ABSTRACT
Psychische en neurologische stoornissen en aandoeningen veroorzaakt door middelengebruik (MNS-aandoeningen) komen veel voor en veroorzaken over de hele wereld een grote ziektelast en invaliditeit. Om de kloof tussen de beschikbare middelen en de grote vraag naar hulpverlening te overbruggen, heeft de Wereldgezondheidsorganisatie het Actieprogramma voor de Geestelijke Gezondheid (mhGAP) gelanceerd. Het doel van mhGAP is om zorg en diensten op te schalen met behulp van evidence-based interventies voor de preventie en behandeling van prioritaire MNS-aandoeningen. De mhGAP-interventiegids versie 1.0 voor MNS-aandoeningen voor niet-gespecialiseerde zorginstellingen werd in 2010 ontwikkeld als een eenvoudig technisch hulpmiddel om de geïntegreerde behandeling van prioritaire MNS-aandoeningen mogelijk te maken met behulp van protocollen voor klinische besluitvorming. De mhGAP-IG 1.0-versie wordt gebruikt in meer dan 90 landen en is een groot succes. Het is een genoegen om de mhGAP versie 2.0 te presenteren, met nieuwe informatie over begeleiding gebaseerd op bewijzen, verbeterde bruikbaarheid en nieuwe onderdelen die door zowel zorgverleners als programmamanagers kunnen worden gebruikt voor een nog groter bereik. We hopen dat deze gids een richtlijn zal blijven bieden voor het leveren van zorg en diensten aan mensen met MNS-stoornissen over de hele wereld en dat dit ons een stap dichterbij ons doel van universele gezondheidsdekking brengt.
Subject(s)
Mental Disorders , Mental Health , Nervous System Diseases , Psychotic Disorders , Alcohol-Induced Disorders, Nervous System , Health Planning GuidelinesABSTRACT
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.
Subject(s)
Central Nervous System Depressants/toxicity , Ethanol/toxicity , Hippocampus/drug effects , Neuroprotective Agents/pharmacology , Simvastatin/pharmacology , Alcohol-Induced Disorders, Nervous System/pathology , Animals , Animals, Newborn , Apoptosis/drug effects , Gliosis/chemically induced , Hippocampus/pathology , Male , Memory Disorders/chemically induced , Rats , Rats, Wistar , Spatial Memory/drug effectsABSTRACT
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.
Subject(s)
Alcoholic Korsakoff Syndrome/psychology , Alcoholism/rehabilitation , Cognitive Dysfunction/psychology , Adult , Aged , Aged, 80 and over , Alcohol-Induced Disorders, Nervous System/physiopathology , Alcohol-Induced Disorders, Nervous System/psychology , Alcoholic Korsakoff Syndrome/physiopathology , Alcoholism/physiopathology , Alcoholism/psychology , Cognitive Dysfunction/physiopathology , Executive Function , Female , Hospitalization , Humans , Male , Memory , Mental Status and Dementia Tests , Middle Aged , Neurocognitive Disorders/physiopathology , Neurocognitive Disorders/psychologyABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/physiopathology , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Motor Activity/physiology , Psychomotor Performance/physiology , Age Factors , Animals , Animals, Newborn , Behavior, Animal/physiology , Central Nervous System Depressants/administration & dosage , Disease Models, Animal , Ethanol/administration & dosage , Female , Male , Mice , Mice, Transgenic , Vesicular Inhibitory Amino Acid Transport ProteinsABSTRACT
No disponible
Subject(s)
Humans , Male , Middle Aged , Alcoholism/psychology , Alcoholism/complications , Gastrostomy/psychology , Alcohol-Induced Disorders, Nervous System/diagnosis , Diagnosis, Differential , Risk FactorsABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/metabolism , Cannabinoid Receptor Antagonists/pharmacology , Central Nervous System Depressants/toxicity , Ethanol/toxicity , Hippocampus/drug effects , Neuroprotective Agents/pharmacology , Pyroptosis/drug effects , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Cannabinoid Receptor Agonists/pharmacology , Caspase 1/drug effects , Caspase 1/metabolism , Caspase Inhibitors/pharmacology , Dipeptides/pharmacology , Inflammation , Interleukin-18/metabolism , Interleukin-1beta/drug effects , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Morpholines/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neurotoxicity Syndromes , Phosphate-Binding Proteins/drug effects , Phosphate-Binding Proteins/metabolism , Piperidines/pharmacology , Pyrazoles/pharmacology , para-Aminobenzoates/pharmacologyABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/metabolism , Cerebellar Ataxia/metabolism , Ethanol/adverse effects , Nitric Oxide Synthase Type I/metabolism , Psychomotor Disorders/metabolism , Alcohol-Induced Disorders, Nervous System/chemically induced , Animals , Arginine/pharmacology , Cerebellar Ataxia/chemically induced , Cerebellum/drug effects , Cerebellum/metabolism , Enzyme Inhibitors/pharmacology , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Indazoles/pharmacology , Male , Nitric Oxide Synthase Type I/antagonists & inhibitors , Psychomotor Disorders/chemically induced , Rats, Sprague-DawleyABSTRACT
Objetivo: Describir los patrones de consumo de alcohol y de episodios de consumo intensivo (ECI) en una muestra de estudiantes de Ciencias de la Salud, así como identificar factores asociados. Método: Estudio descriptivo que mediante cuestionario autoadministrado recoge variables sociodemográficas y el diario consumo de alcohol, registrando el número de unidades de bebida estándar consumidas en varios momentos del día. Resultados: Participaron 286 estudiantes (66,1% mujeres) pertenecientes a la Universidad de Cádiz (193 Medicina y 93 Enfermería), con una edad media de 21,1 años (DE 2,8). El 44,8% vive en domicilio familiar. El 65,7% consumió alcohol en la última semana, siendo más frecuente en varones. El patrón de consumo semanal fue del 74,5% para consumo de riesgo bajo, 21% riesgo moderado y 4,5% riesgo elevado. Un 33,9% tuvo entre 1-2 ECI en la última semana, apareciendo estos independientemente del patrón de consumo semanal. De los alumnos que residen fuera del domicilio familiar, un 26,6% tuvieron un consumo de riesgo moderado, un 8,2% riesgo elevado y un 41,8% ECI. Se evidencian asociaciones estadísticamente significativas entre el consumo semanal de alcohol y las variables sexo, domicilio habitual y ECI. Conclusiones: Más de la mitad de los estudiantes consumió alcohol en la última semana, con un consumo mayoritariamente de fin de semana, destacando la alta prevalencia de ECI. Se propone incidir en la detección precoz y campañas en estos grupos
Aim: To describe the alcohol drinking patterns and binge drinking episodes (BDE) in a sample of Health Science students, as well as identify associated factors. Method: It is a descriptive study, in which sociodemographic variables and a weekly alcohol consumption diary recording the number of standard drinking units consumed at different times of the day are collected by means of a self-administered questionnaire. Results: 286 students (66.1% women) from Cadiz University (193 Medical students and 93 Nursing students), with a mean age of 21.1 (SD 2.8) years, took part in this study. Forty-four point 8 percent of the students live with their families. Sixty-five point 7 percent of the students drank alcohol in the previous week, this was more usual in the males. The weekly alcohol consumption pattern was 74.5% for low-risk alcohol consumption, 21% for moderate-risk and 4.5% for a high-risk consumption. Thirty-three point 9 percent had 1-2 BDE over the previous week apart from their weekly consumption pattern. Twenty-six point 6 percent of the students who were emancipated had moderate-risk consumption, 8.2% had a high-risk consumption and 41.8% had a binge drinking episode. There were statistically significant associations between the weekly consumption pattern regarding sex, habitual residence and BDE variables. Conclusions: More than half the students had taken alcohol the previous week, mainly at weekends. The high prevalence of BDE is highlighted. We propose enhancing early detection and prevention campaigns in this population
Subject(s)
Humans , Male , Female , Young Adult , Adult , Alcoholism/epidemiology , Risk Factors , Students, Health Occupations/statistics & numerical data , Alcohol-Induced Disorders, Nervous System/epidemiology , Surveys and Questionnaires , Alcohol-Induced Disorders, Nervous System/prevention & control , Risk-TakingABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/prevention & control , Behavior, Animal/drug effects , Conditioning, Psychological/drug effects , Ethanol/toxicity , Hippocampus/drug effects , Intercellular Signaling Peptides and Proteins/metabolism , Lacosamide/pharmacology , Nerve Tissue Proteins/metabolism , Alcohol-Induced Disorders, Nervous System/metabolism , Animals , Hippocampus/metabolism , Male , Maze Learning/drug effects , Mice , Motor Activity/drug effects , SwimmingABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/therapy , Inflammation/therapy , Mesenchymal Stem Cell Transplantation , Tobacco Use Disorder/therapy , Administration, Intranasal , Alcohol-Induced Disorders, Nervous System/pathology , Alcohol-Induced Disorders, Nervous System/prevention & control , Alcohols/adverse effects , Animals , Brain/drug effects , Brain/pathology , Humans , Inflammation/pathology , Inflammation/prevention & control , Male , Mesenchymal Stem Cells/metabolism , Nerve Tissue/pathology , Nerve Tissue/transplantation , Nicotine/adverse effects , Oxidative Stress/genetics , Rats , Self Administration , Tobacco Use Disorder/pathology , Tobacco Use Disorder/prevention & controlABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/drug therapy , Antioxidants/pharmacology , Apoptosis/drug effects , Aralia/chemistry , Brain/metabolism , Neurons/metabolism , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Acetates/chemistry , Alcohol-Induced Disorders, Nervous System/metabolism , Alcohol-Induced Disorders, Nervous System/pathology , Animals , Antioxidants/chemistry , Brain/pathology , Cell Line , Chronic Disease , Male , Maze Learning/drug effects , Memory/drug effects , Mice , Neurons/pathology , Neuroprotective Agents/chemistry , Plant Extracts/chemistry , Reactive Oxygen Species/metabolismABSTRACT
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¯0.3â¯g/kg/day), or control (dextrose)⯱â¯veliparib (25â¯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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/prevention & control , Benzimidazoles/therapeutic use , Nerve Tissue Proteins/biosynthesis , Phospholipases A2, Cytosolic/biosynthesis , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Alcohol-Induced Disorders, Nervous System/drug therapy , Alcohol-Induced Disorders, Nervous System/enzymology , Animals , Benzimidazoles/pharmacology , Binge Drinking , Dentate Gyrus/drug effects , Dentate Gyrus/enzymology , Dentate Gyrus/pathology , Disease Models, Animal , Entorhinal Cortex/drug effects , Entorhinal Cortex/enzymology , Entorhinal Cortex/pathology , Enzyme Induction/drug effects , Male , Nerve Tissue Proteins/genetics , Phospholipases A2, Cytosolic/genetics , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/metabolism , Alcoholism/metabolism , Corpus Striatum/metabolism , Lipid Metabolism , Metabolomics/methods , Prefrontal Cortex/metabolism , Spectrometry, Mass, Electrospray Ionization , Alcohol-Induced Disorders, Nervous System/pathology , Alcoholism/pathology , Animals , Corpus Striatum/pathology , Disease Models, Animal , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Endoplasmic Reticulum Stress , Fatty Acids/metabolism , Glycerophospholipids/metabolism , Prefrontal Cortex/pathology , Rats, Wistar , Time FactorsABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/congenital , Alcohol-Induced Disorders, Nervous System/diagnosis , Fetal Diseases/diagnosis , MicroRNAs/genetics , Noninvasive Prenatal Testing/methods , Adult , Alcohol-Induced Disorders, Nervous System/genetics , Alcohol-Induced Disorders, Nervous System/pathology , Alcoholism/blood , Alcoholism/diagnosis , Biomarkers/analysis , Biomarkers/blood , Case-Control Studies , Circulating MicroRNA/blood , Extracellular Vesicles/genetics , Extracellular Vesicles/metabolism , Female , Fetal Diseases/genetics , Fetal Diseases/pathology , Fetus/metabolism , Fetus/pathology , Humans , MicroRNAs/analysis , MicroRNAs/blood , Nervous System/metabolism , Nervous System/pathology , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Pregnancy Trimester, First/blood , Prenatal Care/methods , Smoking/adverse effects , Smoking/blood , Young AdultABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/genetics , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Unconsciousness/chemically induced , Unconsciousness/genetics , Adult , Alcohol-Induced Disorders, Nervous System/epidemiology , Australia/epidemiology , Female , Genetic Predisposition to Disease , Humans , Male , Unconsciousness/epidemiologyABSTRACT
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.
Subject(s)
Alcohol-Induced Disorders, Nervous System/physiopathology , Alcoholism/physiopathology , Alcohol-Induced Disorders, Nervous System/etiology , Alcohol-Induced Disorders, Nervous System/metabolism , Alcohol-Induced Disorders, Nervous System/psychology , Alcohol-Related Disorders/metabolism , Alcohol-Related Disorders/physiopathology , Alcohol-Related Disorders/psychology , Alcoholic Korsakoff Syndrome/etiology , Alcoholic Korsakoff Syndrome/metabolism , Alcoholic Korsakoff Syndrome/physiopathology , Alcoholic Korsakoff Syndrome/psychology , Alcoholic Neuropathy/etiology , Alcoholic Neuropathy/metabolism , Alcoholic Neuropathy/physiopathology , Alcoholism/complications , Alcoholism/metabolism , Alcoholism/psychology , Cerebellar Ataxia/etiology , Cerebellar Ataxia/metabolism , Cerebellar Ataxia/physiopathology , Humans , Neurotransmitter Agents/metabolismSubject(s)
Alcohol-Induced Disorders, Nervous System/physiopathology , Brain Ischemia/physiopathology , Epilepsy/physiopathology , Aged , Alcohol-Induced Disorders, Nervous System/complications , Alcohol-Induced Disorders, Nervous System/diagnostic imaging , Alcohol-Induced Disorders, Nervous System/metabolism , Brain Ischemia/diagnostic imaging , Brain Ischemia/etiology , Brain Ischemia/metabolism , Electroencephalography , Epilepsy/diagnostic imaging , Epilepsy/etiology , Epilepsy/metabolism , Female , Humans , Positron-Emission Tomography , Tomography, Emission-Computed, Single-PhotonABSTRACT
Los trastornos por uso de alcohol son preocupantemente altos en la población universitaria. Contar con instrumentos de tamizaje es fundamental para la medición epidemiológica y la práctica clínica. El objetivo de este trabajo es comparar el desempeño de los instrumentos de tamizaje más usados a nivel internacional (AUDIT, AUDIT-C, TWEAK, RAPS-QF y CAGE) en estudiantes universitarios de Argentina. Los instrumentos de tamizaje, junto a la Entrevista Diagnóstica Compuesta Internacional, que permite obtener diagnósticos compatibles con el DSM 5, fueron administrados a una muestra probabilística (N = 2,430) de estudiantes de una universidad pública nacional. Entre otros, se evaluaron los puntos de corte óptimos, la sensibilidad, la especificidad, la consistencia interna y la estabilidad temporal, así como la presencia y la capacidad de discriminación de los ítems. La apreciación global de los resultados sugiere que tanto el AUDIT como el RAPS-QF serían los instrumentos preferibles para detectar la presencia de trastorno por uso de alcohol en esta población
The prevalence of alcohol use disorders in university students is alarmingly high. Screening instruments are fundamental for both, epidemiological research and clinical practice. The aim of this article is to compare the performance of the most widely used screening instruments (AUDIT, AUDIT-C, TWEAK, RAPS-QF, and CAGE) in Argentinean university students. Screening tests, along with the Alcohol Section of the Composite International Diagnostic Interview that yields DSM 5 compatible diagnoses were administered to a probabilistic sample (N = 2,430) of university students from a national public university. The following characteristics were evaluated among others: optimal cut-off points, sensitivity, specificity, internal consistency, temporal stability, and item presence and discrimination capacity. The global appraisal of results suggests that the AUDIT and RAPS-QF would be preferable for evaluating AUD in this population