotective effect was examined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) assays. As a result, AEEF reduced alcohol-induced cytotoxicity and oxidative stress. To evaluate the improvement of learning, memory ability, and spatial cognition, Y-maze, passive avoidance, and Morris water maze tests were conducted. The AEEF groups showed an alleviation of the decrease in cognitive function in alcohol-treated mice. Then, malondialdehyde (MDA) levels and the superoxide dismutase (SOD) content were measured to evaluate the antioxidant effect of AEEF in the brain tissue. Treatment with AEEF showed a considerable ameliorating effect on biomarkers such as SOD and MDA content in alcohol-induced mice. To assess the cerebral cholinergic system involved in neuronal signaling, acetylcholinesterase (AChE) activity and acetylcholine (ACh) content were measured. The AEEF groups showed increased ACh levels and decreased AChE activities. In addition, AEEF prevented alcohol-induced neuronal apoptosis via improvement of mitochondrial activity, including reactive oxygen species levels, mitochondrial membrane potential, and adenosine triphosphate content. AEEF inhibited apoptotic signals by regulating phosphorylated c-Jun N-terminal kinases (p-JNK), phosphorylated protein kinase B (p-Akt), Bcl-2-associated X protein (BAX), and phosphorylated Tau (p-Tau). Finally, the bioactive compounds of AEEF were identified as caffeoylquinic acid (CQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and chikusetsusaponin IVa using the UPLC-Q-TOF-MS system.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/tratamento farmacológico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Aralia/química , Encéfalo/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetatos/química , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Animais , Antioxidantes/química , Encéfalo/patologia , Linhagem Celular , Doença Crônica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Neurônios/patologia , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo
10.
Toxicol Lett ; 313: 19-29, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082522

RESUMO

Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Alcoolismo/metabolismo , Corpo Estriado/metabolismo , Metabolismo dos Lipídeos , Metabolômica/métodos , Córtex Pré-Frontal/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Alcoolismo/patologia , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático , Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo , Córtex Pré-Frontal/patologia , Ratos Wistar , Fatores de Tempo
11.
Alcohol Clin Exp Res ; 43(6): 1103-1112, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063677

RESUMO

BACKGROUND: Individuals differ in their sensitivity to alcohol's physiological effects, including blacking and passing out. Blackouts are periods of impaired memory formation when an individual engages in activities they later cannot recall, while passing out results in loss of consciousness. METHODS: The sample consisted of 3,292 adult twins from the Australian Twin Registry. Univariate twin analyses were conducted to examine the contributions of genetic and environmental influences to blacking and passing out occurrence and susceptibility (accounting for frequency of intoxication). Evidence for shared etiology of susceptibility to blacking and passing out was examined using bivariate twin analyses. RESULTS: Although blacking and passing out were strongly associated (odds ratio (OR) = 4.45, 95% confidence interval (CI): [3.85, 5.14]), the genetic epidemiology was quite different. Genetic (43%) and nonshared environmental (57%) influences contributed to liability for blackout occurrence. For passing out occurrence, there was evidence of sex differences. Among men, genetic (32%) and nonshared environmental (68%) influences contributed, whereas among women, there were shared (29%) and nonshared environmental (72%) influences. After accounting for frequency of intoxication, genetic influences on blackout susceptibility remained significant; in contrast, only nonshared environmental influences were significant for passing out susceptibility. There was evidence for overlapping genetic and nonshared environmental factors influencing susceptibility to blacking and passing out among men; among women, there were overlapping nonshared environmental influences. CONCLUSIONS: Blacking and passing out are 2 common sedative-like effects of heavy drinking, and people differ considerably in their susceptibility to these effects. This study suggests that differences in blackout susceptibility can be explained by genetic factors in both men and women, while differences in susceptibility to pass out after consuming alcohol may be attributable to environmental influences, particularly among women. These environmental factors may include changing social and cultural norms about alcohol use, drinking context, and the type(s) of alcohol consumed.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/genética , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Inconsciência/induzido quimicamente , Inconsciência/genética , Adulto , Transtornos do Sistema Nervoso Induzidos por Álcool/epidemiologia , Austrália/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Inconsciência/epidemiologia
12.
Prenat Diagn ; 39(8): 609-615, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31069822

RESUMO

OBJECTIVE: We have developed novel methods for isolating fetal central nervous system (CNS)-derived extracellular vesicles (FCEs) from maternal plasma as a non-invasive platform for testing aspects of fetal neurodevelopment in early pregnancy. We investigate the hypothesis that levels of defined sets of functional proteins in FCEs can be used to detect abnormalities in fetal neuronal and glial proliferation, differentiation, and survival. METHOD: Maternal plasma was obtained between 10 and 19 weeks from women with current heavy EtOH exposure and matched controls. FCE levels of synaptophysin, synaptotagmin, synaptopodin, and neurogranin were quantified normalized to the exosome marker CD81. Quantitative RT-PCR was performed with specific primers for miR-9. RESULTS: FCE cargo protein levels of synaptophysin, synaptotagmin, synaptopodin, and neurogranin were all significantly reduced in pregnancies exposed to current heavy EtOH use (P < .001 for all). Both synaptophysin and neurogranin appeared to be particularly discriminatory with no overlap between exposed and control subjects. Up to tenfold inhibition (90%) in MicroRNA-9 was observed in FCEs from EtOH exposed fetuses compared with controls. CONCLUSION: Our results suggest that FCEs purified from maternal plasma may be a powerful tool to assess abnormal proliferation and differentiation of CNS stem cells as early as the late first trimester. What's already known about this topic? Exosomes/extracellular vesicles (ECVs) are emerging as exciting novel biomarkers in neurologic disease (Alzheimers) What does this study add? Evidence that Fetal CNS ECVs can be isolated from maternal blood The origin of the ECVs appears to be the fetal brain and not the placenta Findings with ECVs correlates with fetal exposure to alcohol. Potential for first trimester prenatal diagnosis of fetal neurologic disease.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/congênito , Transtornos do Sistema Nervoso Induzidos por Álcool/diagnóstico , Doenças Fetais/diagnóstico , MicroRNAs/genética , Teste Pré-Natal não Invasivo/métodos , Adulto , Transtornos do Sistema Nervoso Induzidos por Álcool/genética , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Alcoolismo/sangue , Alcoolismo/diagnóstico , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/sangue , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Doenças Fetais/genética , Doenças Fetais/patologia , Feto/metabolismo , Feto/patologia , Humanos , MicroRNAs/análise , MicroRNAs/sangue , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/diagnóstico , Primeiro Trimestre da Gravidez/sangue , Cuidado Pré-Natal/métodos , Fumar/efeitos adversos , Fumar/sangue , Adulto Jovem
13.
Clin Liver Dis ; 23(1): 141-155, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454828

RESUMO

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Alcoolismo/fisiopatologia , Transtornos do Sistema Nervoso Induzidos por Álcool/etiologia , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/psicologia , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Síndrome Alcóolica de Korsakoff/etiologia , Síndrome Alcóolica de Korsakoff/metabolismo , Síndrome Alcóolica de Korsakoff/fisiopatologia , Síndrome Alcóolica de Korsakoff/psicologia , Neuropatia Alcoólica/etiologia , Neuropatia Alcoólica/metabolismo , Neuropatia Alcoólica/fisiopatologia , Alcoolismo/complicações , Alcoolismo/metabolismo , Alcoolismo/psicologia , Ataxia Cerebelar/etiologia , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/fisiopatologia , Humanos , Neurotransmissores/metabolismo
16.
Rev Epidemiol Sante Publique ; 65(6): 443-452, 2017 Nov.
Artigo em Francês | MEDLINE | ID: mdl-29110959

RESUMO

BACKGROUND: France has a complex system for the taxation of alcoholic beverages. In the French overseas territories (FOT), the system includes little-known specificities whose purpose is to preserve the sugar-cane-rum sector, a pillar for the weak economies in these territories. Taxes are reduced for traditional rums produced and sold locally. This favors the marketing of alcoholic spirits at low prices. In metropolitan France, on the contrary, spirits are heavily taxed drinks and their share in consumption is minor. Reunion Island (RI) is a FOT confronted with significant socioeconomic precariousness and with one of the highest national morbidity and mortality rates associated with alcohol abuse. Spirits account for half of the total consumption of pure alcohol, with a strong predominance for local traditional rums. These products are preferentially consumed by vulnerable subjects, often affected by an alcohol-use disorder. METHODS: This study consists of three parts. First, a comparative analysis of alcoholic beverage prices between RI and mainland France. Second, an analysis of the bibliography on the consequences of preferential consumption of spirits. Third, a literature review on the impact of taxation on alcohol-related morbidity and mortality. RESULTS: In France, the cheapest gram of pure alcohol is found in the FOT. The preferential consumption of spirits is associated with more frequent and more rapid complications. It is correlated with the level of alcoholic psychoses. Taxation is effective in reducing damage caused by the abuse of alcoholic beverages. The World Health Organization recommends the application of a minimum price for alcohol and tax increases. CONCLUSION: The reduced taxation of the traditional rums of the FOT does not take into account public health data. Its purpose is economic. In RI, it contributes to a high level of consumption of spirits and encourages excess mortality through alcohol abuse. It constitutes an inequality of health for these populations. Changes in this tax system is desirable in order to reduce the harm caused by alcohol. It should be closer to the tax system in force in metropolitan France. Alcohol lobbies and lack of political courage have so far inhibited this change to the detriment of the health of the populations.


Assuntos
Bebidas Alcoólicas , Comércio , Cultura , Saúde Pública , Impostos , Consumo de Bebidas Alcoólicas/economia , Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos do Sistema Nervoso Induzidos por Álcool/epidemiologia , Bebidas Alcoólicas/efeitos adversos , Bebidas Alcoólicas/economia , Bebidas Alcoólicas/estatística & dados numéricos , Comércio/estatística & dados numéricos , França/epidemiologia , Humanos , Morbidade , Mortalidade , Psicoses Induzidas por Substâncias/economia , Psicoses Induzidas por Substâncias/epidemiologia , Saúde Pública/economia , Saúde Pública/normas , Saúde Pública/estatística & dados numéricos , Reunião/epidemiologia , Impostos/estatística & dados numéricos
17.
Free Radic Biol Med ; 108: 692-703, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450149

RESUMO

Alcohol hangover (AH) is the pathophysiological state after a binge-like drinking. We have previously demonstrated that AH induced bioenergetics impairments in a total fresh mitochondrial fraction in brain cortex and cerebellum. The aim of this work was to determine free radical production and antioxidant systems in non-synaptic mitochondria and synaptosomes in control and hangover animals. Superoxide production was not modified in non-synaptic mitochondria while a 17.5% increase was observed in synaptosomes. A similar response was observed for cardiolipin content as no changes were evidenced in non-synaptic mitochondria while a 55% decrease in cardiolipin content was found in synaptosomes. Hydrogen peroxide production was 3-fold increased in non-synaptic mitochondria and 4-fold increased in synaptosomes. In the presence of deprenyl, synaptosomal H2O2 production was 67% decreased in the AH condition. Hydrogen peroxide generation was not affected by deprenyl addition in non-synaptic mitochondria from AH mice. MAO activity was 57% increased in non-synaptic mitochondria and 3-fold increased in synaptosomes. Catalase activity was 40% and 50% decreased in non-synaptic mitochondria and synaptosomes, respectively. Superoxide dismutase was 60% decreased in non-synaptic mitochondria and 80% increased in synaptosomal fractions. On the other hand, GSH (glutathione) content was 43% and 17% decreased in synaptosomes and cytosol. GSH-related enzymes were mostly affected in synaptosomes fractions by AH condition. Acetylcholinesterase activity in synaptosomes was 11% increased due to AH. The present work reveals that AH provokes an imbalance in the cellular redox homeostasis mainly affecting mitochondria present in synaptic terminals.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Córtex Cerebral/patologia , Radicais Livres/metabolismo , Mitocôndrias/metabolismo , Terminações Pré-Sinápticas/metabolismo , Acetilcolinesterase/metabolismo , Animais , Cardiolipinas/metabolismo , Metabolismo Energético , Etanol/toxicidade , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Oxirredução , Terminações Pré-Sinápticas/patologia , Superóxidos/metabolismo , Sinaptossomos/metabolismo
19.
Nutr Neurosci ; 20(9): 547-554, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27367870

RESUMO

OBJECTIVES: Ethanol consumption induces neurological disorders including cognitive dysfunction. Oxidative damage is considered a likely cause of cognitive deficits. We aimed to investigate the effects of rosmarinic acid (RA) in different doses for 30 days on chronic ethanol-induced cognitive dysfunction using the passive avoidance learning (PAL) and memory task in comparison with donepezil, a reference drug. We also evaluated the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation in hippocampus as possible mechanisms. METHODS: Memory impairment was induced by 15% w/v ethanol (2 g/kg, i.g.) administration for 30 days. RA (8, 16, and 32 mg/kg, i.g.) or donepezil (2 mg/kg, i.g.) was administered 30 minutes before ethanol. The acquisition trial was done 1 hour after the last administration of RA and donepezil. At the end, animals were weighed and hippocami were isolated for analyzing of oxidant/antioxidant markers. RESULTS: Ethanol caused cognition deficits in the PAL and memory task. While RA 16 and 32 mg/kg improved cognition in control rats, it prevented learning and memory deficits of alcoholic groups. RA 8 mg/kg did not influence cognitive function in both control and alcoholic rats. RA 32 mg/kg had comparable effects with donepezil in prevention of acquisition and retention memory impairment. The higher doses of RA not only prevented increased lipid peroxidation and nitrite content but also decreased SOD, CAT, GSH, and FRAP levels in alcoholic groups and exerted antioxidant effects in non-alcoholic rats. DISCUSSION: We showed that RA administration dose-dependently prevented cognitive impairment induced by chronic ethanol in PAL and memory and disturbed oxidant/antioxidant status as a possible mechanism. The antioxidant, anticholinesterase, and neuroprotective properties of RA may be involved in the observed effects. Therefore, RA represents a potential therapeutic option against chronic ethanol-induced amnesia which deserves consideration and further examination.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/prevenção & controle , Antioxidantes/uso terapêutico , Cinamatos/uso terapêutico , Depsídeos/uso terapêutico , Suplementos Nutricionais , Deficiências da Aprendizagem/prevenção & controle , Transtornos da Memória/prevenção & controle , Nootrópicos/uso terapêutico , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Animais , Antioxidantes/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/uso terapêutico , Cinamatos/administração & dosagem , Depsídeos/administração & dosagem , Donepezila , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Indanos/uso terapêutico , Deficiências da Aprendizagem/etiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/uso terapêutico , Distribuição Aleatória , Ratos Wistar
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