Alcohol-induced Brain Research Articles

To study impact of drug abuse in adolescence

Adolescent drug usage can lead to a variety of outcomes that are different from those associated with adult drug use. Alcohol is a common illicit substance in youth, and the molecular mechanisms behind alcohol-induced neuro inflammation, brain injury, and behavioural dysfunction caused by ethanol are not fully understood. In the adult brain, alcoholism is associated with a higher chance of neuropsychiatric diseases. Adolescent alcohol use can cause long-lasting modifications to the control of cytokines and the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis, which can impact neuropathology and behaviour long into adulthood... Synthetic androgens used for muscle and strength gain, especially in adolescence, are called alcoholic androgenic steroids (AAS). Adult neuropathology and alcoholism can be prevented and treated using AAS, an anabolic steroid.

Polysaccharides from Eucommia ulmoides Oliv. leaves alleviates alcohol-induced mouse brain injury and BV-2 microglial dysfunction

Acute alcohol intoxication is a harmful clinical condition characterized by behavioral and neurological symptoms, for which few effective therapies are available at present. Dysfunction of microglial BV-2 cells has been reported to be associated with acute alcohol-induced brain injuries. In the present study, the protective effects of Eucommia ulmoides Oliv. leaves polysaccharides (EULP) on acute alcoholic brain injury and microglial dysfunction were investigated. 14-day pretreatment of EULP significantly attenuated neurobehavioral deficit and neurotransmitter damage in the brain tissue of mice caused by acute alcohol exposure. Additionally, EULP regulated the metabolic disorder of brain tissue. Consistently, it was shown that EULP pretreatment significantly improved alcohol-induced phagocytosis decrease, oxidative stress and inflammation in BV-2 cells. Therefore, EULP may be proposed and employed as a potential therapeutic agent for alcohol-induced brain damage.

Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury.

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in Aldh2-KO mice compared to corresponding WT mice. Alcohol-exposed Aldh2-KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut-brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury.

Current trends in the role of neuroinflammation & α-synuclein in alcohol use disorder: A systematic quantitative literature review.

The neurodegenerative effects alcohol use disorder (AUD) have been well characterized and are likely due to the long-term effects of alcohol on the brain. The molecular events that underlie regional neuronal loss are a focus of current research. Chronic inflammation in the central nervous system, termed neuroinflammation, contributes to the progressive loss of neurons in the brain. Using data from genome-wide association studies and genetic and gene expression data, α-synuclein was identified as a gene of interest for AUD almost 10 years ago. Despite this and the well-recognized role of α-synuclein in mediating neuroinflammation in other neurodegenerative diseases, its role in alcohol-induced brain damage and AUD is yet to be elucidated. This systematic literature review quantifies and analyzes relationships between AUD, α-synuclein, and neuroinflammation. The review identified fewer studies focused on the role in AUD of α-synuclein (30) than on neuroinflammation (177), with published studies heavily centered on the myeloid differentiation primary response 88 (MyD88)-dependent toll-like receptor 4 (TLR4) pathway. The systematic review revealed that no original literature investigates the roles of α-synuclein and neuroinflammation in AUD and that there are significantly fewer published articles on the role of α-synuclein in AUD than in other neuroinflammatory conditions. Studies of the role of neuroinflammation in AUD are largely centered on the TLR4 signaling cascade, followed by TLR2 and TLR3, and soluble cytokines such as IL-10, IL-1β, and TNF-α. Key research themes identified in other neurodegenerative disorders provide new insights for further investigation in AUD.

Therapeutic potential of Lingjiao Gouteng decoction in acute alcohol intoxication and alcohol-induced brain injury involving the RhoA/ROCK2/NF-κB signaling pathway

Ethnopharmacological relevanceAlcohol misuse persists as a prevalent societal concern and precipitates diverse deleterious consequences, entailing significant associated health hazards including acute alcohol intoxication (AAI). Binge drinking, a commonplace pattern of alcohol consumption, may incite neurodegeneration and neuronal dysfunction. Clinicians tasked with managing AAI confront a dearth of pharmaceutical intervention alternatives. In contrast, natural products have garnered interest due to their compatibility with the human body and fewer side effects. Lingjiao Gouteng decoction (LGD), a classical traditional Chinese medicine decoction, represents a frequently employed prescription in cases of encephalopathy, although its efficacy in addressing acute alcoholism and alcohol-induced brain injury remains inadequately investigated. Aim of the studyTo investigate the conceivable therapeutic benefits of LGD in AAI and alcohol-induced brain injury, while delving into the underlying fundamental mechanisms involved. Materials and methodsWe established an AAI mouse model through alcohol gavage, and LGD was administered to the mice twice at the 2 h preceding and 30 min subsequent to alcohol exposure. The study encompassed the utilization of the loss of righting reflex assay, histopathological analysis, enzyme-linked immunosorbent assays, and cerebral tissue biochemical assays to investigate the impact of LGD on AAI and alcohol-induced brain injury. These assessments included a comprehensive evaluation of various biomarkers associated with the inflammatory response and oxidative stress. Finally, RT-qPCR, Western blot, and immunofluorescence staining were carried out to explore the underlying mechanisms through which LGD exerts its therapeutic influence, potentially through the regulation of the RhoA/ROCK2/NF-κB signaling pathway. ResultsOur investigation underscores the therapeutic efficacy of LGD in ameliorating AAI, as evidenced by discernible alterations in the loss of righting reflex assay, pathological analysis, and assessment of inflammatory and oxidative stress biomarkers. Furthermore, the results of RT-qPCR, Western blot, and immunofluorescence staining manifest a noteworthy regulatory effect of LGD on the RhoA/ROCK2/NF-κB signaling pathway. ConclusionsThe present study confirmed the therapeutic potential of LGD in AAI and alcohol-induced brain injury, and the protective effects of LGD against alcohol-induced brain injury may be intricately linked to the RhoA/ROCK2/NF-κB signaling pathway.

Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes.

Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.

Huangqi Gegen decoction ameliorates alcohol-induced cognitive dysfunction via attenuating oxidative stress and enhancing blood-brain barrier integrity in rats through the Keap1-Nrf2/HO-1 signaling pathway.

Chronic alcohol abuse causes cognitive deficits. Huangqi Gegen Decoction (HGD), a traditional Chinese herbal formula comprising Huangqi and Gegen, has been documented for its therapeutic efficacy in the treatment of alcoholic liver injury. However, its potential neuroprotective effects against alcohol-induced brain injury remain unexplored. This study aims to evaluate the neuroprotection of HGD on alcohol-induced cognitive dysfunction and the associated mechanism. Wistar rats were orally administered 50% ethanol for 10 weeks, followed by treatment with HGD at doses of 16, 32, or 64 mg/kg/day for an additional 6 weeks. The spatial learning and memory abilities of rats were assessed through the Morris Water Maze experiment. The pathological condition in the hippocampus was assessed using H&E and Nissl staining. Tight junction proteins, oxidative stress, and inflammation cytokines were measured by IF, ELISA, PCR, and western blot. The mRNA and protein expression of Keap1, Nrf-2, HO-1, and NQO-1 were tested by PCR and western blot. Results showed that HGD effectively mitigated cognitive dysfunction and pathological changes in alcohol-induced rats while enhancing the expression of ZO-1, Occludin, and Claudin-5. Furthermore, HGD effectively mitigated oxidative stress by reducing levels of ROS and MDA, while elevating levels of SOD, CAT, and GSH-PX in brain tissue. Moreover, HGD significantly suppressed microglial activation and down-regulated expressions of IL-1β, IL-6, and TNF-α. Mechanistically, HGD remarkably up-regulated the expression of Nrf-2, HO-1, and NQO-1 while down-regulating Keap1 expression. These findings suggest that HGD may be a promising therapeutic agent for alleviating alcohol-induced cognitive dysfunction.

Study on the correlation between prefrontal cortex thickness and alcohol addiction using magnetic resonance imaging in alcohol-dependent patients

Objective: To investigate the correlation between alcohol addiction and prefrontal cortex thickness using magnetic resonance imaging (MRI). Subject and method: Conducted at the Thai Nguyen National Hospital from 2020 to 2022, the cross-sectional study involved 70 alcohol-dependent individuals and 70 healthy counterparts. Participants, right-handed males, were categorized based on DSM-5 criteria diagnosed with alcoholism or no by a psychiatrist. MRI imaging, employing a Siemens 1.5 Tesla scanner, captured brain structural data. Statistical analysis included Student's t-test and multivariate linear regression models. Result: While age and intracranial volume showed no significant differences between healthy and addicted groups, BMI differed significantly. Dorsolateral prefrontal cortex thickness reductions were observed in various regions for the alcoholic group, with significant correlations (p<0.001). Age and intracranial volume emerged as predictors for specific regions. Conclusion: Alcohol addiction is associated with decreased gray matter thickness in the prefrontal cortex, emphasizing the role of age and intracranial volume in predicting these structural changes. The study underscores the need for further research to comprehensively understand the complexities of alcohol-induced brain damage.

Lipidomic changes of cerebral cortex in aldehyde dehydrogenase-2 knock-in heterozygote mice after chronic alcohol exposure.

Alcohol is the main legal drug in the world, and excessive consumption of alcohol seriously damages the morphological structure and function of various organs. The insufficiency of an essential enzyme in ethanol metabolism, aldehyde dehydrogenase-2 (ALDH2), will aggravate the alcohol-induced brain injury. The effect of ALDH2 after chronic alcohol exposure on global lipid profiling of the brain remains unclear. In this study, ALDH2*2 knock-in mice were fed the Lieber-DeCarli liquid diet containing ethanol for 8 weeks. Blood alcohol and acetaldehyde levels were examined, and the mice were tested through novel object recognition and the Y-maze test to evaluate cognitive impairment toward the end of the study. The lipidome profiling of cerebral cortex samples was investigated using a lipidomics method based on ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS). Compared with similarly treated wild-type (WT) mice, ALDH2*2 mice exhibited poor cognitive performance, though the result did not achieve statistical significance. The lipidomics results indicated that 74 differential lipid species were selected in WT mice, of which 57 species were up-regulated, and 17 were down-regulated. Moreover, 99 differential lipids were identified in ALDH2*2 mice, of which 73 were up-regulated, and 26 were down-regulated. For ALDH2*2 mice, the number of changed significantly glycerophospholipids (GPs) subtypes was lower than that of WT mice. Interestingly, compared with WT mice, a lower proportion of polyunsaturated fatty acids (PUFAs) was found in ALDH2*2 mice. Collectively, the results provide clear evidence for a lipidomic signature of marked changes in the cerebral cortex of ALDH2*2 mice after chronic alcohol exposure. • The cerebral cortex of heterozygous ALDH2*2 mice showed more significant changes in lipidome profiles after chronic alcohol exposure than wild-type mice.• Most lipids were significantly up-regulated in both groups of mice, whereas the increase in TAG was restricted to WT mice.• For ALDH2*2 mice, GPs substances changed significantly, and SHexCer and SM subclasses in sphingolipids also deserved attention.

КОГНИТИВНЫЕ РАССТРОЙСТВА, АССОЦИИРОВАННЫЕ С НАРУШЕНИЕМ ДЕТОКСИЦИРУЮЩЕЙ ФУНКЦИИ ПЕЧЕНИ, У БОЛЬНЫХ АЛКОГОЛЬНОЙ ЗАВИСИМОСТЬЮ, НОВЫЕ ПОДХОДЫ В ПЕРСОНАЛИЗИРОВАННОЙ ТЕРАПИИ

Introduction. The disruption of the detoxifying function of the liver, the direct toxic effects of alcohol and its metabolites, as the well as increased permeability of the blood-brain barrier lead to alcohol-induced brain damage. A complication of alcoholic liver disease is progressive cognitive dysfunction. Target. Assessment of impairments in the detoxification function of the liver and cognitive disorders in personalized therapy for patients with alcohol dependence. Materials and methods. The study included 30 men 41.5 years of age (32.3-53.0) with mental and behavioral disorders associated with alcohol use, impaired liver detoxification function, and cognitive disorders. To assess cognitive impairment, the following were used: Hamilton Anxiety Scale, Montreal Cognitive Assessment Scale (MoCA), obsessive-compulsive alcohol craving scale, and short-term and long-term memory assessment. Cognitive functions were examined upon admission and on days 10 and 18 of therapy. Biochemical blood parameters (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, indirect bilirubin, cholesterol, malondialdehyde, reduced glutathione) were studied before and after treatment. Results. Against the background of complex therapy, there was a decrease in craving for alcohol, assessed on the obsessive-compulsive scale from 36 (34-39) to 9 (8-11) points on the 10th day of therapy and 3 (2-5) points at the end of the course of treatment (p=0.0001). Biochemical parameters of the blood have improved significantly. Cognitive abilities assessed on the MoCA scale improved from 23.5 (20.3-26.3) to 27 (25.8-28) points, p=0.0001. Prediction of a favorable outcome of therapy (MoCA score greater than 26 points after a course of treatment) is possible based on initial indicators. AST level less than 112 U/L, ALT less than 120 U/L, direct bilirubin less than 9.8 µmol/L and cholesterol less than 6, 7 mmol/l. The probability of achieving less than 7 points on the obsessive-compulsive scale after 10 days of treatment can be predicted by the level of indirect bilirubin before starting therapy of less than 14.2 µmol/l and the initial score on the Hamilton anxiety scale of less than 20.5 points. Conclusions. Restoring liver detoxification function and improving cognitive potential through the use of drugs that combine neuroprotective and hepatoprotective effects in complex therapy is an effective method of treating patients with alcohol dependence. Prediction of a favorable outcome of therapy is possible based on initial biochemical parameters and assessment on the Hamilton Anxiety Scale.

Association between abnormal plasma metabolism and brain atrophy in alcohol-dependent patients.

In this study, we aimed to characterize the plasma metabolic profiles of brain atrophy and alcohol dependence (s) and to identify the underlying pathogenesis of brain atrophy related to alcohol dependence. We acquired the plasma samples of alcohol-dependent patients and performed non-targeted metabolomic profiling analysis to identify alterations of key metabolites in the plasma of BA-ADPs. Machine learning algorithms and bioinformatic analysis were also used to identify predictive biomarkers and investigate their possible roles in brain atrophy related to alcohol dependence. A total of 26 plasma metabolites were significantly altered in the BA-ADPs group when compared with a group featuring alcohol-dependent patients without brain atrophy (NBA-ADPs). Nine of these differential metabolites were further identified as potential biomarkers for BA-ADPs. Receiver operating characteristic curves demonstrated that these potential biomarkers exhibited good sensitivity and specificity for distinguishing BA-ADPs from NBA-ADPs. Moreover, metabolic pathway analysis suggested that glycerophospholipid metabolism may be highly involved in the pathogenesis of alcohol-induced brain atrophy. This plasma metabolomic study provides a valuable resource for enhancing our understanding of alcohol-induced brain atrophy and offers potential targets for therapeutic intervention.

Detrimental Effects of Alcohol-Induced Inflammation on Brain Health: From Neurogenesis to Neurodegeneration.

Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.

Alcohol-induced brain deficit in alcohol dependence.

Although numerous adverse effects of alcohol addiction on health, behavior, and brain function were widely reported, the neurobiological mechanism of alcohol dependence remains largely unknown. In this study, a total of twenty-nine patients with alcohol dependence and twenty-nine status-matched normal controls (NCs) were recruited. Percent amplitude of fluctuation (PerAF) was applied to identify alcohol-related brain activity deficits. We found that alcohol dependence was associated with widespread differences in the left orbitofrontal cortex, right higher visual cortex, right supramarginal gyrus, right postcentral gyrus, and bilateral cerebellum posterior lobe with decreased PerAF, but no brain areas with increased PerAF differences were found. ROC curve showed that decreased PerAF revealed extremely high discriminatory power with a high AUC value of 0.953, as well as a high degree of sensitivity (96.6%) and specificity (86.2%), in distinguishing patients with alcohol dependence from NCs. In the alcohol dependence group, the amount of daily alcohol consumption showed significant negative correlations with the right cerebellum posterior lobe and right higher visual cortex. These findings suggest that the cerebellar-visual-orbitofrontal circuit was disturbed by alcohol dependence. The proposed new method of PerAF may be served as a potential biomarker to identify the regional brain activity deficits of alcohol dependence.

Successful word retraining, maintenance and transference of practice to everyday activities: A single case experimental design in early onset alcohol-induced brain damage

ABSTRACT Word retraining programs have been shown to improve naming ability post-stroke and in progressive aphasias. Here, we investigated benefits for a 22-year-old Danish man (DJ), whose difficulties followed brain damage from heavy alcohol misuse. Using a multiple baseline-across-behaviours design (target behaviour: retrieval of word list items), DJ completed a 4-week “Look, Listen, Repeat” program on a computer. Ninety personally relevant target words were selected to create three matched lists. List 1 was trained for 10 sessions over 2 weeks, followed by 9 sessions for List 2 over 2 weeks, while the third list remained untrained. Naming performance was evaluated at baseline, during the intervention, and at 1 and 4 months post-training. Naming improved following each intervention block (p < .001), with only one data point overlapping between the baseline and treatment phases for trained items. Untrained words remained unchanged (p = 1.00), with 50% of data points non-overlapping across baseline to treatment phases. Performance was maintained over time, and appeared to generalize, with DJ naming more trained objects in their natural setting (85%) than untrained items (64%). While more evidence is needed, brief (20-minute), intensive (5-day/week) word retraining programs may assist word retrieval for people with brain damage associated with alcohol misuse.

Purkinje cell-specific deletion of CREB worsens alcohol-induced cerebellar neuronal losses and motor deficits.

Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to fetal alcohol spectrum disorder (FASD) in the offspring. However, not all fetuses are equally vulnerable to alcohol toxicity. These differences in vulnerability among individuals are likely due, at least in part, to genetic differences. Some genes encode neuroprotective molecules that act through signaling pathways to protect neurons against alcohol's toxic effects. One signaling pathway that can protect cultured neurons against alcohol-induced cell death invitro is the cAMP pathway. A goal of this study was to determine whether the cAMP pathway can exert a similar neuroprotective effect against alcohol invivo. A key molecule within the cAMP pathway is cAMP response element binding protein (CREB). In this study, CREB was specifically disrupted in cerebellar Purkinje cells to study its role in protection of cerebellar neurons against alcohol toxicity. Mice with Purkinje cell-specific knockout of CREB were generated with the Cre-lox system. A 2×2 design was used in which Cre-negative and Cre-positive mice received either 0.0 or 2.2mg/g ethanol by intraperitoneal (i.p.) injection daily over postnatal day (PD) 4-9. Stereological cell counts of cerebellar Purkinje cells and granule cells were performed on PD 10. Motor function was assessed on PD 40 using the rotarod. Purkinje cell-specific disruption of CREB alone (in the absence of alcohol) induced only a small reduction in Purkinje cell number. However, the loss of CREB function from Purkinje cells greatly increased the vulnerability of Purkinje cells to alcohol-induced cell death. While alcohol killed 20% of Purkinje cells in the Cre-negative (CREB-expressing) mice, alcohol killed 57% of Purkinje cells in the Cre-positive (CREB-nonexpressing) mice. This large loss of Purkinje cells did not lead to similar alcohol-induced losses of granule cells. In the absence of alcohol, lack of CREB function in Purkinje cells had no effect on rotarod performance. However, in the presence of alcohol, disruption of CREB in Purkinje cells substantially worsened rotarod performance. Disruption of a single gene (CREB) in a single neuronal population (Purkinje cells) greatly increases the vulnerability of that cell population to alcohol-induced cell death and worsens alcohol-induced brain dysfunction. The results suggest that the cAMP pathway can protect cells invivo against alcohol toxicity and underline the importance of genetics in determining the neuropathology and behavioral deficits of FASD.

NADPH oxidase-induced activation of transforming growth factor-beta-1 causes neuropathy by suppressing antioxidant signaling pathways in alcohol use disorder

Oxidative signaling and inflammatory cascades are the central mechanism in alcohol-induced brain injury, which result in glial activation, neuronal and myelin loss, neuronal apoptosis, and ultimately long-term neurological deficits. While transforming growth factor-beta1 (TGF-β1) has a significant role in inflammation and apoptosis in myriads of other pathophysiological conditions, the precise function of increased TGF-β1 in alcohol use disorder (AUD)-induced brain damage is unknown. In this study, our objective is to study ethanol-induced activation of TGF-β1 and associated mechanisms of neuroinflammation and apoptosis. Using a mouse model feeding with ethanol diet and an in vitro model in mouse cortical neuronal cultures, we explored the significance of TGF-β1 activation in the pathophysiology of AUD. Our study demonstrated that the activation of TGF-β1 in ethanol ingestion correlated with the induction of free radical generating enzyme NADPH oxidase (NOX). Further, using TGF-β type I receptor (TGF-βRI) inhibitor SB431542 and TGF-β antagonist Smad7, we established that the alcohol-induced activation of TGF-β1 impairs antioxidant signaling pathways and leads to neuroinflammation and apoptosis. Blocking of TGF-βRI or inhibition of TGF-β1 diminished TGF-β1-induced inflammation and apoptosis. Further, TGF-β1 activation increased the phosphorylation of R-Smads including Smad2 and Smad3 proteins. Using various biochemical analyses and genetic approaches, we demonstrated the up-regulation of pro-inflammatory cytokines IL-1β and TNF-α and apoptotic cell death in neurons. In conclusion, this study significantly extends our understanding of the pathophysiology of AUD and provides a unique insight for developing various therapeutic interventions by activating antioxidant signaling pathways for the treatment of AUD-induced neurological complications.

Evaluation of spectrum of brain changes in alcohol dependence syndrome patients by magnetic resonance imaging

Background: Alcohol is socially and legally accepted substance of abuse ethanol intoxication may lead to loss of subcortical white matter, cerebral atrophy, Wernicke’ sencephalopathy, Marchiafava-Bignami disease etc. [1]Thus the main purpose of the study is to diagnose the alcohol-induced brain changes in Alcohol dependence syndrome patients and thus help in the planning of early treatment of the diagnosed condition, thereby preventing the further neurological decline.Aims1.To describe the various magnetic resonance imaging findings in alcohol dependence syndrome patients.2.To correlate the cortical changes to the number of years of drinking in alcohol dependence syndrome patients.Materials and Methods: The Study group consisted of 55 patients, who fulfilled the alcohol dependence syndrome criteria according to the International Classification of Disease criteria (ICD-10). Alcohol use disorder identification test scale was applied and individual with alcohol dependence score of >15 (for men) were considered for study. MRI brain protocol was used and MRI sequences were meticulously evaluated.Global cortical atrophy scale was used to qualitatively assess the cortical atrophy on FLAIR images. Scoring is given to each lobe separately after assessing the sulci and gyri appearance in each lobe.Results: Most common MRI brain finding was cerebral atrophy (40%) followed by cerebellar atrophy (21.8%), non specific T2 hyperintensities (14.5%) hepatic encephalopathy (5.4%), least common being central pontine myelinosis (1.8%) and marchiafava bignami disease (1.8%).Most common lobe to show changes of atrophy was frontal lobe, followed by parietal, temporal and least occipital lobe.Conclusions: MRI is the most sensitive imaging modality to identify various neuroimaging findings in alcohol dependence syndrome patients. Cortical atrophy findings were seen more in patients who were chronic drinkers with long duration history of alcohol intake alcohol intake of more than 20 years There was a significant association noted between duration of drinking and atrophic changes and the results were statistically significant (p

Neurofilament Light Chain as a Biomarker for Monitoring the Efficacy of Transcranial Magnetic Stimulation on Alcohol Use Disorder.

ObjectiveThis study assessed the effects of repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) on serum neurofilament light chain (NfL) levels, alcohol consumption, craving, and psychological impairment in participants with alcohol use disorder (AUD).MethodsParticipants with AUD were randomly assigned to receive one of two treatments (active or sham rTMS). All participants received 10 daily active or sham rTMS sessions over the left DLPFC for 2 weeks, with follow-up visits at baseline and immediately after the completion of the treatments. Serum samples were obtained before and after the intervention. Days of heavy drinking, visual analog scale (VAS) scores, and mental health component scores (MCSs) of the Medical Outcomes Study 36-Item Short Form Health Survey were used to assess the effects of rTMS.ResultsActive rTMS had a significant effect on reducing days of heavy drinking, alcohol craving, and serum NfL levels, and improved social functioning and mental health. The improvement with active rTMS was significantly greater than that with sham rTMS. Correlation analysis revealed that the reduction in the baseline drinking level was positively correlated with declines in the VAS and NfL levels but not with psychological scores.ConclusionRepetitive transcranial magnetic stimulation of the left DLPFC was associated with reducing alcohol consumption and craving in patients with AUD and positively impacted neuropsychological and social function. Serum NfL levels may be useful as an early serological indicator of alcohol-induced brain injury.

Study on the autophagy-related mechanism of puerarin in improving the cognitive impairment induced by alcohol in female mice

ABSTRACT Primary Objective This study aimed to investigate the effects of low-, medium-, and high-dose puerarin on cognitive impairment induced by 50% alcohol in mice and revealed the role of autophagy-related signaling pathways (mTOR and JNK pathways) in this process. Research Design The alcohol-induced brain injury model was treated with different concentrations of puerarin. The cognitive function of mice was evaluated by the behavioral test, and the changes of target proteins in hippocampus of each experimental group were detected. Methods and Procedures 40 female Kunming mice were randomly divided into 5 groups. The cognitive ability of mice was tested by Morris water maze, the morphological changes in the CA1 area of hippocampus were observed by HE staining, and the target proteins in hippocampus were measured by WB and IHC. Main Outcomes and Results Compared with the 50% alcohol group, the expression of p-mTOR/mTOR and p-4E-BP1/4E-BP1 in hippocampus was significantly decreased, while the expression of p-JNK/JNK, Beclin1, and LC3 was significantly increased in the medium- and high-dose puerarin groups. Conclusions Puerarin could improve the cognitive impairment induced by 50% alcohol. The mTOR and JNK pathways related to autophagy might be involved in this process.