Role of glial cells in neurotoxicological effects of alcohol

Abstract

Alcohol (ethanol), presumably consumed as wine as far back as 7000 BC, is most likely the first addictive substance known to man. In modern days, its abuse leading to neurotoxicity and a myriad of organ damages, is of considerable social and medical concern. In the United States alone, approximately 180,000 people die yearly because of alcohol-related accidents and diseases. Given its ubiquitous nature, alcohol may interact with many cellular components. In this chapter, we specifically concentrate on its neurotoxic mechanisms involving glial cells and their role in neuroinflammation. Moreover, exploitation of this knowledge for potential novel interventions in alcohol-induced neurotoxicity are touched upon.

1. Introduction

Globally, more than 2.6 million die annually because of ethanol (alcohol) consumption, rendering it a worldwide medical and social concern. Abuse of alcohol leads to alcohol use disorder (AUD), defined as a “chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences.” AUD afflicts more than 400 million people worldwide (WHO, June 2024), and it is estimated that more than 209 million people live with alcohol dependence, defined as not being able to stop drinking without experiencing withdrawal symptoms.

Alcohol consumption as well as death-related cases vary between different age groups, and between men and women. For example, adolescents are at a greater susceptibility to alcohol’s damaging effects, likely due to neuronal maturation and refinements that peak during adolescence (Getachew et al., 2024). Moreover, adolescent’s early consumption of alcohol enhances their risk of AUD in adulthood (Nixon and McClain, 2010; Crews et al., 2016). Thus, people of younger age (20–39 years) have the highest proportion (13 %) of alcohol-attributable deaths, and men consistently have higher rates of alcohol-related hospitalizations than women. On the other hand, women have a faster progression of AUD, probably due to lower average body weights and less total body water. Women are also at greater risk of alcohol-induced hangovers, liver inflammation and fibrosis, cardiovascular diseases and other organ damages compared to men of comparable weight, as they attain higher blood alcohol concentrations (BACs) and its toxic metabolite acetaldehyde (Gochfeld, 2017).

Women are particularly susceptible to alcohol-induced cancers, especially breast cancer. Indeed, in a large epidemiological study in the United Kingdom, it was found that for every 10 g of alcohol consumed per day, there was a 12 % increase in the risk of breast cancer in women (Allen et al., 2009). Finally, men commit suicide about four times more often than women and are much more likely to have been drinking alcohol when committing suicide (WHO, June 2024). However, the gap between men and women drinking appears to be slowly disappearing, at least in the United States. Indeed, a recent report indicates that adolescents and emerging adult females (18–25-year-old) are more likely to report drinking and getting drunk than their male peers (White, 2020).

Although extensive effort is being expended on elucidating the neurobiological bases of addiction in general, and alcohol in particular, only limited pharmacological tools in combating AUD are available. These include opioid receptor antagonists such as nalmefene or naltrexone that blunt the rewarding effects of alcohol, disulfiram (Antabuse), an aldehyde dehydrogenase inhibitor that induces aversion, and acamprosate, a synthetic gamma amino butyric acid (GABA) analog with functional antagonism of the glutamate N-methyl-d-aspartate (NMDA) receptor. For life-threatening withdrawal symptoms, benzodiazepine followed by behavioral cognitive therapy are applied (Airagnes et al., 2019).

In addition to the fact that the efficacy of these medications is not optimal, the treatment rate is rather low in that about one in six people globally receives treatment, with even lower rates in lower-middle-income countries (Mekonen et al., 2020). A further consideration in this regard is not only the damage during intoxication, e.g., from falls and other accidents but also damage due to poor diet and vitamin deficiencies that could lead to Wernicke-Korsakoff syndrome (WKS), characterized by changes in the vision, ataxia and impaired memory (Nutt et al., 2021). Thus, there is an urgent need for providing more efficacious treatments. In this regard, understanding the neurotoxic mechanisms of alcohol may provide better preventive and/or interventions in alcohol-induced neuronal damage. Here, we provide an up-to-date information on the role of glial cells in acute and chronic alcohol-induced neurotoxicity and potential novel interventions.

2. Alcohol

We use the term alcohol interchangeably with ethanol, an alcohol with chemical composition (C₂H₅OH), which has also been used for disinfection and sterilization, as well as managing the toxicities of methanol (CH₃OH), and ethylene glycol (C₂H₆O₂), both of which are metabolized by the same enzyme, alcohol dehydrogenase (ADH), which also metabolizes ethanol. Metabolism of methanol leads to formation of the neurotoxic substances such as formaldehyde and formic acid, and metabolism of ethylene glycol leads to formation of toxic substances such as glycolic and oxalic acids. Because the affinity of ethanol for ADH is much higher than the other two alcohols, its administration spares their metabolism and hence their toxicities (Le Daré et al., 2019; Mathew and Goyal, 2021).

3. Binge vs heavy drinking

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines binge drinking as a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 %—or 0.08 g of alcohol per deciliter—or more. This can be brought about in men if they have 5 dinks or more, and in women if they have 4 drinks or more in 2 h. In adolescent boys and girls this BAC may be achieved with less number of drinks. A drink is defined as a beverage containing approximately 14 g of alcohol, which can be equivalent to 12 ounces of beer, 5 ounces of wine or 1.5 ounces of spirits such as vodka, whiskey, etc.

Heavy drinking is defined as having five or more episodes of binge drinking in the past month. Heavy drinking increases one’s risk for longterm alcohol-related health problems and developing AUD. High-intensity drinking, which peaks around age 21, is defined as alcohol intake at levels twice the threshold for binge drinking, meaning 8 or more drinks for women and 10 or more drinks for men on one occasion. This pattern of drinking, most common among young adults attending college, is associated with an even greater risk of detrimental consequences. Moreover, repeated episodes of binge drinking during adolescence, a unique phase in brain development, can not only affect brain maturity but also result in lingering behavioral deficits (e.g., social interaction), as well as in cognitive functions including learning, memory, and attention (Crews et al., 2016; Hauser et al., 2023; Getachew et al., 2024).

Acute intoxication is influenced by the volume and percentage of alcohol, the interval over which it is ingested, weight, size, body fat percentage, sex of the individual as well as the level of tolerance of the individual. The latter, also referred to as tachyphylaxis may develop rapidly and can play a critical role in alcohol addiction (Haass-Koffler and Perciballi, 2020; Elvig et al., 2021). Thus, alcohol effects are dose dependent. At lower BAC (e.g., 0.08 %), impairments in judgment and attention; at moderate concentration (e.g., 0.1–0.3 %), slurred speech, ataxia, and nystagmus (uncontrollable eye movements); and at higher concentration (e.g., above 0.4 %), stupor, coma, and respiratory depression leading to death, may occur.

Complications associated with chronic alcohol abuse may include sleep disturbance, hypoglycemia, electrolyte disturbance, hypotension, acute or chronic myopathy, peripheral polyneuropathy, and WKS, characterized by ophthalmoplegia, ataxia, confusion, amnesia and confabulation. It is suspected that some alcohol-related neurological effects may be due to nutritional deficiencies such as thiamine (Fernandes et al., 2017).

Heavy alcohol use may not only increase the risk of ischemic and hemorrhagic stroke, but also that of Marchiafava-Bignami disease, a rare but fatal degenerative disorder (Fernandes et al., 2017; Xu et al., 2019; Nehring and Freeman, 2020).

4. Neurotoxicity

Neurotoxic effects of alcohol, whether induced by binge or chronic intake, involves several brain regions and numerous neurotransmitters. Elucidation of the molecular bases of these effects can lead to novel interventions.

5. Tolerance

Tolerance, defined as a reduction in the effects of alcohol due to previous exposure, may be considered a neuroadaptive response initially. However, because it leads to the escalation of drinking and dependence, it can precipitate neurotoxicity and/or AUD (Koob, 2021). Several types of tolerance to alcohol have been described. For example, dispositional or metabolic tolerance characterized by faster metabolism of the alcohol; acute tolerance or acute functional tolerance which may occur within a single session of alcohol exposure and is influenced by family and drinking history; and chronic tolerance which is associated with an increase in alcohol metabolism (i.e., pharmacokinetic tolerance); as well as pharmacodynamic tolerance which may involve receptor desensitization. It is believed that a number of neurotransmitter systems including cholinergic, glutamate/nitric oxide, GABA, opioids, dopamine (DA), norepinephrine, serotonin, adenosine, cannabinoids, and peptides such as vasopressin, neuropeptide Y, neurosteroids, and protein kinase C, all of which modulate tolerance, and the “intoxicating” effects of alcohol, play a role (Nunes et al., 2019; Elvig et al., 2021). Recent studies in invertebrate models show that tolerance to alcohol involves neuroadaptive changes in the neurotransmitter systems, ion channels, and synaptic proteins. Moreover, it has been hypothesized that changes in neuronal excitability are an adaptive response to ethanol (Bhandari et al., 2024).

It is also noteworthy that in general men tolerate alcohol better than women, likely due to less water content in women and hence less chance of diluting alcohol and therefore greater concentration reaching the tissues. In addition, alcohol history, liver function, use of other substances or drugs, or other comorbid conditions may affect the individual’s tolerance to alcohol. On the other hand, people with enzyme capacities to faster convert alcohol to acetaldehyde (e.g., higher ADH activity) and slower capacity to metabolize acetaldehyde (e.g., lower acetaldehyde dehydrogenase) would exhibit a much lower tolerance to alcohol and hence exhibit a reduced chance of excessive drinking and developing AUD (Wilson and Matschinsky, 2020; Elvig et al., 2021).

6. Brain regions

It is believed that the effects of alcohol on cerebellum is responsible for the myriads of motor impairments including general weakness, ataxia, dysarthria (motor speech disorder), and nystagmus (involuntary, rhythmic eye movements) (Dolbec et al., 2020). On the other hand, alcohol’s effects on prefrontal cortex and limbic system, is believed to be responsible for impaired executive function, addictive properties, and negative emotions including anxiety (Vetreno and Crews, 2014; Reglodi et al., 2019). Alcohol also affects the lateral orbitofrontal cortex, essential for flexible decision-making (Gioia and Woodward, 2021).

7. Mechanisms

Although alcohol does not appear to have any specific receptor, a number of neurotransmitter systems and cellular mechanisms mediate its varied effects including its neurotoxicity. Here, following a brief discussion of the neurotransmitter and receptor systems, and involvement of neuroplasticity and neurogenesis, we concentrate on the role of glial cells in relation to neuroinflammatory responses resulting in alcohol neurotoxicity.

8. Neurotransmitters and receptors

Alcohol’s interactions with both ionotropic and metabotropic glutamate receptors, the nicotinic cholinergic receptors, as well as with DAergic system are believed to play a critical role in its rewarding and addictive properties (Meyerhof et al., 2006; Kalejaiye et al., 2013; Wu et al., 2014; Rahman, 2015; Alasmari et al., 2018; Johnson and Lovinger, 2020; Miller and Kamens, 2020). On the other hand, its interaction with serotonergic receptors and corticotropin-releasing factor (CRF) are suspected to be related to alcohol-induced anxiety and depression (Forster et al., 2018; Pleil and Skelly, 2018). Alcohol’s interaction with GABA may have a pivotal role in the modulation of sleep and developmental plasticity (Granato and Dering, 2018).

Although several studies ascribe the neurotoxic properties of drugs of abuse including alcohol to the opioid sigma receptors and cannabinoid receptors (Rousseaux and Greene, 2016; Sabino et al., 2017; Kunos, 2020; García-Baos et al., 2021), glutamatergic hyperactivation and overstimulation of the NMDA receptors are believed to be primarily responsible for the excitotoxicity. Thus, neurodegeneration may be brought about by accumulation of cytosolic calcium, and oxidative/nitrosative stress due to excess glutamate release. It is suggested that chronic alcohol consumption causes astrocyte damage and hence impairs the ability of these glial cells to regulate extracellular glutamate concentration, leading to hyperglutamatergic excitotoxicity (Lovinger, 1993; Collins and Neafsey, 2016; Kamal et al., 2020). It is of relevance to note that glutamate excitotoxicity has also been implicated in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) (Kamal et al., 2020; Egunlusi and Joubert, 2024).

Given the extensive involvement of many neurotransmitters in AUD, it is not surprising that several receptor systems may provide viable interventional targets. Indeed, potential exploitation of both muscarinic and nicotinic cholinergic receptors, both metabotropic and ionotropic glutamate receptors, GABA, opioid, cannabinoid, as well as tyrosine kinase receptors in AUD was recently reviewed (Tizabi et al., 2021). Specifically, it was shown that ketamine, an NMDA receptor antagonist, differentially attenuated alcohol intake in male versus female Alcohol Preferring rats (Rezvani et al., 2017), and that both ketamine and NBQX, an AMPA/kainate receptor antagonist reduced alcohol drinking in male Wistar rats (Ruda-Kucerova et al., 2018). Moreover, administration of GluN2B-containing NMDAR antagonist reduced the neuronal loss and the behavioral effects following alcohol withdrawal in adult mice (Gakare et al. 2022). These findings together with ample evidence implicating NMDA receptors in excitotoxicity, suggest that NMDA receptors could be a promising target in countering alcohol-induced neurotoxicity (Carles et al., 2024; Egunlusi and Joubert, 2024).

9. Neurotrophic factors

Neurotrophic factors (NFs) are varied protein molecules that play a key role in mediating all aspects of neuronal functions including their development, maintenance, plasticity, neurogenesis, and survival at various stages of life (Bothwell, 2016; Ledda and Paratcha, 2016; Vilar and Mira, 2016; Ibanez and Andressoo, 2017; Fursa et al., 2024; Hernández-Del Caño et al., 2024). The two most studied factors are brain-derived NF (BDNF), and glial-derived NF (GDNF), where the association of the former with neurodegenerative and neuropsychiatric conditions such as PD and major depressive disorder (MDD) is well documented (Tizabi et al., 2024). For example, BDNF and its receptor TrkB have been implicated in mood disorders due to their regulation of synaptic plasticity (Manji et al., 2003; Caviedes et al., 2017). It is postulated that alcohol-induced impairments in cognitive behavior, sleep, and mood regulation are due to reduction of BDNF and elevation of inflammatory markers such as interleukin (IL)–1β and tumor necrosis factor (TNF)-α in discrete brain regions. Curiously, neuroinflammation precipitated by alcohol can further impair neuroplasticity and neurogenesis and hence contribute to more drinking (Hurley and Tizabi, 2013; Crews et al., 2017; de Timary et al., 2017). Thus, a vicious cycle where alcohol-induced reduction in BDNF results in neuroinflammation which reduces BDNF ensues. This inverse relationship between inflammation and neuroplasticity can therefore result in symptom manifestation following alcohol toxicity.

10. Neurogenesis

Neurogenesis is a rather complex neurobiological process whereby new neurons are generated from neural stem cells (NSCs) or neural progenitor cells (NPCs). This occurs primarily in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, where the destination of the latter is mainly the striatum (Borsini et al., 2015). Although approximately 700 new neurons are generated daily in adult human hippocampus, they fall short of repairing the damaged ones brought about by toxicants, infection, injury, etc. The reason for the limited capacity to replace the damaged neurons is that pathological perturbations via activation of microglia for example, cause the release of pro-inflammatory cytokines that not only can lead to neuronal death but can also hinder the neurogenesis process (Das and Basu, 2008; Shigemoto-Mogami et al., 2014; Borsini et al., 2015).

Regarding alcohol’s effect on neurogenesis, it is estimated that alcohol exposure can reduce neurogenesis in the hippocampus by almost 40 % (Anderson et al., 2012; Geil et al., 2014). It is noteworthy that adult neurogenesis is comprised of four distinct components (e.g., cell proliferation, differentiation, migration, and survival), any one of which or their combination can be affected by alcohol (Geil et al., 2014). Moreover, using rodent models, it was shown that alcohol reduces proliferation and neurogenesis in the hippocampus through apoptosis and that chronic binge alcohol consumption increases neural degeneration months after abstinence via necrosis. In sum, intoxication may lead to neurodegeneration via several mechanisms including increased oxidative stress and release of proinflammatory proteins that are neurotoxic (Crews and Nixon, 2009; Geil et al., 2014). On the other hand, abstinence after binge ethanol intoxication may lead to normalization of brain function via enhanced neurogenesis (Crews and Nixon, 2009; Geil et al., 2014).

11. Other mechanisms

It is noteworthy that many other mechanisms may contribute to alcohol-induced neurotoxicity. These include perturbations of the hypothalamic–pituitary-adrenal (HPA) axis, mitochondrial metabolism leading to reactive oxygen species (ROS) and oxidative stress, endothelial disruption leading to nitric oxide and neuroinflammation, disruption of cellular bioenergetics, lipid membrane impairment, induction of edema and heat shock proteins, enhanced apoptosis, autophagy dysregulation, gene and epigenetic dysregulation, disturbance in the gut microbiota (dysbiosis) and the gut-brain axis, among others (Geil et al., 2014; Collins, 2015; Kondela et al., 2017; Tajuddin et al., 2018; Kouzoukas et al., 2019; Nakayama and Hasegawa, 2022; Gervasi and Mandalari, 2023; McMahan et al., 2023; Crews et al., 2024). However, here we mainly concentrate on neuroinflammation and the role of glial cells as this may be a common denominator among at least several mechanisms mentioned above (Guerri and Pascual, 2019).

12. Neuroinflammation

As mentioned above, alcohol-induced neuroinflammation, due to increase in release of cytokines such as IL-1β and TNF-α, and decreased neurogenesis, may enhance alcohol-drinking behavior and alcohol-induced neurotoxicity (Hurley and Tizabi, 2013; Crews et al., 2017; de Timary et al., 2017). Mechanisms by which alcohol induces cytokine release and neuroinflammation have been extensively investigated. It is apparent now that alcohol’s interaction with glial cells in general, and microglia in particular, is responsible for neuroinflammation. Thus, here following a brief description of various glial cells, we delve into alcohol’s effect on each type. Various stages of alcohol-induced neurotoxicity with emphasis on neuroinflammation is depicted in Fig. 1.

Fig. 1.

Schematic diagram depicting the consequences of heavy alcohol use either as binge or chronic on motor, nonmotor and cognitive functions. The neurotoxic effects are underscored by inflammation and are influenced by sex and age at every stage. WKS = Wernicke-Korsakoff Syndrome.

13. Glial cells

The name “glia” derived from the Greek word “glue” was ascribed to these cells because it was thought that they provide the scaffolding or the support system to keep the neurons together. It is now well established that glial cells are much more than “glue” with diverse and vital functions (Souza et al., 2019; Bonvento and Bolaños, 2021; Kim and Picciotto, 2023) These include regulation of neurotransmitters (Allen and Eroglu, 2017; Andersen and Schousboe, 2023; Novikov et al., 2023), control of metabolism and energetics (Kim and Picciotto, 2023; Ebling and Lewis, 2018; Chamberlain et al., 2021), fluid and electrolyte homeostasis (Reed and Blazer-Yost, 2022), myelination (Sanchez-Petidier et al., 2022; Wies Mancini et al., 2024), formation of the blood-brain barrier (BBB) (Manu et al., 2023; Fernandes et al., 2024), development and remodeling of synapses (Lalo et al., 2021; Rasia-Filho et al., 2023), neuroendocrine function (Clayton et al., 2022), innate immunity response (Kofler and Wiley, 2011; Chen and Holtzman, 2022), as well as detoxification (Dringen et al., 2015; Ioannou et al., 2019).

14. Relevance to alcohol-induced neurotoxicity

Although glia-mediated brain damage by alcohol is likely multifactorial, consisting of direct actions of alcohol or its metabolites on the glial cells or indirectly via hormonal, hepatic and hemodynamic factors (Miguel-Hidalgo, 2018), it is now well documented that alcohol can significantly influence the function as well as the survival of the glial cells, and induce neurotoxicity (Sushma et al., 2023). It is noteworthy that glial cells play a crucial role in protecting the neurons from the toxic effects of alcohol. However, with exposure to chronic alcohol, uncontrollable levels of ROS may be produced leading to neurotoxicity (Sushma et al., 2023). For example, by producing ROS, alcohol can damage the mitochondria and activate the endoplasmic reticulum (ER) stress pathway, which can lead to cellular dysfunction and/or cell death (Lin et al., 2008; Chen et al., 2023; Sushma et al., 2023). Brain’s unique susceptibility to ROS is believed to be due to several factors including its high oxygen demand, relatively low concentration of the antioxidant enzymes, and poly unsaturated fatty acids (PUFAs) (Sushma et al., 2023). Moreover, alcohol-induced alteration of glial cells in utero has been implicated in the pathophysiology of fetal alcohol spectrum disorder (FASD) (Wilhelm and Guizzetti, 2016; Popova et al., 2023).

15. Microglia

Microglia, representing 10–15 % of all the central nervous system (CNS) cells, are called the resident immune cells of the CNS, as through rapid movements of their fine tenacles called filopodia, they constantly survey the environment to provide rapid protection to any insult (Jäkel and Dimou, 2017; Nebeling et al., 2023). They accomplish this by rapid change in their morphology. Hence, by eliminating pathogens and cell residues, microglia play a key role in maintaining brain homeostasis. Microglia are also involved in neurogenesis, formation and elimination of synapses, and mediating T-cell infiltration into the brain (Pathak and Sriram, 2023). Interestingly, their concentration is particularly high in the hippocampus and the substantia nigra. On the other hand, overactivation of microglia can cause neuroinflammation and subsequent damage or death of neurons leading to neurodegenerative and/or neuropsychiatric conditions (Saitgareeva et al., 2020; Costa et al., 2021; de Marchi et al., 2023; Gao et al., 2023). Microglia can become overactivated due to persistent stress which causes the release of pro-inflammatory cytokines such as IL-1β and IL-6, and induction of a vicious cycle where microglia themselves further produce pro-inflammatory cytokines (Stein et al., 2017; Schramm and Waisman, 2022; Chen et al., 2024). Previously, based on the markers found on their cell surface, microglia were categorized into two main phenotypes: M1 or neurotoxic; and M2 or neuroprotective. However, use of these terminologies is no longer recommended because the same markers may appear in both M1 and M2 phenotype (Wang et al., 2023). Therefore, depending on the environment, microglia can be either protective or harmful.

16. Relevance to alcohol-induced neurotoxicity

Chronic consumption of alcohol can result in neuroinflammation and neuronal damage. Thus, alcohol increases the expression of proinflammatory cytokines such as TNFα, IL-1β, and chemokine CCL2, and microglial activation. Recently, it was suggested that consumption of chronic alcohol by recruitment of peripheral macrophages into the CNS, alters microglia through the CCR2/5 axis. Hence, manipulation of the CCR2/5 axis my offer a therapeutic potential for the treatment of alcohol-associated neuroinflammation (Lowe et al., 2020).

Regarding the differential reaction of adolescent vs adult to either binge or chronic alcohol, the available evidence indicates that adolescents tend to be more vulnerable to conditioned aversion, dopaminergic transmission in reward-related regions, neurogenesis, neurodegeneration, and are more likely to be impacted during adulthood (Crews et al., 2016; Hauser et al., 2023; Getachew et al., 2024). On the other hand, adolescents may be more resilient to motor-impairing, sedative effects, or some cognitive outcomes of alcohol (Weiland et al., 2012; Cousijn et al., 2018; Kuhns et al., 2022). However, in some respects, alcohol may similarly affect adolescent and adults as evidenced by reduced number of microglia in several brain areas including the hippocampus of both adolescent and adult rats (Marshall et al., 2020).

In another study it was revealed that microglia might not be the primary effector cell responsible for regulation of acute and voluntary alcohol behaviors. However, in a model of repeated immune activation using polyinosinic:polycytidylic acid (poly(I:C)) to activate microglia, it was shown that microglia depletion blocked poly(I:C)-induced escalations in alcohol intake, indicating that microglia regulate drinking behaviors with sufficient immune activation (Warden et al., 2021).

Chronic alcohol consumption also induces changes in microglial and neuroimmune-related gene expressions as seen in both murine and human brains after chronic alcohol consumption (Kapoor et al., 2019). Importantly, in a male rat model of four days binge alcohol exposure, it was found that both pro-inflammatory and antiinflammatory microglia are present in the brain, suggesting that anti-inflammatory microglia are likely activated to mitigate the pro-inflammatory response to alcohol (Peng et al., 2017). Furthermore, depletion of microglia by the colony stimulating factor 1 receptor inhibitor, PLX5622, inhibited expression of pro-inflammatory genes and enhanced expression of anti-inflammatory genes in a mouse model of acute binge alcohol withdrawal (Walter and Crews, 2017). Interestingly, similar findings were reported in a human study where microglia activity in the basal ganglia of humans was shown to be altered in AUD and reversed with remission from alcohol (Rasool et al., 2024).

Although it is still unsettled whether activated microglia are key contributor to disease pathogenesis or merely a consequence of exposure to chronic alcohol consumption (Portis and Haass-Koffler, 2020), a recent study does suggest that manipulation of microglia, specifically in the putamen, globus pallidus, and ventral pallidum may offer novel targets for AUD treatment (Rasool et al., 2024).

17. Astroglia (astrocytes)

Astrocytes or astroglia, named because of their star-like shape, are the most abundant cells in the brain with key functional roles in maintaining neuronal integrity. Recent findings indicate a heterogeneity in astrocyte physiology and gene expression (Kim et al., 2022). Astrocytes play a vital function in the CNS by a variety of mechanisms including providing nutrients and removing waste from the neurons, modulating blood flow, maintaining pH homeostasis, regulating the glymphatic network (the fluid dynamics within the CNS), buffering extracellular ions, particularly calcium, releasing gliotransmitters, recycling neurotransmitters, detoxifying ammonia, regulating synaptic plasticity, participating in synaptogenesis and neurogenesis, and being a key component of the blood-brain barrier (BBB) (Stoklund Dittlau and Freude, 2024; Verkhratsky and Nedergaard, 2018; Kim et al., 2022; Purushotham and Buskila, 2023; Das et al., 2024; Ngoc et al., 2024). As such, astrocytes are implicated in a variety of behavioral measurements including cognitive functions (Albini et al., 2023; Soares et al., 2024), and AUD as discussed below.

18. Relevance to alcohol-induced neurotoxicity

Like microglia, astrocytes also play a key role in regulating the brain’s response to alcohol. Indeed, astrocytes are considered critical regulators of alcohol-intake, and that alcohol effect on astrocytes has crucial downstream consequences on neurotransmission and neuronal health (Adermark and Bowers, 2016). Also similar to microglia, astrocytes may impart a beneficial or detrimental effect depending on the nature of the stimulus, (Jiwaji and Hardingham, 2022; Edison, 2024). For example, disruption of their trophic support to neurons may lead to neurological conditions (Rodrigues-Amorim et al., 2018). On the other hand, their role in maintaining glutamate homeostasis by uptake of glutamate from the synaptic cleft, is critical in protecting the neurons from excitotoxicity (Mahmoud et al., 2019). This process is regulated by an astrocyte-rich manganese (Mn)-dependent enzyme, namely glutamine synthetase (GS), that catalyzes the conversion of the glutamate into glutamine in the astrocytes. Glutamine is then released from the astrocytes and taken up by neurons where it is converted back to glutamate. Thus, if astrocytes fail to adequately regulate the glutamate uptake, excitotoxicity will ensue (Sidoryk-Wegrzynowicz and Aschner, 2013; Melkumyan et al., 2022; Qian et al., 2023). Additionally, it is known that GABAergic neurons synthesize GABA from glutamate and that astrocytes can also synthesize and release GABA. Thus, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission as well. Moreover, astrocytic GABA dysregulation has been implicated in a variety of psychiatric disorders, including AUD (Ali et al., 2024).

Astrocytes in different brain areas appear to be mediating the varied effects of alcohol. For example, cortical astrocytes have been shown to regulate ethanol consumption and intoxication in mice (Erickson et al. 2021), whereas astrocytes in the lateral central amygdala may be related to alcohol-induced anxiety and/or increases in proinflammatory cytokine in this area (Melkumyan et al., 2022; Brewton et al., 2023).

Recently, combining calcium signaling measurements and gene expression, alcohol-specific astrocyte subtypes were identified. Thus, various alcohol doses increased intracellular calcium levels in a subset of astrocytes only (Kim et al., 2022). Moreover, effects of alcohol on astrocytes appear to be sex dependent. Thus, GFAP expression is reduced in the extended amygdala of male, but not female mice following chronic or binge drinking (Brewton et al., 2023).

Finally, the well documented bidirectional communication between astrocytes and microglia in inflammatory responses are likely to contribute to glial response to various doses of alcohol (Kim et al., 2022; Bhusal et al., 2023; Brewton et al., 2023; Chen et al., 2023; Xiong et al., 2023).

19. Role of astrocytes in hepatic encephalopathy

Hepatic encephalopathy (HE), a neurological complication resulting from loss of hepatic function and accumulation of ammonia in the brain is characterized by brain edema (swelling), and behavioral changes including confusion, forgetfulness, personality or mood changes, poor concentration and judgment, and sleep disturbance (Hamdani et al., 2021). Glial cells, particularly astrocytes, play a significant role in this condition as they are primarily responsible for detoxifying ammonia (Jaeger et al., 2019; Claeys et al., 2021).

Chronic alcohol via damage to the liver, may further impair the liver’s ability to metabolize ammonia, resulting in hyperammonemia, consequently higher ammonia levels in the brain. Since astrocytes are the most important ammonia-metabolizing cells in the brain, and alcohol can directly damage astrocytes, this can lead to further buildup of ammonia. The higher the ammonia levels, the more inhibition of the transport of glutamine from the astrocytes to neurons and further disruption of normal neurotransmission. Moreover, because of a build-up of glutamine and ammonia in the astrocytes, they can accumulate water and swell, leading to increased pressure in the brain (Hamdani et al., 2021; Claeys et al., 2021).

In addition, there is an interplay between hyperammonemia and microglia that can lead to neuroinflammation and hence further exacerbate HE development. To gain an insight into the cellular perturbations driving HE pathology, cell-type specific transcriptomic changes were investigated in an animal model of HE. It was revealed that astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction, thus the suggestion that glial astrocytes and microglia may offer novel targets for development of novel therapeutic strategies in HE (Claeys et al., 2023).

20. Oligodendrocytes

Oligodendrocytes (OLs), constituting approximately 75 % of all glial cells in certain brain areas, are the major source of myelination in the CNS (Michalski and Kothary, 2015). OLs, not only provide the myelin sheath which is critical in insulating axons and facilitate conduction, but they also provide metabolic and trophic supply, regulate extracellular potassium concentration, and modulate axonal growth via their GDNF and BDNF (Michalski and Kothary, 2015; Han et al., 2022; Zhou and Zhang, 2023). It is noteworthy that white matter, a network of nerve fibers in the brain and spinal cord, gets its color from myelin and that “White Matter Disease” referring to damaged white matter, is characterized by memory, balance and mobility impairments which can be brought about by alcohol and is usually due to reduced blood supply as might also occur during aging (McEvoy et al., 2018; Sorond and Gorelick, 2019; Hoffmann and Miron, 2024). Moreover, it was recently suggested that CNS macrophages, consisting of CNS-resident microglia and cells associated with CNS border regions (e.g., the meninges, vasculature, and choroid plexus), as well as macrophages derived from infiltrating monocytes from the blood, influence the development, maintenance, and regeneration of myelin, and hence further understanding of these interactions could provide novel therapies in White Matter Diseases (Hoffmann and Miron, 2024).

21. Relevance to alcohol-induced neurotoxicity

Although it is well known that alcohol consumption affects oligodendrocytes and the white matter, few studies have attempted to elucidate the mechanism and more importantly determine a dose-response relationship. Whereas most studies have focused on FASD and severe AUD (Marguet et al., 2022; Bazzi et al., 2023), a recent study in mice evaluated transcriptomic changes in mature oligodendrocytes following exposure to moderate and high concentrations of alcohol (Bazzi et al., 2023). It was concluded that alcohol concentration-dependently induced transcriptomic changes in oligodendrocytes with critical downstream impacts on myelin production. Hence, it was suggested that elucidation of changes including changes in cell cycle regulation and inflammation following alcohol exposure, may provide novel targets for modulating myelin production or inhibition (Bazzi et al., 2023).

Alterations in oligodendrocytes as well as astrocytes have been observed in the prefrontal cortex (PFC) of postmortem human subjects with chronic alcohol abuse or dependence, which may explain changes detected by neuroimaging techniques in subjects with AUD (Miguel-Hidalgo, 2018). Importantly, significant interaction or crosstalk between astrocytes and oligodendrocytes exists (Nutma et al., 2020). This communication which is important for glial development, regeneration and repair, may occur directly via direct cell-cell contact or via secreted cytokines, chemokines, exosomes, and signaling molecules. Given the critical role of this communication in maintaining homeostasis, it is not surprising that a failure or miscommunication in this crosstalk can result in CNS diseases (Nutma et al., 2020). Additionally, AUD can affect the expression of astrocyte and myelin proteins and of oligodendrocyte transcription factors. Furthermore, epigenetic modifications and alterations in regulatory microRNAs (miRNAs) may also be occurring that could have profound effects on gene expression and protein translation in these glial cells (Nutma et al., 2020). It was also observed that chronic exposure to alcohol can inhibit myelinogenesis in the adult mouse brain, contributing to alcohol-related cognitive impairments (Guo et al., 2021).

More recently it was reported that adolescent alcohol exposure significantly affected myelin formation, and mature OLs in the medial-PFC of a mouse model with age- and subregional-specificity (Huang et al., 2024). Thus, AUD may be associated with connectivity disturbances between the PFC and other brain regions accompanied by alterations in gap-junction proteins, glutamate transporters or enzymes related to glutamate and GABA metabolism (Nutma et al., 2020; Guo et al., 2021; Huang et al., 2024).

22. Synantocytes (NG2 cells)

Synantocytes also called NG2 cells due to their expression of the protein “NG2” (nerve/glia antigen 2, chondroitin sulfate proteoglycan), which is a marker used to identify this cell population, may be considered the fourth type of glial cells in the CNS (Butt et al., 2005). The term “synantocyte” derived from Greek word refers to their unique characteristic of making numerous contacts with neurons (Butt et al., 2005). NG2 cells also considered as OL progenitor cells (OPCs) are widely distributed throughout the brain, continue to proliferate in adult brain (Hill and Nishiyama, 2014; Somkuwar et al., 2014; Michalski and Kothary, 2015; Kirdajova and Anderova, 2020), and can also be transformed into astrocytes and neurons (Hill and Nishiyama, 2014; Michalski and Kothary, 2015; Kirdajova and Anderova, 2020). NG2 cells have been implicated in many neurodegenerative diseases including AD, multiple sclerosis (MS), glioma, experimental autoimmune encephalomyelitis (EAE), a disease associated with increased BBB permeability, traumatic brain injury, epilepsy, acute ischemic stroke, neurovascular unit formation during development, neuroinflammation, as well as in neuropsychiatric diseases (Vélez-Fort et al., 2009; Xu et al., 2011; Dimou and Gallo, 2015; Ferrara et al., 2016; Nakano et al., 2017; Yu et al., 2022; Zhang et al., 2019; Hu et al., 2023; Poggi et al., 2023; Timmermann et al., 2023). These cells maintain a crosstalk with microglia and astrocytes (Zhang et al., 2022), and by inhibiting microglia-to-neuron prostaglandin E2 signaling may also provide protection against prion neurotoxicity (Liu et al., 2024).

23. Relevance to alcohol-induced neurotoxicity

Alcohol exposure can negatively affect the development, morphology, and gene expression of NG2 cells and be toxic to their survival. In contrast, abstinence from alcohol can increase NG2 differentiation, remyelination and lead to brain growth. Alcohol inhibition of myelinogenesis can contribute to cognitive impairments. Thus, regular heavy drinking can cause brain cells to die and brain tissue to shrink. Moreover, NG2 cells may also contribute to addictive component of alcohol (Somkuwar et al., 2014; Guo et al., 2021).

It was recently reported that NG2 cells form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 cells can stimulate GABA release and enhance inhibitory synaptic transmission, triggering anxiety-like behavior (Zhang et al., 2021). Moreover, this action involved glutamic acid decarboxylase 67 (GAD67) and vesicle-associated membrane protein 2 (VAMP-2), involved in GABA synthesis, and in the fusion of synaptic vesicles and the release of neurotransmitter, respectively (Zhang et al., 2021; Agarwal et al., 2024). Whether the same mechanism might involve alcohol’s effect is yet to be determined.

24. Ependymal cells

Ependymal cells, derived from radial glial cells in the embryo, are neuroepithelial, nonmotile, multiciliated cells at birth before they mature to motile multiciliated cells during the first two postnatal weeks (Deng et al., 2023). Initially, these cells project short and randomly oriented cilia into the ventricles, but during maturation, as the cilia length increases, they start beating and orienting in the same direction (Deng et al., 2023). Ependymal cells form the epithelial lining of the central canal of the spinal cord and the ventricles, and as glial cells in the CNS, play key roles in brain metabolism, waste clearance, and production and flow of cerebrospinal fluid (CSF). Specifically, these cells form critical components of the blood-CSF barrier and the CSF-brain barrier, which provide protection against the entry of foreign substances into the CSF (Aschner and Philbert, 2010; Nelles and Hazrati, 2022; Deng et al., 2023; Groh et al., 2024).

Three distinct types of ependymal cilia, type-I, type-II and type-III based upon their beating frequency, their beating angle, and their distinct localization within the mouse brain (lateral ventricle) have been identified (Omran et al., 2017; Deng et al., 2023). Additionally, they have a prominent role in energy metabolism due to containing a large number of mitochondria and have been implicated in several neurological conditions such as spinal cord injury and hydrocephalus (Nelles and Hazrati, 2022; Deng et al., 2023). Indeed, their potential manipulation as therapeutic intervention in these conditions has been suggested (Deng et al., 2023).

25. Relevance to alcohol-induced neurotoxicity

Alcohol has been shown to act as a risk factor in the impairment of the motility of ependymal cilia in the brain (Omran et al., 2017). Specifically, it was reported that oral gavage of alcohol decreased the beating frequency of all three types of ependymal cilia in both the third and the lateral ventricles of rats (Omran et al., 2017). Moreover, chronic alcohol use can impair ependymal cilia mobility in the ventricles and disrupt the flow of CSF in the brain. This can lead to alcohol-associated encephalopathy or as described above, WKS, which occurs in around 1–2 % of the population in the United States. and is most often seen in males, and patients of lower socioeconomic status (Patel et al., 2023).

Since alcohol exposure may cause hydrocephalus, a recent study was conducted to determine the effect of vaporized nasal alcohol exposure on the choroid plexus, and ependymal cells. It was observed that rats exposed to vaporized nasal alcohol had degeneration of choroid plexus and ependymal cells with ciliopathy and enlarged lateral ventricles or hydrocephalus (Kanat et al. 2024). The authors contended that because alcohol is often used for hygiene and specifically for prevention of transmission of the Sars-Cov-2-virus, the results could have human implication (Kanat et al., 2024).

26. Therapeutic implications and future directions

Neurotoxicity of alcohol may involve a myriad of cellular and molecular mechanisms, many of which have been amply reviewed (Tizabi et al., 2021; LaHood and Kok, 2023). Moreover, novel interventions based on our current understanding of the subject have been proposed (Tizabi et al., 2021; LaHood and Kok, 2023). Here, we concentrated on the role of various glial cells in alcohol-induced neurotoxicity (Fig. 2). Since alcohol’s detrimental effects could involve any of these glial cells, which have also been implicated in a variety of neuropsychiatric/neurodegenerative disorders (Soares et al., 2024; Tizabi et al., 2024), further elucidation of their structure and function could provide novel targets in mitigating alcohol-induced neurotoxicity as well as potential co-morbid conditions.

Fig. 2.

Schematic diagram depicting the role of various glial cells on alcohol-induced neurotoxicity. Specific effects of alcohol on each glial cell type are highlighted. Not shown are the extensive interactions between the glial cells. AUD = alcohol use disorder, BBB = blood-brain barrier, EAE = experimental autoimmune encephalomyelitis, WKS = Wernicke-Korsakoff Syndrome.

Abbreviations

ADH

alcohol dehydrogenase.

AD

Alzheimer’s disease.

AUD

Alcohol-Use Disorder.

BAC

blood alcohol concentration.

BBB

blood-brain barrier.

BDNF

brain-derived neurotrophic factors.

CNS

central nervous system.

CREB

cAMP response element-binding protein.

CRF

corticotropin-releasing factor.

CSF

cerebrospinal fluid.

DG

dentate gyrus.

EAE

experimental autoimmune encephalomyelitis.

ER

endoplasmic reticulum.

FASD

fetal alcohol spectrum disorder.

GABA

gamma aminobutyric acid.

GAD67

glutamic acid decarboxylase 67 glial-derived neurotrophic factor.

GPCRs

G protein-coupled receptors.

HE

hepatic encephalopathy.

HPA

hypothalamic–pituitary-adrenal.

IL

interleukin.

MDD

major depressive disorder.

miRNA

microRNA.

MS

multiple sclerosis.

NBQX

2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline.

NF

neurotrophic factor.

NIAAA

National Institute on Alcohol Abuse and Alcoholism.

NMDA

N-methyl-d-aspartate.

NPC

neural progenitor cell.

NSC

neural stem cell.

OL

oligodendrocyte.

OPC

oligodendrocyte progenitor cell.

PARP-1

poly (ADP-ribose) polymerase-1.

PD

Parkinson’s disease.

PFC

prefrontal cortex.

PUFA

poly unsaturated fatty acid.

ROS

reactive oxygen species.

SGZ

subgranular zone.

SVZ

subventricular zone.

TNF-α

tumor necrosis factor.

VAMP-2

vesicle-associated membrane protein 2.

WHO

world health organization.

WKS

Wernicke-Korsakoff syndrome.