Alcohol exposure significantly reduces viability and induces oxidative stress in both differentiated and undifferentiated neuronal cells in a dose- and exposure duration-dependent manner. Despite being more resistant to alcohol-induced cytotoxicity, differentiated neuronal cells exhibit higher susceptibility to alcohol-induced oxidative protein damage than undifferentiated cells. Moreover, the characteristics of oxidatively damaged proteins observed in the study resemble those found in adult post-mortem brain tissues. Alcohol-induced neurotoxicity was measured through a wide range of assays, including cell viability quantification, mitochondrial morphology and functionality assessments, production of reactive oxygen species (ROS), and cellular accumulation of oxidatively damaged proteins. Post-mortem brain tissues obtained from alcohol-addicted individuals were also analyzed to determine the reproducibility of any in vitro observations in humans.
Cognitive-behavioral therapy in conjunction with pharmacological options is developing interest as a treatment regime to enhance alcohol abstinence along with relapse prevention. The adverse effect of disulfiram is outrageous over the clinical success towards preventing alcohol relapse. Naltrexone is an opioid receptor antagonist, found to be more effective to prevent relapse and maintain abstinence that reduces the rewarding effect of alcohol by generating fewer withdrawal effects 127,128. Acamprosate enhance the tolerance of alcohol withdrawal symptom by stabilizing the activity of N-methyl-D-aspartate (NMDA)-mediated glutamatergic excitation during early abstinence. However, their full clinical success has not been established and it depends on the administration, target, and severity of the disease. Alcohol is the most commonly used recreational beverage and drug of abuse among the adult population, alcohol-related death is the third leading preventable cause of death in the United States which accounts for more than 3.3 million global deaths annually 1,2.
- Another critical factor is alcohol’s interference with brain-derived neurotrophic factor (BDNF), a protein crucial for neuronal growth, survival, and plasticity.
- The extent of reversibility depends on various factors, including the severity of alcohol use and individual health conditions.
- However, their full clinical success has not been established and it depends on the administration, target, and severity of the disease.
- It also causes changes in the acetylation of histones H3 and H4 in the prefrontal cortex, nucleus accumbens, and striatum, suggesting chromatin remodeling changes which may mediate long-term alterations.
- The hippocampus’s vulnerability to alcohol-induced damage underscores the importance of moderation to preserve cognitive health.
Long-term impact of alcohol on the brain
This review provides insight into alcohol mediated brain damage and establishes evidence that changes in the pathophysiology and lifestyle modifications can be an option for recovery and cell restoration in alcohol-induced neurodegeneration. With the application of antioxidant therapy to control the oxidative response mediated inflammation, we expect to improve the outcome of neurocognitive function and structural stability of BBB with re-myelination and regrowth of neuronal processes to diminish neurodegeneration in patients with AUD. In the course of this phenomenon, further activation of astrocytes amplifies mitochondrial phosphorylation with downregulation of the tight junction which enhances the permeability of the BBB system. Thus, ethanol exposure results in BBB disruption by a complex immune-regulatory loop between BMECs and astrocytes. Evidence from animal models and cell culture reports further strengthens the idea that chronic excessive alcohol exposure downregulates the tight junction proteins (claudin, occludin, zonula occludens) which are responsible for maintaining BBB integrity 43. Both acute and chronic alcohol exposure can increase the production of ROS and enhance peroxidation of lipids, protein, and phosphorylation of mitochondria resulting in decreased ATP production by disrupting phospholipid-containing cell membrane structure 44.
Alcohol and the Brain: An Overview
Heavy drinking slows the cerebral cortex, which takes in and processes new information in your brain. In a study published in 2018, people who regularly had 10 or more drinks per week had one to two years shorter life expectancies than those who had fewer than five drinks. That number increased to four or five years shorter for people who had 18 drinks or more per week. The researchers linked alcohol consumption to various types of cardiovascular problems, including stroke. Experts believe that drinking does not actually lead to brain cell death—at least not directly.
This underscores the need to examine sex- and gender-related alterations on brain function and structure in alcohol use; improving our understanding of these effects may enable tailoring of pharmacotherapeutic treatments to improve outcomes. To probe impulsiveness through fMRI, response inhibition tasks are commonly used, such as the Go/no-go (GNG) task and Stop Signal Task (SST). Such studies have found that adolescents who later transitioned into heavy drinking had lower BOLD activation at baseline and increased activation in frontal regions when subsequently drinking heavily compared with continuous non-drinkers 110,111. This supports the role of impaired response inhibition as a risk factor rather than a consequence of alcohol consumption.
Effects on brain development can be long-lasting
A compromised BBB allows toxins and inflammatory molecules to enter the brain, further damaging neural tissue and impeding regeneration. This barrier dysfunction also limits the delivery of nutrients and growth factors necessary for neurogenesis, creating a double-edged sword that exacerbates alcohol-induced brain damage. Among them is Wernicke-Korsakoff syndrome, a serious neurological disorder linked to alcohol use that does result in the loss of brain neurons. It’s important to note that its relationship to alcohol misuse is indirect; the loss of neurons is caused by a deficiency in an important B vitamin called thiamine, which is common among those who misuse alcohol. Prenatal alcohol exposure can cause brain damage, leading to a range of developmental, cognitive, and behavioral problems, which can appear at any time during childhood.
Effects of alcohol exposure on mitochondria
N-methyl-D-aspartate (NMDA) is a primary excitatory brain neurotransmitter that binds to the glutamate receptor usually found in nerve cells. Depolarization and activation of the nerve action potential are maintained by the influx of different types of ions (Na+ and Ca2+) into the cell through the NMDA receptors 58. It is believed that alcohol acts as an antagonist for the NMDA receptor, so in the case of AUD, it causes hypofunction of the NMDA receptor which may result in neuronal network impairment with loss of synaptic plasticity 60. To maintain normal neuronal function and homeostasis, the physiological actions of the NMDA receptor are required.
- In a recent UK BioBank study of 25,378 individuals, increased within-network connectivity was identified within the default mode network (DMN) in those with higher alcohol consumption 46.
- Preclinical imaging has identified D3 receptor antagonism as a plausible therapeutic target to ameliorate alcoholism and its potential efficacy as an intervention is currently under investigation using fMRI 131 and combined PET/MR techniques 132.
- Chronic alcohol use impairs the cerebral cortex’s ability to process information efficiently, leading to difficulties in learning, attention, and impulse control.
- According to earlier studies, alcohol withdrawal seizures commonly occur due to an imbalance between glutamatergic and GABAergic neurotransmission which can be detected by MRS of the human brain 107.
- Alcohol use is deeply embedded in many cultures, and moderate consumption is often socially acceptable or even encouraged.
Transmission electron microscopy (TEM) analysis revealed significant alterations in mitochondrial morphology in alcohol-exposed cells. A substantial reduction in adenosine triphosphate (ATP) levels was also observed in both differentiated and undifferentiated neuroblastoma cells. Alcohol also decreases the effects of glutamate, which regulates dopamine in your brain’s reward center. “If you’re using alcohol to cope with stress or anxiety, if you’re going out and intending to drink one drink and you’re not able to stop yourself from drinking, it’s important to talk to your doctor and meet with a specialist,” encourages Dr. Anand. In addition to dementia, long-term alcohol use can lead to other memory disorders like Korsakoff syndrome or Wernicke’s encephalopathy.
If this leads to an agglomeration of pro-inflammatory and neurotoxic mediators for a prolonged period in the glial environment, then it leads to neuroinflammation and neurodegeneration 63,66. In AUD, ethanol metabolites alter the expression of astrocytes and oligodendrocytes which leads to impaired cell to cell communication. Signal transmission and cell interaction are accomplished by the formation and maintenance of the myelin sheath which is usually disrupted by alcohol metabolites. Alcohol interferes with the neuronal homeostasis process including the ability to form colonies, integrate, differentiate, and mainly proliferate 11.
Heavy drinking for females is eight or more drinks per week, and 15 or more drinks per week for males. The National Institute on Alcohol Abuse and Alcoholism notes that a number of factors influence how alcohol affects the brain, including how much and how often a person drinks, how long the individual has been drinking, prenatal exposure to alcohol, and the overall state of a person’s health. Although alcohol might not actually “kill” brain cells, research does suggest that high levels of alcohol can interfere with neurogenesis (the formation of new brain cells).
However, this accumulation was significantly higher in differentiated cells after 12 hours of exposure to 50 mM ethanol. Alcohol doesn’t kill brain cells, but it does have both short- and long-term effects on your brain, even in moderate amounts. But if you find yourself drinking heavily or binge drinking often, consider reaching out for help. A recent study published in the journal Antioxidants reports that alcohol exposure can lead to the accumulation of oxidatively damaged proteins in neuronal cells. Scar tissue impairs the liver’s ability to create proteins, filter the blood, and other bodily functions.
However, this physiological process can be interrupted by ethanol consumption before or after 65 years of age where ethanol Alcohol and Brain Cells metabolites hinder the growth of the progenitor’s dendritic arbor to regulate the complexity of synaptic connections and thus may contribute to neurodegeneration 91,92. Studies on the rodent and human brain delineated that excessive ethanol intake induces neuronal injury during various developmental stages including neurodegeneration and this type of ethanol-induced neurodegeneration seems to be connected with glial activation and neuroinflammation 23,63,64. Astrocytes and oligodendrocytes play a crucial role in the molecular mechanism of signal conduction and neurotransmission in both gray and white matter. Besides, astrocytes, oligodendrocytes, and myelin protein take part in the maintenance of plasticity of gray and white matter 65. In alcohol-related brain damage, ethanol and its metabolites have the potential to disrupt glial physiology and neurobiology in gray and white matter. Ethanol triggers the TLR4 receptor-dependent or -independent pathways of microglial activation which stimulates the NF-kB, interleukins IL1, IL6, CCL2, and in turn, evokes the expression of proinflammatory cytokines surrounding the astrocytes and oligodendrocytes 49,64.
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Crucially, the difference showed a linear increase with age and was at its greatest in old age which further offers support to the notion of a greater vulnerability to the effects of alcohol in later life. Interestingly, previous research established the evidence of recovery and regeneration of cortical volume including white matter thickness in short-term abstinence as well as improvement in neurocognitive deficits particularly visuospatial abilities, working memory, and motor skills 22,23. The mechanism of alcohol-induced degeneration and alcohol abstinence regeneration is a complex phenomenon that is determined by a person’s genetic characteristics, dominant brain activity, coexisting risk factors, and genetic process related to aging 24. Sometimes, an immune-competent status with a pharmacological trigger or lifestyle modification can be a way to prevent the alcohol-induced neuronal insult and might play a significant role in brain recovery. This review will cover possible mechanisms of neurotoxicity in AUD to support an effort to establish a multidisciplinary therapeutic approach to prevent or reverse neurological damage.