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/metabolismoRESUMO
Opioid peptides play a key role in ethanol reinforcement and alcohol drinking behavior. However, regulation of opioid levels by peptidase-degrading activities in ethanol's actions in brain is still unclear. The aim of this work was to study the acute effects of ethanol (2.5 g/kg) on enkephalinase (NEP) and aminopeptidase N (APN) activities and expression in regions of the mesocorticolimbic system, as well as on corticosterone levels in serum for up to 24 h after administration. Enzymatic activities were measured by fluorometric assays, mRNA's expression by reverse transcriptase polymerase chain reaction (RT-PCR) and corticosterone levels by radioimmunoassay. Acute ethanol administration modified peptidase activity and expression with different kinetics. Ethanol induced a transitory increase and decrease in NEP and APN activities in the frontal cortex (FC) and ventral tegmental area (VTA), whereas only increases in these activities were observed in the nucleus accumbens (NAcc). Ethanol induced an increase in NEP mRNA in the FC and decreases in APN mRNA in the FC and NAcc. In contrast, ethanol produced biphasic effects on both enzymes expression in the VTA. Corticosterone levels were not changed by ethanol. Our results suggest that NEP and APN could play a main role in ethanol reinforcement through regulation of opioid levels in mesolimbic areas.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Antígenos CD13/genética , Etanol/toxicidade , Sistema Límbico/enzimologia , Neprilisina/genética , Área Tegmentar Ventral/enzimologia , Doença Aguda , Animais , Antígenos CD13/biossíntese , Sistema Límbico/efeitos dos fármacos , Masculino , Neprilisina/biossíntese , Ratos , Ratos Wistar , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Ethanol (EtOH) is a drug widely consumed throughout the world that promotes several neurochemical disorders. Its deleterious effects are generally associated with modifications in oxidative stress parameters, signaling transduction pathways, and neurotransmitter systems, leading to distinct behavioral changes. Taurine (2-aminoethanesulfonic acid) is a ß-amino acid not incorporated into proteins found in mM range in the central nervous system (CNS). The actions of taurine as an inhibitory neurotransmitter, neuromodulator, and antioxidant make it attractive for studying a potential protective role against EtOH-mediated neurotoxicity. In this study, we investigated whether acute taurine cotreatment or pretreatment (1 h) prevent EtOH-induced changes in acetylcholinesterase (AChE) activity and in oxidative stress parameters in zebrafish brain. The results showed that EtOH exposure (1% in volume) during 1 h increased AChE activity, whereas the cotreatment with 400 mg·L(-1) taurine prevented this enhancement. A similar protective effect of 150 and 400 mg·L(-1) taurine was also observed when the animals were pretreated with this amino acid. Taurine treatments also prevented the alterations promoted in superoxide dismutase and catalase activities by EtOH, suggesting a modulatory role in enzymatic antioxidant defenses. The pretreatment with 150 and 400 mg·L(-1) taurine significantly increased the sulfydryl levels as compared to control and EtOH groups. Moreover, 150 and 400 mg·L(-1) taurine significantly decreased thiobarbituric acid reactive species (TBARS) levels, but the cotreatment with EtOH plus 400 mg·L(-1) taurine did not prevent the EtOH-induced lipoperoxidation. In contrast, the pretreatment with 150 and 400 mg·L(-1) taurine prevented the TBARS increase besides decreased the basal levels of lipid peroxides. Altogether, our data showed for the first time that EtOH induced oxidative stress in adult zebrafish brain and reinforce the idea that this vertebrate is an attractive alternative model to evaluate the beneficial effect of taurine against acute EtOH exposure.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Transtornos do Sistema Nervoso Induzidos por Álcool/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Taurina/farmacologia , Acetilcolinesterase/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/enzimologia , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/fisiologia , Especificidade da Espécie , Taurina/metabolismo , Peixe-ZebraRESUMO
Alcohol intake during pregnancy has a tremendous impact on the developing brain. Embryonic and early postnatal alcohol exposures have been investigated experimentally to elucidate the fetal alcohol spectrum disorders' (FASD) milieu, and new data have emerged to support a devastating effect on the GABAergic system in the adult and developing nervous system. GABA is a predominantly inhibitory neurotransmitter that during development excites neurons and orchestrates several developmental processes such as proliferation, migration, differentiation, and synaptogenesis. This review summarizes and brings new data on neurodevelopmental aspects of the GABAergic system with FASD in experimental telencephalic models.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Etanol/toxicidade , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Telencéfalo/efeitos dos fármacos , Telencéfalo/embriologia , Ácido gama-Aminobutírico/efeitos dos fármacos , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/patologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Depressores do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Feminino , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/embriologia , Vias Neurais/crescimento & desenvolvimento , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Telencéfalo/crescimento & desenvolvimento , Ácido gama-Aminobutírico/metabolismoRESUMO
The purpose of this study was to further address the hypothesis that ethanol activates GABAergic neurons in specific brain neurocircuits that mediate motivated behavior and control of action, such as the central extended amygdala and medial prefrontal cortex. Male Sprague-Dawley rats received habituation to 7 days of daily intragastric administration of water (5 ml/kg) followed by a single acute intragastric dose of ethanol (2.5 g/kg) or water then, 2 h later, by paraformaldehyde perfusion. Rats left undisturbed in the animal room throughout the experiment were also perfused (naive group). Brain sections were processed for single Fos immunohistochemistry or dual Fos immunohistochemistry/glutamic acid decarboxylase (GAD) mRNA in situ hybridization. Intragastric water administration increased the number of Fos-immunoreactive cells in the infralimbic cortex and lateral part of the central nucleus of the amygdala compared with the naive group. Ethanol administration increased the number of Fos-immunoreactive cells in the infralimbic (+57.5%) and prelimbic (+105.3%) cortices, nucleus accumbens shell region (+88.2%), medial part of the central nucleus of the amygdala (+160%), and lateral part of the bed nucleus of the stria terminalis (+198.8%) compared with the water-treated group. In the nucleus accumbens shell region, central nucleus of the amygdala, and bed nucleus of the stria terminalis, more than 80% of Fos-immunoreactive neurons were GABAergic after ethanol administration. In contrast, in the prelimbic cortex, 75% of Fos-immunoreactive neurons were not GABAergic. These results constitute new evidence for region-specific functional interactions between ethanol and GABAergic neurons.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Etanol/farmacologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Contagem de Células , Depressores do Sistema Nervoso Central/farmacologia , Esquema de Medicação , Glutamato Descarboxilase/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. Ethanol (EtOH) was added to cultures, either alone or in combination with 30 ng/ml GDNF. Exposure to EtOH (86 and 172 mM; 60 and 120 min) increased the frequency of apoptotic cells identified by nuclear DNA staining with 4,6-diamidino-2-phenylindole (DAPI). Cultures treated with GDNF showed a decrease in ethanol-induced apoptosis. A jun N-terminal kinase (JNK) pathway is activated by EtOH and their pharmacological inhibition (by SP600125) neutralized ethanol-induced apoptosis, suggesting a role for JNK in EtOH neurotoxicity. Immunocytochemically detected phospho-JNK (p-JNK) showed an unusual filamental expression, and localized together with actin stress fibers. Examination of the cytoskeleton showed that EtOH depolymerized actin filaments, inducing p-JNK dissociation and translocation to the nucleus, which suggests that released p-JNK may contribute to glial cell death after EtOH exposure. Treatment with GDNF, in turn, may neutralize the ethanol-induced cell death pathway. Either a phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor (LY294002) or an inhibitor of the extracellular signal-regulated kinase (ERK) 1, 2 pathways (UO126) failed to neutralize GDNF protective effects. However, the simultaneous use of both inhibitors blocked the protective effect of GDNF, suggesting a role for both signaling cascades in the GDNF protection. These findings provide further insight into the mechanism involved in ethanol-induced apoptosis and the neurotrophic protection of glial cells.