Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders

Abstract

Overexposure of humans to heavy metals and essential metals poses a significant risk for the development of neurological and neurodevelopmental disorders. The mechanisms through which these metals exert their effects include the generation of reactive oxygen species, mitochondrial dysfunction, activation of inflammatory pathways, and disruption of cellular signaling. The function of glial cells in brain development and in the maintenance of homeostasis cannot be overlooked. The glial cells are particularly susceptible to metal-induced neurotoxicity. Accumulation of metals in the brain promotes microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity, inducing alteration in synaptic transmission, cognitive deficit, and neuronal damage. In this review, we highlighted the role of glial dysfunction in some selected neurodegenerative diseases and neurodevelopmental disorders. We further dive into how exposure to metals such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, and lead affect the functions of the microglia, astrocytes, and oligodendrocytes and the mechanisms through which they exert the effects on the brain in relation to some selected neurodegenerative diseases and neurodevelopmental disorders. Potential therapeutic interventions such as the use of new and improved chelating agents and antioxidant therapies might be a significant approach to alleviating these metal-induced glial perturbations.

1. Introduction

The toxicity of the nervous system has been a health concern globally, with millions of people affected across continents [1,2]. Human exposure to environmental toxicants, whether naturally occurring or introduced through human activities, poses significant risks to neurological health [1,3]. Metals are readily accumulated in the brain, which, under physiological states, are integrated into essential metalloproteins required for energy balance and neuronal health [4,5]. Metal-induced neurotoxicity can arise from a disruption in essential metals homeostasis or exposure to heavy metals [4,6,7,8]. Metals are vastly used in industrial applications and household utensils or equipment, contributing to their prevalence and neurotoxic effects [9,10].

Human exposure to heavy metals, such as lead (Pb), mercury (Hg), nickel (Ni), arsenic (As), cadmium (Cd), aluminum (Al), manganese (Mn), and iron (Fe), has been associated with various neurological diseases, including neurodevelopmental disorders such as autism spectrum disorders (ASD) and neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s disease (PD) (see reviews [10,11,12,13]). Metals exert their neurological effects by impacting various molecular mechanisms such as oxidative stress [10,14,15], mitochondrial dysfunction [16], activation of inflammatory pathways [17,18], and disruption of cellular signaling [19].

Evidence has shown that metal-induced neurotoxicity alters glial cell function in the central nervous system (CNS), resulting in oxidative damage, inflammation, alterations in synaptic function and plasticity, neuronal communication, cognitive impairment, and motor deficit. Glial cells have been reported to be involved in various biological processes, such as in maintaining brain homeostasis and defense against pathological insults both in neurodevelopment and in the adult brain (see reviews [20,21]). Perturbation to glial cells at any stage of life will impact neuronal function, synaptic formation, pruning, plasticity, and transmission, resulting in intellectual disabilities, cognitive impairments, and motor and behavioral deficits observed in neurological conditions (see review [22]).

Glial cells are particularly vulnerable to metal-induced neurotoxicity. Various studies have shown that both essential and non-essential metals can accumulate in the brain and promote microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity and inducing alterations in synaptic transmission and neuronal damage [23]. Mn, Fe, Al, Pb, and Cd exposure have been reported to cause an increase in microglia and astrocytes activation, triggering pro-inflammatory and oxidative stress responses that exacerbate the neurotoxic effect of these metals, disrupting neuronal homeostasis, axonal transport, neurotransmitter synthesis, and synaptic transmission, contributing to the development and progression of various neurodegenerative disorders such as AD and PD including neurodevelopmental disorders like ASD [24,25].

Studies have shown that exposure to these metals has been linked to disruption in learning and memory function, microglia activation, and upregulation of inflammatory cytokines associated with long-term potentiation impairment [26]. Activation of astrocytes and microglia results in the release of pro-inflammatory cytokines, exacerbating neuronal damage [27]. Furthermore, some of these heavy metals have been reported to alter the myelination process [28], as well as alter oligodendrocyte differentiation [29]. Glial dysfunction has been implicated in AD, and perturbation to astrocytes and microglia contributes to amyloid-beta plaque formation and neuroinflammation (see reviews [30,31]). Glial cells fail to support dopaminergic neurons, accelerating neurodegeneration in PD [32]. Neurodevelopmental disorders, such as autism, alter the glial function and affect synaptic development and plasticity [33,34]. Other neurological conditions such as depression and attention deficit hyperactive disorder (ADHD) are also linked to glial dysregulation, impacting mood and cognitive functions (see reviews [22,35]).

This review focuses on the role of glial perturbations in metal-induced neurotoxicity and its implications for neurologic disorders. We highlighted the mechanisms involved in metal entry into the CNS, their interaction with glial cells, and the resultant mechanism of neurotoxicity and how they contribute to brain damage.

2. Glia and Glial Dysfunction

2.1. Glial Cells

Glial cells make up 90% of the cells in the human brain, and they play an important function in brain development. They are known for their functions in supporting neurons and the maintenance of stability in the nervous system. Glial cells are made of five subtypes: star-shaped astrocytes, microglia, oligodendrocytes, Schwann cells, and the recently discovered NG2-glia with a yet-to-be-known function [36]. One glial cell can impact the function of another glial cell, so trauma to one can cause an impairment in neuron–glia communication [37].

2.1.1. Astrocytes

Astrocytes are glial cells that are found in the brain and spinal cord, and they majorly function to provide homeostasis in the CNS. A distinct characteristic of astrocytes is the deep expression of glial fibrillary acidic protein (GFAP), which increases with age [38]. In the brain, there are four classes of structurally and anatomically recognized GFAP+ astrocytes located in different layers of the brain: interlaminar, protoplasmic, varicose, and fibrous astroglia [39].

Amongst the glial cells, astrocytes are the most abundant, constitute about 20–40% of the glial cells in the brain, and have unique ramified processes [40]. Astrocytes serve as an intermediary between peripheral and central systems because they possess abundant stellate processes that enable them to interact with neurons, blood vessels, and other cells [41]. Astrocytes play an important role in synapse formation, maturation, and elimination; removal of debris and dead cells [42]; maintenance and repair of the blood–brain barrier (BBB) [43]; as well as other effects beneficial to the CNS. Astrocytes supply energy and provide metabolic nutrients to neurons through the astrocyte–neuron–lactate shuttle and give support to neurons [44]. They store glucose as glycogen granules that are metabolized to lactate and then transported to neurons [45]. The neurons further transform the lactate into pyruvate, which is used in the production of ATP [46] and the maintenance of metabolic activity [47].

Additionally, astrocytes secrete neurotrophic factors like mesencephalic astrocyte-derived neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) that protects the midbrain neuronal cells [48]. BDNF facilitates the maturation, differentiation, and survival of neural cells [49,50]. They also protect the brain in cases of hypoglycemia, cerebral ischemia, and neurotoxicity [51]. Astrocytes also maintain water and ionic homeostasis in the brain through a membrane-bound transporter system and equally maintain extracellular K+ ion concentration at a level that supports neuronal function [52]. Furthermore, they regulate the level of ions and neurotransmitters at the synapses, hence their involvement in synaptic transmission [21,53].

2.1.2. Microglia

Microglia are distinct immune cells of the nervous system that serve as the first responders in cases of trauma to the brain [54]. They make up about 10% of the cells found in the brain [55]. They are actively involved in almost all pathological cases like inflammation, stroke, neurodegenerative diseases, and viral and bacterial infections [56]. In the human brain, the microglial population is not uniformly distributed, and there are about 5-fold variations in density across various brain regions [57]. In any given pathology, microglia have different responses to pathological stimulation in relation to phagocytic actions and transcriptional profiles at different ages and varying brain regions [54]. Microglia help in phagocytosis and the removal of dead cells, microbes, protein aggregates, and other substances that threaten the CNS during CNS injury. Microglia also secrete chemoattractants, neurotrophic factors, and cytokines that help in immune activation and tissue repair in the CNS [58]. Microglia directly aid in in vitro and in vivo survival of neurons, neurogenesis, and oligodendrogenesis [59]. Healthy microglia play a role in controlling neuronal activities, synaptic activity, and functional plasticity because they produce a wide range of signaling molecules like cytokines, neurotransmitters, and extracellular matrix [60]. Research has also shown microglia involvement in synaptic pruning, neural circuit formation, and maintenance, as well as synaptic modulation during normal and pathological conditions [61,62]. A distortion or disruption in microglial homeostasis can have a direct impact on early age or late or adult onset of several neurodegenerative diseases [63].

2.1.3. Oligodendrocytes

Oligodendrocytes are formed from oligodendrocyte progenitor cells (OPCs), which constitute about 5–8% of the glial cells in the CNS and are also known as neuron–glia antigen 2 (NG2)-positive glia [64,65]. Oligodendrocytes help to maintain axonal integrity and provide axons with trophic support necessary for neuronal function [66]. The differentiation of OPCs involves a series of specific phenotypic stages that are characterized by different complex trophic signals and migratory abilities with the neurons, as well as morphological changes with the expression of distinct progressive markers [67]. Oligodendrocytes, the myelin-producing cells, constitute about 45–75% of glia in the CNS [68]. Myelin sheaths help axons perform saltatory conduction, thereby speeding up the conduction of action potential in neurons [69]. Oligodendrocytes also supply energy substrates to neurons via cytoplasmic “myelinic channels” and monocarboxylate transporters, allowing for the rapid delivery of short-chain carbon metabolites like pyruvate and lactate [70]. They also supply information for the sustenance of synaptic transmission and plasticity at the CNS [71]. The powerful contribution of oligodendrocytes to brain function is seen in diseases where there is a loss of myelin, like multiple sclerosis (MS), where patients exhibit neurological impairments [72]. Oligodendrocytes also contribute to metabolic supply and ion buffering to some survival and excitability properties of neurons [73]. Seeing that oligodendrocytes give trophic and metabolic support for neurons and axons, any decrease or trauma to oligodendrocytes will negatively impact neuronal function and viability [74].

2.2. Glial Dysfunction in Brain Disorders

Due to the roles of glial cells in the maintenance of homeostasis and the overall functioning of the brain, any insult or dysfunction to them might be a great contributing factor to the development and progression of numerous neurological and psychiatric conditions. This section will dive into glial dysfunction in some selected neurodegenerative diseases.

2.2.1. Glial Dysfunction in AD

Glial cells have a vital function in facilitating synapse loss and changes in synaptic plasticity. Research has shown that irregular activity and dysfunction of glial cells in AD are linked to impaired cognitive function [75]. Microglia become persistently activated, resulting in neuroinflammation, compromised ability to phagocytose amyloid beta (Aβ), and the release of inflammatory cytokines via the NLRP3 inflammasome (see reviews [76,77,78]). The release of pro-inflammatory substances by microglia and their inability to maintain glutamate homeostasis contribute to synaptic dysfunction. In addition, there is a build-up of complement system proteins that leads to synaptic phagocytosis and loss, which is observed in certain glial-mediated processes [75]. More recent studies have revealed that dysfunction in astrocyte TDP-43 plays a role in cognitive impairment by disrupting normal chemokine-mediated communication between neurons and astrocytes [75,79]. Dysfunction of oligodendrocytes can lead to damage to the myelin sheath and a reduction in neuronal conductivity, resulting in an impairment in the efficient transmission of electrical signals along nerve fibers [80]. Multiple studies have shown an association between the reduction of myelin and the accumulation of Aβ in AD [81,82,83]. Studies using single-cell transcriptome analysis have shown that oligodendroglia, like neurons and microglia, undergo transcriptional alterations in response to AD pathogenesis [84,85]. Additionally, synaptic dysregulation is induced by the interaction between microglia, astrocytes, and oligodendrocytes. The release of interleukin 1 alpha (IL-1α), tumor necrosis factor-alpha (TNF-α), and C1q by activated microglia results in the formation of the astrocyte A1 phenotype, which leads to the dying of neurons and oligodendrocytes [86,87]. To induce the release of synaptic harmful glutamate, microglia activate CXCR4 and CCR5 on astrocytes [88]. Microglia can produce CXCL7, which can cause synaptic dysfunction by damaging astrocytes and myelin [89].

2.2.2. Glial Dysfunction in PD

Microglia and astrocytes, among other glial cells, have been reported to contribute to PD progression by losing their typical homeostatic functions and accumulating neurotoxic functions (see review [90]). The expression of numerous PD-associated genes in both glial cells and neurons suggests that non-cell-autonomous mechanisms are involved in the degenerative processes of PD [91]. In PD, the build-up of abnormal α-Synuclein (α-Syn) causes microglia and astrocytes to become activated, resulting in a series of neuroinflammatory reactions (see reviews [92,93]). Astrocytes, crucial for CNS homeostasis and neuron support, become dysfunctional in PD, failing to protect neurons and releasing neurotoxic substances like TNF-α and interleukin 1 beta (IL-1β) (see reviews [87,94]). Pathological α-Syn in astrocytes induces neuroinflammation and reactive astrogliosis, worsening neurodegeneration (see reviews [95,96]). Microglia play a vital role in the development of PD by regulating neuroinflammation [97]. Genetic mutations in key PD-associated genes such as SNCA, PARK2, PINK1, PARK7, and LRRK2 influence microglial behavior, leading to inflammatory responses and neuronal damage [91,98]. α-Syn aggregates have been shown to activate microglia, while mutations in parkin and PINK1 disrupt mitochondrial quality control, enhancing inflammatory phenotypes [99,100].

2.2.3. Glial Dysfunction in ASD

Gliogenesis disturbances are linked to ASD through mechanisms such as synaptic function and neuroinflammation. Clinical and preclinical studies suggest heightened activation of astrocytes in ASD, leading to neuroinflammation (see review [101]). Astrocytes are also involved in regulating metabolism and calcium signaling, both of which are associated with ASD. Studies on mice with astrocyte IP3R2 knockout show behaviors resembling autism, highlighting the significance of calcium signaling in ASD development [102,103]. Increased GFAP immunostaining, indicative of astrocyte activation, has also been reported in animal models of ASD (see reviews [104,105]). Activated microglial cells release neurotrophic factors that support neuronal survival but also produce pro-inflammatory mediators like interleukin 6 (IL-6) and TNF, which can be neurotoxic. They also play a key role in synapse removal or pruning and may use trogocytosis to phagocytose abnormal or unnecessary synapses, a process critical for brain connectivity [106]. Microglial dysfunction, including increased density, abnormal morphology, and elevated expression of inflammatory genes, has been observed in both preclinical and human studies of ASD [107,108]. These impairments contribute to inflammation and disrupted synaptogenesis, underlying autistic symptoms [101]. Oligodendrocytes and their precursor NG2 cells are involved in brain development and form synapses with neurons in mature brains. Studies in animal models suggest that changes in oligodendrocyte and NG2 cell populations may contribute to social behavior deficits and ASD pathogenesis [109].

2.2.4. Glial Dysfunction in ADHD

ADHD is one of the most prevalent neurodevelopmental disorders associated with impairments in social skills and academic performance in children [110]. In ADHD, increased glutamatergic excitation and decreased GABAergic (Gamma-aminobutyric acid) inhibition are associated with astrocyte dysfunction and impaired glutamate uptake [35]. Studies have demonstrated changes in GABA levels in some brain regions, linking these changes to ADHD symptoms and suggesting a deficit in inhibitory control [111,112]. Reduced glial GABA levels in the cerebellum and hippocampus may underlie inattention and hyperactivity, as observed in animal models of ADHD, such as GAT-1 KO mice [113,114]. Studies have reported that a heightened state of activity in ADHD might be a result of a deficiency in lactic acid production by astrocytes in the brain [115,116,117]. Astrocytes can also induce inflammatory states that are associated with the severity of the disease [118].

2.2.5. Glial Dysfunction in MS

Glial cells are key players in MS, driving inflammation and neurodegeneration through complex interaction [119]. Dysregulated communication among these cells amplifies inflammation, impairs remyelination, and hinders recovery by disrupting essential functions like myelin debris clearance and oligodendrocyte support [120,121]. Astrocytes adopt a reactive, pro-inflammatory phenotype characterized by hypertrophy and increased expression of GFAP. They release cytokines such as IL-6 and TNF-α, as well as chemokines like CCL2 and CXCL10, which recruit leukocytes to the CNS and perpetuate inflammation [122]. Reactive astrocytes also produce demyelination signaling molecules, exacerbate axonal damage, and phagocytose myelin debris, though their efficiency is limited compared to microglia and macrophages [123]. Over time, chronic inflammation in progressive MS leads to intracellular Fe accumulation in astrocytes, disrupting antioxidant pathways and contributing to cellular damage [124,125,126].

Oligodendrocytes, essential for forming and maintaining myelin sheaths around axons, are critically impaired in MS, leading to hallmark demyelination and neurological deficits [127]. Autoimmune attacks damage oligodendrocytes and their myelin sheaths, resulting in conduction deficits, while persistent loss contributes to axonal degeneration and irreversible disability [128]. Chronic MS lesions show impaired remyelination, as OPCs fail to differentiate due to an inflammatory microenvironment, oxidative stress, and extracellular matrix changes [129]. Additionally, mitochondrial dysfunction in oligodendrocytes exacerbates energy deficits, further driving demyelination and impairing repair processes [80,129].

2.2.6. Glial Dysfunction in CNS Tumors

Glial dysfunction significantly contributes to the progression of various CNS tumors. In glioblastoma (GBM), astrocytes and microglia are extensively reprogrammed to adopt tumor-supportive roles [130]. Tumor-associated microglia (TAMs) in GBM often exhibit an M2-like phenotype, promoting immune evasion, angiogenesis, and tumor growth [131]. In meningiomas, while these tumors originate from arachnoid cap cells, nearby astrocytes and microglia amplify inflammatory signaling that accelerates tumor progression [132]. Similarly, metastatic brain tumors recruit and reprogram local astrocytes and microglia to establish a supportive niche that enhances tumor survival and proliferation [133].

Reactive astrocytes and TAMs support tumor progression through immunosuppression, secretion of growth factors, and extracellular matrix remodeling, while oligodendrocytes are indirectly affected, experiencing apoptosis and functional disruption in the tumor microenvironment [134,135,136]. Tumor–glial interaction plays a central role in the progression of CNS tumors, where tumor cells secrete cytokines, chemokines, and exosomes that reprogram glial cells. For example, glioma cells release IL-6 and CCL2, recruiting microglia and astrocytes and altering their behavior to support tumor growth [137,138]. In response, glial cells secrete factors that enhance tumor cell proliferation, invasion, and immune evasion, creating a reciprocal activation cycle. Glial cells also contribute to an immunosuppressive tumor microenvironment (TME) by expressing immune checkpoint molecules like PD-L1, inhibiting cytotoxic T-cell activity, and recruiting immunosuppressive regulatory cells such as Tregs and myeloid-derived suppressor cells (MDSCs) [138,139]. Additionally, astrocytes and microglia promote angiogenesis essential for tumor survival and disrupt the BBB, facilitating the infiltration of peripheral immune cells and tumor-promoting factors [140,141]. Astrocytes and TAMs also remodel the extracellular matrix (ECM) by secreting matrix metalloproteinases (MMPs), providing pathways for tumor invasion and migration [142,143].

3. Metal Neurotoxicity as a Risk Factor for Brain Disorders

Metal neurotoxicity, caused by exposure to metals like Mn, Pb, As, Ni, Co, Cd, Al, Fe, and Hg, disrupts the physiological balance necessary for life, posing a serious risk for neurological disorders (Figure 1). These disorders often result from the progressive loss and death of neurons due to metal-induced glial perturbations. Our previous review on the epigenetic influence of environmentally neurotoxic metals has thoroughly elucidated the association between metal exposure and several neurological disorders, particularly AD and PD, as well as ADHD and ASD (see review [10]).

AD is a neurodegenerative disorder marked by memory loss and cognitive decline [144]. Research shows that metals like Pb, Hg, Cd, and Al are linked to AD development (see review [145]). These metals can accumulate in the brain over time, leading to oxidative stress, inflammation, and damage to neurons, which are central to AD pathology [146]. Pb levels were found to be significantly lower in AD patients compared to controls, but there were significant increases in circulatory levels of Al, Hg, and Cd [147]. These results imply that increased levels of these elements in the bloodstream, particularly in serum, may contribute to AD development. The level of cerebrospinal fluid AD markers is highly correlated to the level of essential and trace metals in AD patients [148]. In another study, copper (Cu) level was seen to increase in the plasma level of patients with AD [149]. Furthermore, cognitive impairment with an increase in CSF levels of Fe, Al, and Pb was reported in cigarette smokers when compared with non-smokers, implying that these metals are risk factors in the pathogenesis of AD [150]. However, a significant increase in As, among other metals, was reported in the nails and hair of the elderly, which correlates to an increase in cholinesterase, which is associated with the pathophysiology of AD [151].

PD is a chronic and progressive neurodegenerative disorder predominantly caused by the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNpc) [152]. This neuronal loss results in the hallmark motor symptoms of PD, which include resting tremors, bradykinesia, and muscular rigidity. Exposure to metals such as Pb, Mn, Cu, and Hg has been linked to the development and progression of PD through multiple mechanisms. These metals can induce oxidative stress, impair mitochondrial function, and promote α-Syn aggregation, all of which contribute to the degeneration of dopamine-producing neurons in the substantia nigra (see reviews [153,154]). Hg and Pb top the list of all the metals as the most effective α-Syn elevators [155]. A systematic review and meta-analysis identified a strong correlation between elevated cumulative Pb levels in bone and an increased risk of developing PD. Increased risk of PD was associated with exposure to Hg, underscoring the importance of exposure to these metals in the disease’s development [153]. An increase in serum Mn levels was seen in PD patients when compared with the control group, which indicated that occupational exposure was associated with this increase [153]. Another study that used patients who experienced dental amalgam filling, which is high in Hg compared to those who did not, reported a higher risk of PD even after all necessary comorbidity adjustments in a population-based study [156]. Although normal urine concentrations of Mn, blood Pb level, and plasma Fe and Cu level were seen in a confined space bridge worker, the mean weight of Mn in the air around the workspace was higher, and higher PD symptoms were reported in this worker later in life [157].

ASD may have a mixed genetic, epigenetic, and environmental cause, yet the exact cause of it is still unknown [158]. Several metals are implicated as possible risk factors for the development of ASD, including exposure to Pb, Hg, As, Ni, and Cd, amongst others (see reviews [11,159]). When compared to neurotypical controls, systematic review and meta-analysis studies reveal that children with ASD have greater amounts of Pb in their hair, blood, and urine [160]. Dickerson et al. [161] highlighted a positive link between the level of Pb in the blood and the severity of ASD symptoms. More complex is the relationship between Hg and ASD, with some studies finding a higher level of Hg in children with ASD while others did not. A highlight of the findings of Rossignol et al. [162] revealed inconsistency in the findings, coupled with the note that several studies reported a significant link between Hg levels and ASD. While research on the link between As and ASD is relatively sparse compared to Pb and Hg, some studies have suggested a potential association [163]. As exposure has been shown to affect neurodevelopment through various mechanisms, including interference with cellular signaling pathways, induction of oxidative stress [164], and disruption of epigenetic regulation [159]. Furthermore, inorganic As, with a mixture of other metals, was reported to adversely affect fine motor function and visual and verbal function in young children [165]. Though Frye and colleagues reported lower prenatal and postnatal Cu and prenatal Ni concentrations in children with ASD when compared with children without ASD, high Mn deposit in deciduous teeth of children with ASD with neurodevelopmental regression was associated with lower mitochondrial respiration prenatally. They concluded in their work that prenatal metal nutrition may be important for development, and cellular dysregulation is related to exposure to toxic metal prenatally or postnatally [166]. The evidence linking metal neurotoxicity to ASD highlights the importance of environmental factors in the etiology of this complex disorder.

ADHD is a common neurodevelopmental disease marked by impulsivity, hyperactivity, and persistent inattention [167]. Certain metals, like Mn, Pb, and Hg, are particularly notable in the development of ADHD (see review [168]). A study conducted on children living in Spain shows a positive correlation between high urine metal concentrations such as Pb, Cu, and Zn with a decrease in working memory function and verbal executive functions [165]. Although the exact mechanism of Mn neurotoxicity is not fully understood, it is known to be harmful to cells and to disrupt enzyme activity, receptor activity, and transport systems [169]. Elevated Mn levels have been linked to hyperactive behaviors and attention deficits [170]. Similarly, Pb exposure has significant neurotoxic effects, particularly in children. According to Roy et al. [171], an Indian study found that children aged 3–7 had blood Pb levels linked to higher scores on the ADHD index. Braun et al. [172] also found a correlation between elevated risk of ADHD and even low levels of Pb exposure. Sanders et al. [173] highlighted that Pb exposure results in oxidative stress and disturbs calcium homeostasis, leading to neuronal apoptosis and neuroinflammation, processes linked to the pathophysiology of ADHD. Furthermore, neurodevelopmental problems, including ADHD, have been related to prenatal and early-life exposure to Hg [174]. Hg interferes with neurodevelopment in a number of ways by blocking the migration and differentiation of neurons, causing oxidative stress, and disrupting neurotransmitter systems [175]. Hg can also cause immunological dysregulation and neuroinflammation, which can exacerbate the symptoms of ADHD [176].

4. Pathways of Metal Entry into the Brain

The CNS and brain are majorly exposed to heavy metals via inhalation, ingestion, dermal absorption [177], and BBB permeation [178] (see Figure 2). Disruption of the tight junction of the BBB allows easy access to many substances in the brain. This disruption can be caused by infections (bacterial or viral), which have the potential to induce inflammation and cause the release of cytokines [179]. Oxidative stress resulting from reactive oxygen species (ROS) and exposure to toxins from the environment can damage tight junction-embedded proteins, thereby causing permeability (Lehner et al., 2011 [180]).

The transporter-mediated pathway involves the utilization of specific aided transporters made up of proteins. A classic example of a non-essential metal that utilizes the transporter-mediated pathway is Pb. Pb has been studied in vivo and in vitro with mechanisms involving three suggested major stages: binding, transport, and release [19,181]. The binding is achieved by mimicking calcium ions due to their similar ionic radius and charge. Then, it is transported via the calcium transporters and is finally released inside the endothelial cells [182]. Research evidence has demonstrated divalent metal transporter 1 (DMT1)-facilitated transport of Fe and Pb in yeast mutants and HEK293 cells [183], as well as the involvement of intracellular transporters for Cu and Zn in AD animal models, indicating that the observed increase in levels of Fe, Zn, and Cu might result from the disruption in the activity of transporters [184]. Other modes of metal entry into the brain include adsorptive-mediated transcytosis [185] and the selective transportation of specific substances across the cell membrane [186]. In vivo and in vitro studies have reported that the latter occurs when metals like Fe and Hg form receptor complexes inside the cell via endocytosis; these are then transported across the cell as vesicles and are finally released into the brain [187,188,189,190,191].

5. Biochemical Interactions of Metals with Glia

The interaction of specific metals and the glial cells causes metabolic stress, which perturbs normal CNS homeostasis, thus affecting the structural support provided by these cells [192]. Several processes have been described by Martínez-Hernández et al. [23]; however, the mechanism encompasses four major processes: (1) metal binding, (2) oxidative stress, (3) inflammatory response, and (4) disruption of metal homeostasis (see Figure 3). Firstly, the metals bind to proteins and enzymes, causing an alteration and conformational change in glial cell structure and function, leading to protein and enzyme impairment, as seen in AD [193]. For example, Pb exerts its neurotoxic effects on the CNS by binding to astrocytic glutamate transporters [194] and disrupting trans-synaptic transmission across synapses [195,196,197,198,199].

Additionally, metals activate the immune cells residing in the CNS (microglia) by initiating an inflammatory response (acute or chronic) [23], whether an acute protective inflammatory response or chronic effects or release of pro-inflammatory cytokines and neurotoxic antagonists [200]. For instance, Alanazi et al.’s [201] study reported that Cd activates microglia, causing the release of pro-inflammatory cytokines like interleukin (IL)-17A, IL17F, IL21, TNF- α, and other transcription factors (like STAT3 and RORꝨ). This results in prolonged microglial activation, which is implicated in the pathogenesis of neurodegeneration diseases like PD and MS [202].

Heavy metals disrupt the homeostatic balance of essential metals in glial cells through biochemical interactions, leading to cellular impairment. For instance, zinc (Zn) plays a key role in antioxidant defense systems, DNA repair, and enzyme function [203]. However, Cd disrupts Zn homeostasis in astrocytes by competing with Zn for binding sites, thereby displacing Zn and perturbing its normal functions [204,205]. This eventually weakens the antioxidant defense of glial cells and causes CNS disease susceptibility [206]. Also, considering that Zn is responsible for the functioning of metallothioneins (a protein that catalyzes the detoxification of metals against oxidative stress), the Cd-induced Zn homeostasis imbalance can further lead to uncontrolled cellular damage that is implicated in many neurodegenerative diseases [207,208].

6. Mechanisms of Metal Neurotoxicity

There are several factors responsible for the biological responses observed in metal neurotoxicity (see Figure 1); these include apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction [209]. Metals initiate oxidative stress by depleting antioxidant levels and facilitating ROS generation [210,211]. Fe, As, and Cu are known to generate hydroxyl radicals (OH) from hydrogen peroxide, causing DNA damage, protein denaturation, and lipid damage [212,213]. Cd exerts its oxidative stress effect by ROS accumulation [214], binding proteins to sulfhydryl groups in glutathione (GSH), and causing depletion of GSH and inhibition of antioxidant enzymes responsible for initiating anti-oxidative processes [215].

Heavy metal exposure impairs the electron transport chain responsible for producing ATP and cell energy in the mitochondria [18,215]. The chronic inhibition of complexes I (oxidoreductase), III (cytochrome bc1 complex), and IV causes an increase in ROS levels [216]. Metals inhibit specific complexes to carry out these processes [217]. For instance, Pb inhibition of complex III, causing impairment in ATP production, was identified as a major source of ROS generation [218], as well as Hg inhibition of complexes II, III, and IV, causing impairment in the synthesis of ATP [219]. Also, studies have reported that metals cause the opening of the mitochondrial permeability transition pore (MPTP), increasing pro-apoptotic factors [209,220,221,222]. Cd exposure has been found to cause mitochondrial swelling and a loss of membrane potential [223,224]. Similarly, As induces this mechanism of release of pro-apoptotic factors, which affect the mitochondrial structural integrity [225]. Further, Al causes an imbalance in calcium levels, leading to increased calcium levels and overload in the mitochondria [226]. Moreover, mitochondrial DNA is damaged as a result of a metal-induced mutation in genetic structure and a lack of proper repair mechanisms [227].

Metals induce apoptosis, which can be triggered through the intrinsic pathway, extrinsic pathway, and endoplasmic reticulum stress pathway. Cd exposure affects the endoplasmic reticulum structure and normal function, which causes stress and activation of unfolded protein response, leading to apoptosis [228]. Pb exposure has been found to activate caspase-dependent apoptotic pathways and disrupt calcium balance in astrocytes, leading to increased calcium levels; this results in the activation of calpains, which are responsible for initiating apoptotic cascade [173,229,230]. The initiation of this cascade leads to the breakage of cellular structures, affecting the morphological and biochemical characteristics with indications of DNA fragmentation, chromatin condensation, cell shrinkage, and astrocyte damage [231]. Furthermore, Hg also induces apoptosis in neurons by affecting membrane potential and releasing cytochrome [232]. This cytochrome C interacts with apoptosis protease activating factor-1 (Apaf-1) in the cytosol to form apoptosome, which activates caspase-9 [233]. The activated caspase-9 activates caspase 3, which initiates apoptosis that significantly contributes to neurodegenerative diseases.

In addition to apoptosis, metals also trigger other forms of cellular death, including necroptosis, ferroptosis, and even more specific forms like cuproptosis and calcicoptosis. Cuproptosis is a Cu-induced cell death mechanism recently discovered by Peter Tsvetkov and his team in 2022 [234]. It results from Cu directly binding to lipoylated tricarboxylic acid (TCA) cycle components, leading to Cu-dependent mortality. This causes the loss of iron–sulfur cluster proteins and the aggregation of lipoylated proteins, ultimately resulting in proteotoxic stress and cell death [234]. Zhang and colleagues also developed the term ‘calcicoptosis’ to describe a distinct biological effect caused by Ca²⁺ excess [235]. Exogenous Ca²⁺, one of the primary metal elements in the extracellular environment, can alter intracellular Ca²⁺ homeostasis and cause Ca²⁺ overload, which might result in cell death in some conditions. Calcium peroxide (CaO₂) nanoparticles were used in their investigation to cause Ca²⁺ overload in tumor cells, which resulted in oxidative stress, mitochondrial malfunction, endoplasmic reticular vacuolization, and specific cell death.

Necroptosis is another type of controlled cell death resembling apoptosis and necrosis and is triggered when apoptosis is inhibited [236]. Necroptosis depends on the protein RIPK3—which has been known to regulate inflammation, cell survival, and disease, as well as its substrate MLKL. Deregulation of necroptosis has been linked to the pathogenesis of various neurodegenerative and inflammatory diseases [237,238,239]. Necroptosis has been observed upon exposure to metals such as Cd [240] and selenium (Se) [241]. Ferroptosis is characterized by the accumulation of lipid peroxides in the cell membrane, leading to increased membrane rigidity and eventual cell death [242]. This process relies on the activation of Fe-dependent enzymes, including lipoxygenases and lysosomal Fe, which are released from the storage of ferritin [243]. Metals trigger ferroptosis specifically by inducing ferritinophagy, generating mitochondrial ROS—leading to its dysfunction, increasing DMT-1 and TfR cellular Fe uptake, and inhibiting Xc-system and glutathione peroxidase 4 (GPX4) activity [244]. Metal complexes, such as the osmium-peroxo complex, activate the ferroptosis pathway by generating ROS and inhibiting the reduction of oxidized glutathione (GSSG) to GS [245].

Neurotoxicity induced by metals commonly involves chronic inflammation through the activation of glial cells, leading to the release of pro-inflammatory cytokines (IL-1b, TNF α) and associated chemokines [26,246,247], as well as dysfunction of extracellular glutamate levels and maintenance of ionic balance [248]. Metals also stimulate the NF-κB (nuclear factor kappa-light-chain-enhancer of B cells) pathway, which plays a key role in regulating inflammation [249]. This mechanism causes the activation of genes responsible for pro-inflammation, which contributes to chronic inflammation overall [250].

6.1. Metal Neurotoxicity on Astrocytes

Astrocytes are important in the maturation of synapses, protecting the BBB, buffering extracellular glutamate levels, and maintaining ionic balance within the brain; any dysfunction will lead to excitotoxicity and risk of neurodegeneration [248]. There are various mechanisms through which metals exert their toxic effects on astrocytes, thereby disrupting their functions that lead to neurodegenerative diseases. Highlighted below are some of the selected metals known to induce toxicity to astrocytes.

Pb is a widely recognized environmental toxin, and the CNS is a primary target of its toxicity [19,251,252]. It is an abundantly distributed toxic heavy metal in the environment that disrupts almost all the functions in the human body. Pb is suggested to be transported to the CNS through the BBB [253]. Human exposure to Pb is caused majorly by Pb-associated occupations with diverse sources such as industrial processes, Pb-made pipes, battery recycling, Pb-made painting, book printing, etc. [254]. Numerous studies on Pb have shown that this metal is a neurotoxic metal, attributed to diverse neurological disorders, capable of triggering neuronal injury, and able to imitate or cease the action of calcium as a moderator of cell function. Excessive exposure to Pb in the brain causes its accumulation by astrocytes, where it is then stored as metal deposits [255]. This prevents a significant amount of Pb from entering surrounding sensitive CNS cells like oligodendrocytes and other neurons [256,257]. Astrocytes contribute significantly to neuroprotection in the brain [258,259]. This is achieved through the following mechanisms: increased GSH, ROS, and GPx levels; reduced glutathione reductase, superoxide dismutase (SOD), and GST levels; as well as morphological remodeling induced by astroglial reactivity [260,261]. Pb toxicity leads to perturbations in these processes, causing these cell types to become reactive, lose their normal functions, and gain deleterious ones, thus playing a role in the development of the disease of various neurological disorders [262,263,264]. Astrocyte oxidative stress has been shown to be a key modulator of PD pathogenesis, and the reactive astrogliosis observed in this condition results from cellular stress and inflammation [265]. Pb intoxication can also perturb the normal physiology of the nervous system by altering glutamate metabolism [194,266]. Early studies have demonstrated that even at very low doses, Pb inhibits glutamine synthase activity in developing astrocytes [267]. This is extremely important, given the critical role glutamate—a by-product of glutamine synthase activity—plays in cognition [268,269]. The GSH system, and, consequently, the CNS defense against oxidative stress, is affected when astrocytic glutamine synthase is inhibited. In rat astrocytes expressing water channel AQP4, exposure to Pb in vitro produced a notable increase (40%) in water permeability [270], indicating osmotic disruption as a mechanism involved in Pb intoxication (Table 1).

As in the case of Pb exposure, astrocytes can accumulate and act as a reservoir for methylmercury (MeHg) in the brain [255]. The first observed instance of astrocyte involvement and proliferation in MeHg toxicity was in 1975 using monkeys [271]. The LAT1 (neutral amino acid transporter system) found in the membranes of astrocytes selectively mediates the absorption of cysteine-MeHg, resulting in its accumulation [272,273]. While this astroglial accumulation serves as the initial defense mechanism against MeHg neurotoxicity, excessive accumulation causes astrocyte swelling, resulting in neuronal damage [273]. MeHg induces pro-oxidant effects in glia and neurons through two mechanisms: the generation of ROS and antioxidant defense. These mechanisms account for a significant portion of the metal’s CNS toxicity [274,275,276]. Astrocytes have been implicated in oxidative stress responses following MeHg intoxication [277,278]. To protect neurons from MeHg-induced oxidative stress, astrocytes synthesize and release cysteine, a GSH precursor, into the extracellular space [279]. MeHg disrupts the synthesis of GSH in astrocytes by inhibiting cysteine uptake [280], impairing the antioxidant defense, and consequently rendering the cell vulnerable to MeHg toxicity. This toxicity has been evidenced using GFAP in both in vitro and in vivo studies to demonstrate astrocytic reactivity as a result of MeHg exposure [281,282,283]. MeHg also affects mitochondrial health [284], disrupts calcium homeostasis [285], and neurotransmitter metabolism, including γ-aminobutyric acid and glutamate signaling processes [286,287]. MeHg inhibits astrocyte uptake of glutamate-mediated excitatory signaling while increasing its release from the pre-synaptic terminal, resulting in neuronal excitotoxicity and dysfunction [288,289]. Additionally, an increase in TNF-α levels has been connected to Hg exposure. TNF-α induces neuroinflammation and cellular death, resulting in symptoms like those of PD [154].

Human astrocytes accumulate Ni in a time and concentration-dependent manner [290]. The aggregation and accumulation of Ni in astrocytes indicates its susceptibility to Ni-induced cytotoxicity [290]. The neurotoxic impacts of Ni have been previously elucidated to include ROS generation among other mechanisms, resulting in oxidative stress and, consequently, cell death [291,292]; these mechanisms have been actively associated with neurodegenerative diseases, including AD and PD [293,294]. Ni also triggers apoptotic pathways by inhibiting the expression of the anti-apoptotic protein Bcl-2 and the upregulation of caspase-3/7 activity [290]. Furthermore, Ni delays the transition from the G2 to M phase during cell cycle progression in astrocytes, hence disrupting the normal cell cycle. This disruption may be linked with alterations and variations in the expression of cell cycle regulatory proteins, including cyclin B1 and p27. Collectively, these mechanisms underscore the interplay between Ni exposure and astrocytic cell health, highlighting the potential risks associated with Ni neurotoxicity in the CNS [290].

Cytotoxicity studies in human brain cells indicate that astrocytes are more resistant to Ars than other cells [295]. Excessive exposure to Ars affects astrocytes in a time and concentration-dependent manner [296,297]. Low As exposure does not adversely affect astrocyte viability, unlike high exposure. At elevated levels, astrocytes absorb more arsenite than arsenate, which impairs the brain’s antioxidant system function [296,297]. Astrocytes exposed to arsenite experience perturbed GSH metabolism [297], as well as rapid GSH export, glucose depletion, and lactate synthesis, all of which contribute to Ars-induced neurotoxicity [298]. Ars toxicity disrupts astrocytic homeostasis, impairing neuronal signaling. This is evidenced by disrupted synapse formation in primary neurons due to the inhibited expression of key signaling proteins, such as adenylate cyclase, calmodulin-dependent protein kinase II (CaMKII), and N-methyl-D-aspartate (NMDA) receptors [299]. Additionally, arsenite influences neuronal signaling by interfering with glutamate-induced release of glycine, γ-aminobutyric acid, and D-serine from astrocytes [300]. A study demonstrated that arsenite interferes with glutamine synthetase and transporters activity and expression [301]. Alterations in the functioning of these transporters have been correlated with the pathology of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) [302,303,304]. Furthermore, Ars toxicity may alter brain homeostasis by activating astrocyte-mediated inflammatory response involving interleukin 1β, interleukin 6, cyclooxygenase 2, tumor necrosis factor-alpha, etc. [305]. In addition, Ars intoxication also compromises astrocytes and brain functioning by disrupting glucose metabolism, which could lead to astrocyte death, thereby contributing to adverse neurological deficits [298,306].

Recent findings have demonstrated Cd’s ability to accumulate in and penetrate the CNS through disruption of the BBB, leading to cerebral damage [307,308,309]. In mouse astrocytes, Cd causes toxicity by mediating oxidative stress as well as depleting GSH levels [310,311,312]. This involves the release of intracellular Ca²⁺, the generation of ROS, and mitochondrial damage in rat astrocytes [311]. PD etiology is influenced by astrocyte activation, which is mediated by perturbed intracellular Ca²⁺ signaling [313]. A study by Nedzvetsky et al. [314] observed a decrease in glucose-6-phosphate dehydrogenase (G6PD) expression, an enzyme that helps protect red blood cells from premature destruction in Cd toxicity. Given that G6PD is essential for energy metabolism, mitochondrial function, and antioxidant defense [315], it is reasonable to suggest that Cd may compromise the viability of primary astrocytes by disrupting glycolysis [314]. Various substances have been shown to ameliorate the neurotoxic impacts of Cd exposure [314,316]. Curcumin, for example, has been found to maintain the viability of astrocytes by interacting with soluble glycolytic enzymes to mitigate the toxic effect of Cd. It also prevents the depletion of the cytoskeleton as well as key enzymes involved in the efficient utilization of glucose [314]. Caffeine is another substance that has been found to reduce the level of phosphorylated NF-kB—a transcriptional factor that controls both antioxidant and inflammatory cellular responses [317,318,319], indicating neuroprotection following Cd treatment in mice through the NF-κB-dependent pathway [316].

Al is a known metal with cytotoxic and neurotoxic effects [320]; it easily penetrates the brain, where it exerts its effects [321,322]. Al generally induces neurotoxicity by increased ROS generation and glutathione depletion, which results in mitochondrial dysfunction and, consequently, apoptosis [321,322]. The class III phosphatidyl inositol-3 kinase PI3K/Beclin 1-dependent autophagy signal is activated through the stimulation of endoplasmic reticulum stress and the impairment of protein-folding as a result of Al accumulation in astrocyte cells; this influences their survival and functionality, and consequently, astrocyte cell death [323,324,325]. This Al-induced astroglial apoptosis is characterized by soma shrinkage, nuclear condensation, and DNA fragmentation [323]. Astrocytes possess a range of cellular defense mechanisms, including antioxidant enzymes such as glutathione peroxidase, catalase, and SOD, which mitigates the neurotoxic damage caused by ROS [326,327]. Increased ROS generation triggers astrocyte death in part by affecting these antioxidant and catalase activities [328,329,330]. Results from a study showed that Al causes neuronal mortality in SNpc by impairing Fe metabolism and promoting neurotoxicity through the stimulation of astrocytes and pro-inflammatory markers [331]. This process could contribute to PD [12].

Fe is the most abundant metal in the brain, playing a crucial role in normal brain function and development [332]. Various neurodegenerative diseases, including AD and PD, can be caused by excessive Fe accumulation in the brain [333,334,335]. Astrocytes in the CNS accumulate Fe (Fe²⁺) via the plasmalemma transporters ZIP14 and DMT. The pathogenesis of age-dependent neurodegeneration involves Fe-induced mitochondrial dysfunction and oxidative stress, which may be triggered by Fe overload in astrocytes and lead to neurotoxicity [336,337]. Liang et al. [338] showed that an overload of Fe in the brain could impair the brain-wide glymphatic system, which is responsible for facilitating the clearance of waste proteins through a perivascular pathway [339]. A study demonstrated that the injection of Fe dextran further worsened the functioning of the glymphatic system and exacerbated depressive-like behavior induced by chronic unpredictable mild stress, consequently triggering neuronal apoptosis [338]. This glymphatic system functioning could also be suppressed by downregulating the expression of the astrocytic water channel aquaporin 4 (AQP4) [340]. Studies have shown that Fe oxide nanoparticles, which are widely used in biological and medical fields, cause toxic damage to human astrocytes [341,342]. In a 6-OHDA lesioned mouse model, both mRNA and protein levels of ceruloplasmin (CP) in the substantia nigra were significantly reduced, suggesting that decreased CP expression, which causes Fe accumulation, may play a critical role in neuronal death observed in PD [343].

Mn is found in all body tissues and is crucial for the normal regulation and functioning of many biochemical and cellular processes [14,344]. In the brain, Mn is preferentially deposited in astrocytes because of the presence of high-capacity transporters within these cells, resulting in higher accumulation than other neurons [345]. Subcellularly, Mn accumulates primarily in the mitochondria [346]. Studies have demonstrated that Mn induces oxidative stress in primary astrocyte cultures, leading to the disruption of mitochondrial functioning and, consequently, the perturbation of energy production [347,348]. Mn also affects astrocytes by disrupting glutathione synthesis, hence influencing the cell’s antioxidant defense mechanism [349,350,351]. Furthermore, Mn inhibits the synthesis of glutamine (an astrocyte-specific enzyme), impedes glucose metabolism [352,353], and impairs neurotransmission. AD pathology has been associated with a significant alteration in glutamine metabolism. For example, cortical homogenates from AD brains were found to have reduced glutamine synthetase activity when compared to homogenates from normal brains [354].

6.2. Metal Neurotoxicity and Microglia

Microglia functions as the brain’s resident macrophages [58], engaging in diverse roles from early development through adulthood. These roles include immune surveillance, synaptic pruning, neurogenesis, and detoxification [355]. Additionally, as a main source of pro-inflammatory cytokines, they play a crucial role in neuroinflammation [58,356], and they continuously monitor their surroundings and impact brain function by releasing substances such as cytokines, chemokines, and growth factors [357]. Microglial cells are known as both friends and foes because of their dual neuroprotective and neurotoxic actions, suggesting that their function in the CNS is multifaceted [358]. Microglia can be activated and undergo phenotypic changes depending on the brain microenvironment. Upon activation, microglia can transform into M1 or M2 phenotypes [359]. The M1 phenotype is known for its role in secreting pro-inflammatory molecules such as TNF-α, interferon-gamma (IFN-γ), IL-1β, and interleukin 6 (IL-6); in contrast, M2 produces anti-inflammatory molecules such as interleukin 4 (IL-4), interleukin 10 (IL-10), interleukin 13 (IL-13), and arginase 1 (Arg-1) [58]. Studies have reported that environmental exposure to heavy metals and/or perturbations in the hemostasis of the essential metals readily present in CNS can trigger microglia activation and can subsequently stimulate an inflammatory reaction, which is influenced by factors such as persistence stimulation of cytokines, receptor activation, disruption of signaling pathways, or even the absence of sufficient anti-inflammatory mediators to mitigate the response, resulting in neurological impairments. Highlighted below are some of the metals that have been found to trigger microglia activation and, in turn, result in neurological disorders.

Pb alters microglia functions in the brain by triggering their phenotypic changes, specifically increasing the expression of the M1 phenotype and decreasing the expression of the M2 phenotype [360]. Pb exposure has been linked to observable morphological changes and increased cytokine production in activated microglial cells [26]. This suggests that there might be a connection between Pb exposure, microglia activation in the CNS, and neurological disorders. A study by Kumawat et al. [361] reported that exposure to Pb in mouse BV2 induces activation of microglia, resulting in a significant increase in pro-inflammatory cytokines, specifically TNF-α, monocyte chemoattractant protein-1, and IL-6, in particular, in a dose-dependent manner. This study further reported that Pb exposure significantly led to an increase in cyclooxygenase-2 enzyme expression, an enzyme known for its common features in inflammation and produces neurotoxic prostanoids. Similarly, Zhu et al. [362] offered additional evidence verifying microglia activation by Pb exposure. In this study, Pb-treated BV2 cells exhibited a dose-dependent rise in the inducible nitric oxide synthase (INOS) marker, an immunofluorescent (IF) marker that labels microglia M1 phenotype. Additionally, Iba-1 IF labeling was used in the study to label microglia on BV2 cells, exhibiting morphological alterations typical of activated microglia. Furthermore, the investigation revealed elevated concentrations of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. These studies validate that exposure to Pb can potentially induce an acute inflammatory response in the CNS. On the other hand, growing evidence has suggested that microglia activation is pivotal in the degeneration of dopaminergic neurons observed in PD [363]. The current understanding of the etiology of PD indicates that excessive production of inflammatory cytokines by microglia [364,365], most especially the generation of ROS and nitric oxide by activated microglia [363], is a major contributor to the destruction of DA neuronal tissue [366,367]. There are several pro-inflammatory stimuli through which microglial cells can be activated to induce dopamine neurotoxicity in rodent models of PD [368,369]. Agents like Pb (that directly activate microglia, as explained above) have been found to result in the loss of DA neurons in Caenorhabditis elegans [370]. This indicates that Pb is a pro-inflammatory stimulus that induces the microglia activation for the production of inflammatory cytokines (Table 1).

Ni can trigger microglia activation to produce pro-inflammatory cytokines and has also been implicated in the development of several neurodegenerative diseases, such as PD. PD, a prevalent neurodegenerative disease characterized by dopaminergic neuronal loss in the substantial nigra and α-syn accumulation [371], has also been associated with microglia activation in the substantial nigra. A study by Xidong et al. [372] reported that Ni nanoparticles exacerbated α-syn amyloid-induced formation in EOC 13.31 mouse microglia cell line and increase the inflammation and oxidative stress by upregulating the expression of TNF-a mRNA, IL-1b mRNA, IL-6 mRNA, Bax mRNA, and caspase-3 mRNA. Similarly, a study also found that there is an elevated level of Ni concentrations in the plasma of patients with PD [373].

Exposure to As has been closely linked to various diseases, such as bladder and lung cancer [374]. The ability of this metalloid to cross the BBB makes it highly toxic to the nervous system [375,376]. It causes instability in mitochondrial membranes, depletes cellular energy, and directly impacts multiple areas of the brain, including microglial cells [377]. Several studies have linked As with the activation of microglia, which in turn triggers the production of pro-inflammatory cytokines [378,379]. Although various association studies have not definitively shown that As causes neurodegenerative diseases, several toxicity mechanisms of this metalloid closely resemble those associated with neurodegeneration [380]. These include inflammation, oxidative stress, autophagy [381], altered protein degradation [382], and mitochondrial perturbation [383].

As reported by Yang et al. [384], Cd is identified as a neurotoxic metal that accumulates in microglia. This accumulation leads to cytotoxic effects in a dose-dependent manner, subsequently inducing oxidative stress. This oxidative stress enhances intracellular ROS and reduces the uptake of 3H-dopamine, which may be a significant factor in the damage Cd causes to dopaminergic neurons. Tsai et al. [385] also indicated that Cd triggers microglia activation in the rostral ventrolateral medulla (RVLM), leading to higher levels of pro-inflammatory cytokines and chemokines, hypoxia, and apoptotic cell death in the RVLM.

Al exhibits strong biological reactivity and is particularly harmful to neuronal biochemistry by crossing the BBB [386,387]. Excessive exposure to Al has also been closely associated with microglia activation. A study reported that Al can directly affect microglial function in vivo by inducing phagocytosis, proliferation, migration, and the release of TNF-α and nitric oxide in immortalized BV-2 microglial cells [388]. Al has been associated with the progression of neurodegenerative diseases, including ALS, AD, dementia, and Parkinsonism. Although the molecular mechanisms are not well established, it is suggested that Al’s ability to potentiate oxidative stress and inflammatory events plays a significant role [24].

Fe has been associated with microglia health in numerous studies. McCarthy et al. [389] demonstrated that microglia sequester both extracellular and intracellular Fe in response to pro-inflammatory and anti-inflammatory stimuli, thereby influencing Fe transport and metabolism in the brain. Fe accumulation in microglia has been intricately linked to various neurodegenerative diseases, especially AD [390]. McIntosh et al. [391] reported that (IFN)γ and Aβ increased ferritin (a Fe storage protein) in the brain while decreasing ferroportin (the principal protein for Fe transport), leading to Fe accumulation in microglia. The study further indicated that Fe accumulation is characteristic of less efficient glycolytic microglia, which are characterized by downregulation in phagocytic and chemotactic functions. This suggests an association between these metabolic shifts and the progression of AD. Kenkhuis et al. [390] also suggested that Fe accumulation by microglia influences their functional phenotype, especially in conjunction with Aβ.

Mn is a pro-inflammatory stimulus that can trigger microglia activation to generate pro-inflammatory cytokines, oxidative stress, and ROS species, as reported in previous studies [392,393,394]. Likewise, there has been growing evidence in the literature linking the neurotoxic effects of Mn, microglia activation, and several neurological disorders, most especially Parkinsonism, a Mn-induced neurological disorder that is attributed to Parkinsonian symptoms. In the last twenty years, there has been an emerging interest in the potentiality of Mn to act as an exogenous trigger to induce Parkinsonism, a distinct form of manganism [395,396,397]. Tatyana et al. [398] demonstrated that excessive Mn exposure can lead to Parkinsonism. The study observed that exposing LN3-labeled microglia in the substantia nigra to Mn increased the number of microglia showing reactive changes, accompanied by upregulation of the expression of iNOS, L-ferritin, and intracellular ferric Fe, particularly noticeable in dystrophic compartments. A study by Yan et al. [399] reported that overexposure to Mn induces the downregulation of SIRT1, which then triggers microglia activation, accompanied by a rise in IL-6, IL-1β, and TNF-α mRNA expression and neuronal apoptosis, which are hallmarks of neurodegenerative disease. Similarly, Kirkley et al. [400] demonstrated that exposing primary microglia cultures to Mn increased the expression of pro-inflammatory genes such as nitric oxide synthase 2 (Nos2), IL-1β, and caspase 1. This led to a shift towards a mixed M1/M2 phenotype, accompanied by morphological changes characterized by debranched structures.

6.3. Metal Neurotoxicity on Oligodendrocytes

Unlike in the past, when the neurotoxic effect of metals on the brain was mostly focused on neurons and a lesser degree on microglia and astrocytes as cellular targets, more research has now uncovered the role of metal neurotoxicity on oligodendrocytes [401,402]. The neurotoxic effect of various essential and non-essential metals has been seen to disrupt this glial cell differentiation as well as induce myelin degradations and oligodendrocyte apoptosis, subsequently leading to various neurological dysfunctions such as MS [403]. The potential mechanisms at which these various metals induced toxicity to oligodendrocytes and myelin have been elucidated. These mechanisms include thyroid hormone disruption [404,405], inflammatory cytokine release by microglia [406,407], glutamate excitotoxicity [408,409], and the disruption of cholinergic signaling as acetylcholine signaling has been seen to be involved in the production and maintenance of myelin [410,411]. All of these listed mechanisms ultimately result in oligodendrocyte cell death by oxidative stress [67]. Highlighted below are some of the selected metals known to induce toxicity to oligodendrocytes.

Once in the brain, Pb can cause demyelination and disrupt essential functions by competing with calcium (Ca²⁺), as well as Zn (Zn²⁺) and Fe (Fe²⁺), for their binding sites [412]. According to a study by Ma et al. [413], long-term Pb build-up causes oligodendrocyte development to be distorted, which in turn causes demyelination by reducing the expression of Olig2 and CNPase proteins in vitro. Furthermore, their study also showed that Pb decreases the production of the sodium/calcium exchanger 3 (NCX3) mRNA, which is one of the main pathways for Ca²⁺ extrusion at the plasma membrane during OPC development. On the other hand, they found that over-expression of NCX3 in Pb-exposed OPCs resulted in a notable increase in CNPase expression and myelin basic protein (MBP) fluorescence signal in positive regions, which restored OPC differentiation to balance Pb toxicity. These findings suggest a possible mechanism by which Pb exposure disturbs oligodendrocyte differentiation, i.e., by disrupting NCX3 function through the induction of intracellular calcium overload, which in turn leads to glutamate excitotoxicity (Table 1).

Both human and animal exposure to MeHg decreases the velocity of the auditory brainstem response, an indicator of demyelination [414]. MeHg has been linked to increased oxidative stress, increased excitotoxicity, DNA damage, and changes in microvasculature in the neonatal brain, as well as calcium (Ca²⁺) dyshomeostasis [287,415]. Though there is limited research targeting the direct role of Hg or MeHg in oligodendrocyte functions, Hg has been seen to be found in oligodendrocytes of patients with neuropsychiatric conditions disorders [416,417]. The presence of Hg with its synergetic actions with other metals was seen in oligodendrocytes and neurons in the brain regions implicated in PD patients, pointing to the neurotoxic effect of Hg on the pathophysiology of PD [418]. Issa et al. [419] discovered that metal ions, such as Hg²⁺, cause cytotoxic effects in the oligodendrocyte cell line (MO3.13). The results of their investigation revealed that cell viability was lowered proportionally to the dosage of both MeHg and Hg, with MeHg being the more hazardous.

Ni-induced toxicity in astrocytes [290] and microglia [372] is documented; however, there are limited studies on oligodendrocytes. Studies have been performed on the thermal binding interaction of Ni ions with MBP [420]. Ni ions show damage to oligodendrocytes, and their inclusion with other essential (Cu²⁺, Cr³, Co²⁺) and non-essential (Pb²⁺, Cd²⁺, Al³⁺) heavy metals has been seen to induce damage on oligodendrocytes [401]. Similarly, few reports have demonstrated As’s impact on oligodendrocytes. A study investigating the prolonged impacts of sodium arsenite in drinking water for 12 months in rodents showed significantly decreased levels of myelin basic protein in the corpus callosum and prefrontal cortex [421]. As neurotoxicity has also been reported to mimic Guillain–Barre syndrome, a type of demyelinating disease [422]. Furthermore, high serum levels of As have also been seen in MS patients [423].

Cd, a carcinogenic metal, has been known to induce OPC death primarily through apoptosis [424]. Even transient Cd exposure can damage OPCs and potentially impair neonatal myelination via a reduction in the activity of mitochondrial dehydrogenase and an increase in lactate dehydrogenase release [425]. Additionally, Cd has also been reported to induce thyroid hormone disruption [426], as thyroid hormone signaling is important for the formation of myelin as it controls the maturation and differentiation of oligodendrocytes [404,405].

Al has been reported to target oligodendrocytes for its toxic impact in vivo [427]. Most Al in circulation is bound to transferrin (Tf), the Fe transport protein, as it is established that Al alters Fe and Mn uptake and the regulation of surface transferrin receptors in cultured rat oligodendrocytes [428,429] even at a low dose of about 1.25 μM [430]. Therefore, while the neurological impacts of Al toxicity are well-documented in other neurological disorders [431,432], its specific impact on oligodendrocytes and its potential role in MS warrant further investigation.

Fe is an essential metal in the brain and contributes to the production of myelin via oligodendrocytes [433]. Studies have shown that oligodendrocytes, among all other glial cells, possess the highest level of Fe concentration [434,435]. Despite this uniqueness of oligodendrocytes with Fe accumulation, the receptors required for the uptake of Fe by oligodendrocytes have been a subject of matter as it is known that mature oligodendrocytes do not express transferrin receptors [436]. However, it has been suggested that they take up Fe as H-chain ferritin through a specific receptor called the membrane protein TIM2 (T-cell immunoglobulin domain 2 protein) [437]. Recently, it has been shown that DMT1, a multimetal transporter, plays a vital role in Fe uptake and the development of oligodendrocytes from OPC [438]. Contrarily, the toxicity of Fe in oligodendrocytes has also been uncovered despite its high accumulation and metabolic requirement for Fe. Increased levels of free Fe have been shown to contribute to dopamine-triggered toxicity in oligodendrocyte progenitor cells [439]. Additionally, under conditions of hypoxia/ischemia, reactive Fe accumulates and contributes to white matter damage, particularly in the embryonic rat brain. This condition is known to trigger apoptosis in oligodendrocytes via endoplasmic reticulum stress and mitochondrial disruption [440].

Mn serves as an enzyme cofactor and is incorporated into several metalloenzymes, including manganese superoxide dismutase (MnSOD) [441,442]. Studies have reported that Mn deficiency can induce demyelination in the optic nerve of Wistar Kyoto rats [443]. However, an overload of Mn in the substantia nigra (SN) region of the brain has been linked with PD [444,445]. Mn has been shown to confer damage to the brain via oxidative stress, inflammation, excitotoxicity, and mitochondrial impairment [394,446,447]. Mn induces the expression of MnSOD [448,449]. The increased expression of MnSOD in developing oligodendrocytes was linked to a protective role in maintaining mitochondrial membrane potential and reducing cell death caused by mild cystine deprivation [449].

Table 1. The neurotoxicity of various heavy metals on glia.

Metal	Key Effects on Glia	Mechanisms of Toxicity	Neurological Impact	References
Lead (Pb)	Astrocyte: Disrupts glutamate metabolism and astrocytic reactivity. Microglia: Triggers phenotypic changes: ↑ M1; ↓ M2. Oligodendrocytes: ↓ Olig2, CNPase expression, and MBP fluorescence signal.	Astrocyte: Imitates calcium; inhibits glutamine synthase; increases osmotic disruption via AQP4. Microglia: Upregulate COX-2 and iNOS expression. Oligodendrocytes: Disrupts NCX3 function, causing intracellular Ca2⁺ overload and glutamate excitotoxicity.	PD and cognitive impairment.	[267,270,360,362,413]
Methylmercury (MeHg)	Astrocyte: Accumulation through LAT1-mediated transport. Astrocyte swelling. Oligodendrocytes: Reduces auditory brainstem response velocity (indicator of demyelination).	Astrocyte: Disrupts cysteine uptake; inhibits glutamate uptake; increases excitotoxicity; induces TNF-α. Oligodendrocytes: Induces oxidative stress, DNA damage, and Ca2⁺ dyshomeostasis	PD-like symptoms.	[272,273,287,288,414]
Nickel (Ni)	Astrocyte: Triggers oxidative stress; apoptosis; cell cycle disruption. Microglia: Induces inflammation and oxidative stress. Oligodendrocytes: Interacts with MBP.	Astrocyte: ROS generation; Bcl-2 inhibition; caspase activation; altered cyclin B1/p27 expression; G2-M phase delay. Microglia: ↑ Expression of TNF-α, IL-1β, IL-6, Bax, and caspase-3. Oligodendrocytes: Synergistic toxicity with other metals.	AD and PD.	[290,291,292,372,401,420]
Arsenic (As)	Astrocyte: Perturbs GSH metabolism; astrocyte-mediated inflammation. Microglia: Activates microglia and triggers cytokine release. Oligodendrocytes: Mimics Guillain–Barré syndrome (GBS)-like symptoms.	Astrocyte: Alters GSH/glucose metabolism; activates inflammatory cytokines (IL-1β, IL-6, TNF-α). Microglia: Increase inflammatory markers such as IL-6 and TNF-α. Oligodendrocytes: ↓ MBP levels in corpus callosum and prefrontal cortex.	ALS, GBS, and cognitive deficits.	[297,298,301,305,378,383]
Cadmium (Cd)	Astrocyte: Oxidative stress; mitochondrial damage; astrocyte activation. Microglia: Activates microglia in RVLM. Oligodendrocytes: Induces OPC apoptosis.	Astrocyte: Disrupts GSH; decreases G6PD expression; activates NF-Κb. Microglia: Dopaminergic neuronal damage and apoptotic cell death in RVLM. Oligodendrocytes: Disrupts thyroid hormone signaling necessary for oligodendrocyte differentiation.	PD.	[311,314,316,385,404,405]
Aluminum (Al)	Astrocyte: Induces ROS, GSH depletion, mitochondrial dysfunction, and apoptosis. Microglia: Induces phagocytosis, proliferation, and migration. Oligodendrocytes: Alters transferrin receptor regulation in oligodendrocytes.	Astrocyte: Activates PI3K/Beclin-1 autophagy; disrupts Fe metabolism. Microglia: ↑ TNF-α and nitric oxide release. Oligodendrocytes: Binds to transferrin to disrupt Fe and Mn uptake, which are necessary for its maturation.	AD and PD.	[323,325,331,388,429,430]
Iron (Fe)	Astrocyte: Overload in astrocytes; oxidative stress; glymphatic system disruption. Microglia: It sequesters with Fe, thus leading to ↑ ferritin and ↓ ferroportin. Oligodendrocytes: Accumulate by oligodendrocytes via TIM2 and DMT1.	Astrocyte: Accumulation via ZIP14/DMT transporters; reduces CP expression; disrupts AQP4 expression. Microglia: Accumulation linked to impaired glycolysis. Oligodendrocytes: Contributes to dopamine-triggered toxicity in OPCs under hypoxia/ischemia.	AD, PD, and depressive-like behavior.	[338,340,343,391,437,438,439]
Manganese (Mn)	Astrocyte: Disrupts mitochondrial and antioxidant functions and inhibits glutamine synthetase. Microglia: Induces microglial morphological and functional changes.	Astrocyte: Inhibits glutamine/glucose metabolism; disrupts neurotransmission. Microglia: Activates microglia to release ROS and cytokines (e.g., IL-6, IL-1β, TNF-α); downregulates Sirtuin 1.	AD, Parkinsonism, manganism, and neurotransmission impairment.	[345,346,347,354,394,398,399,400]

BBB, blood–brain barrier; CP, ceruloplasmin; AQP4, Aquaporin 4; Bcl, B-cell lymphoma 2; G6PD, glucose-6-phosphate dehydrogenase; LAT1, L-type amino acid transporter 1; TNF-α, tumor necrosis factors; IL, interleukin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Bax, Bcl-2-associated X protein; RVLM, rostral ventrolateral medulla; ZIP14, Zn transporter 14; DMT1, divalent metal transporter 1; NCX3, sodium/calcium exchanger 3; CNPase, 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase; MBP, myelin binding protein; OPC, oligodendrocyte precursor cells; TIM2, T-cell immunoglobulin domain 2 protein; PD, Parkinson’s disease; AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis.

Table 1. The neurotoxicity of various heavy metals on glia.

Metal	Key Effects on Glia	Mechanisms of Toxicity	Neurological Impact	References
Lead (Pb)	Astrocyte: Disrupts glutamate metabolism and astrocytic reactivity. Microglia: Triggers phenotypic changes: ↑ M1; ↓ M2. Oligodendrocytes: ↓ Olig2, CNPase expression, and MBP fluorescence signal.	Astrocyte: Imitates calcium; inhibits glutamine synthase; increases osmotic disruption via AQP4. Microglia: Upregulate COX-2 and iNOS expression. Oligodendrocytes: Disrupts NCX3 function, causing intracellular Ca2⁺ overload and glutamate excitotoxicity.	PD and cognitive impairment.	[267,270,360,362,413]
Methylmercury (MeHg)	Astrocyte: Accumulation through LAT1-mediated transport. Astrocyte swelling. Oligodendrocytes: Reduces auditory brainstem response velocity (indicator of demyelination).	Astrocyte: Disrupts cysteine uptake; inhibits glutamate uptake; increases excitotoxicity; induces TNF-α. Oligodendrocytes: Induces oxidative stress, DNA damage, and Ca2⁺ dyshomeostasis	PD-like symptoms.	[272,273,287,288,414]
Nickel (Ni)	Astrocyte: Triggers oxidative stress; apoptosis; cell cycle disruption. Microglia: Induces inflammation and oxidative stress. Oligodendrocytes: Interacts with MBP.	Astrocyte: ROS generation; Bcl-2 inhibition; caspase activation; altered cyclin B1/p27 expression; G2-M phase delay. Microglia: ↑ Expression of TNF-α, IL-1β, IL-6, Bax, and caspase-3. Oligodendrocytes: Synergistic toxicity with other metals.	AD and PD.	[290,291,292,372,401,420]
Arsenic (As)	Astrocyte: Perturbs GSH metabolism; astrocyte-mediated inflammation. Microglia: Activates microglia and triggers cytokine release. Oligodendrocytes: Mimics Guillain–Barré syndrome (GBS)-like symptoms.	Astrocyte: Alters GSH/glucose metabolism; activates inflammatory cytokines (IL-1β, IL-6, TNF-α). Microglia: Increase inflammatory markers such as IL-6 and TNF-α. Oligodendrocytes: ↓ MBP levels in corpus callosum and prefrontal cortex.	ALS, GBS, and cognitive deficits.	[297,298,301,305,378,383]
Cadmium (Cd)	Astrocyte: Oxidative stress; mitochondrial damage; astrocyte activation. Microglia: Activates microglia in RVLM. Oligodendrocytes: Induces OPC apoptosis.	Astrocyte: Disrupts GSH; decreases G6PD expression; activates NF-Κb. Microglia: Dopaminergic neuronal damage and apoptotic cell death in RVLM. Oligodendrocytes: Disrupts thyroid hormone signaling necessary for oligodendrocyte differentiation.	PD.	[311,314,316,385,404,405]
Aluminum (Al)	Astrocyte: Induces ROS, GSH depletion, mitochondrial dysfunction, and apoptosis. Microglia: Induces phagocytosis, proliferation, and migration. Oligodendrocytes: Alters transferrin receptor regulation in oligodendrocytes.	Astrocyte: Activates PI3K/Beclin-1 autophagy; disrupts Fe metabolism. Microglia: ↑ TNF-α and nitric oxide release. Oligodendrocytes: Binds to transferrin to disrupt Fe and Mn uptake, which are necessary for its maturation.	AD and PD.	[323,325,331,388,429,430]
Iron (Fe)	Astrocyte: Overload in astrocytes; oxidative stress; glymphatic system disruption. Microglia: It sequesters with Fe, thus leading to ↑ ferritin and ↓ ferroportin. Oligodendrocytes: Accumulate by oligodendrocytes via TIM2 and DMT1.	Astrocyte: Accumulation via ZIP14/DMT transporters; reduces CP expression; disrupts AQP4 expression. Microglia: Accumulation linked to impaired glycolysis. Oligodendrocytes: Contributes to dopamine-triggered toxicity in OPCs under hypoxia/ischemia.	AD, PD, and depressive-like behavior.	[338,340,343,391,437,438,439]
Manganese (Mn)	Astrocyte: Disrupts mitochondrial and antioxidant functions and inhibits glutamine synthetase. Microglia: Induces microglial morphological and functional changes.	Astrocyte: Inhibits glutamine/glucose metabolism; disrupts neurotransmission. Microglia: Activates microglia to release ROS and cytokines (e.g., IL-6, IL-1β, TNF-α); downregulates Sirtuin 1.	AD, Parkinsonism, manganism, and neurotransmission impairment.	[345,346,347,354,394,398,399,400]

BBB, blood–brain barrier; CP, ceruloplasmin; AQP4, Aquaporin 4; Bcl, B-cell lymphoma 2; G6PD, glucose-6-phosphate dehydrogenase; LAT1, L-type amino acid transporter 1; TNF-α, tumor necrosis factors; IL, interleukin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Bax, Bcl-2-associated X protein; RVLM, rostral ventrolateral medulla; ZIP14, Zn transporter 14; DMT1, divalent metal transporter 1; NCX3, sodium/calcium exchanger 3; CNPase, 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase; MBP, myelin binding protein; OPC, oligodendrocyte precursor cells; TIM2, T-cell immunoglobulin domain 2 protein; PD, Parkinson’s disease; AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis.

7. Current and Potential Therapies for Treating Metal Neurotoxicity in the CNS

Current therapies for metal neurotoxicity primarily focus on reducing systemic and CNS metal loads through chelation, anti-oxidative supplementation, and anti-inflammatory strategies. These strategies are devoted to systemic and CNS metal reduction, suppression of oxidative stress and inflammation, and preservation of neuronal and glial integrity. Chelation therapy has remained one of the most prominent methods for treating metal neurotoxicity. It involves administering agents that convert metals entering the body into complexes that can be easily excreted from the body. Examples of chelators include dimercaptosuccinic acid (DMSA), dimercaprol (British Anti-Lewisite, BAL), and ethylenediaminetetraacetic acid (EDTA). DMSA is FDA-approved for treating lead poisoning and is effective against arsenic and mercury; EDTA is often used for Pb detoxification, while deferoxamine is specific for Fe overload. However, chelators face challenges in crossing the BBB and often require adjunct therapies for effective CNS detoxification. Additionally, chelation therapy can result in side effects such as nephrotoxicity and the depletion of essential metals like Zn and Cu [450,451] (Table 2).

Antioxidant therapies are frequently employed to counteract oxidative stress, which is believed to be a significant factor in metal-induced neurotoxic effects. N-acetylcysteine (NAC), vitamins E and C, coenzyme Q10, and melatonin are some of the key compounds involved in scavenging ROS and protecting glial and neuronal cells. NAC is especially helpful in restoring intracellular glutathione levels, and for added protection, the use of coenzyme Q10 and melatonin is also an excellent way of maintaining mitochondrial integrity and promoting metal detoxification dynamics [452]. Relatively new are the anti-inflammatory agents, which target neuroinflammatory responses frequently elicited by metal toxicity. Current mediators include nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the release of inflammatory cytokines; minocycline, which decreases microglial activation and production of pro-inflammatory cytokines, and corticosteroids, which are reserved for extreme forms of inflammation [358]. Nutritional and lifestyle interventions are equally common and recommended approaches that align with supportive strategies. These include dietary change and supplementation with trace elements such as Zn and Se, both of which protect against Cd and Hg toxicities. Similarly, natural substances, such as the metal-chelating and anti-inflammatory curcumin and polyphenols from green tea and berries, are also beneficial for metal toxicities.

Despite the efficacy of the current therapeutic options, these treatments have limitations, such as lack of or incomplete BBB penetration, dispersed cellular injury inflicted by toxic metals, diverse mechanisms of action, and potential side effects. However, the emerging therapeutic options have shown promising solutions to the possibility of overcoming the constraints of present therapies. They aim to increase their efficacy and target specificity or address underlying molecular mechanisms of neurotoxicity. Nanotechnology-based approaches, for instance, allow the focused delivery of chelators and antioxidants directly to the CNS. Lipid nanoparticles enhance penetration through the BBB, while polymeric nanoparticles enable sustained and controlled drug release. Metal-chelating nanoparticles can bind neurotoxic metals and have been designed specifically for this purpose, which makes detoxification more precise and efficient. For example, calcium channel blockers can reduce metal influx through voltage-gated calcium channels, and heme oxygenase-1 (HO-1) inducers enhance the breakdown of heme, thereby protecting against metal-induced oxidative damage [452].

Gene therapy is another novel approach to combat metal-induced neurotoxicity. This strategy aims to target indirect pathways involved in detoxifying metal ions or enhancing antioxidant defenses. For instance, the overexpression of SOD and glutathione peroxidase genes that encode antioxidant enzymes may prevent oxidative stress mediated by toxic metals. Stem cell-mediated therapies are becoming increasingly prominent due to their potential to heal glial degeneration triggered by metal toxicity [453,454,455]. Stem cells are expected to replace aspirated astrocytes, microglial, or oligodendrocytes and, at the same time, modulate inflammation and oxidative injury in the CNS. These therapies may help restore the cellular and functional integrity of the organism in circumstances of severe neurotoxicity [456,457,458]. Drug pharmacological modulators are also being investigated to target the metal influx and efflux pathways or ones that can augment metal metabolism. For example, calcium channel blockers can reduce metal influx through voltage-gated calcium channels, and heme oxygenase-1 (HO-1) inducers enhance the breakdown of heme, thereby protecting against metal-induced oxidative damage [459,460,461]. Although emerging nanotechnology, gene therapy, and stem cell-based approaches offer hope for more targeted and effective interventions, continued research into these innovative strategies, alongside public health initiatives to reduce environmental and occupational metal exposure, will be crucial in addressing the global burden of metal neurotoxicity.

Table 2. Summary of current and potential therapies for metal neurotoxicity.

Therapy Type	Drug/Approach	Mechanism of Action	Benefits	Limitations	References
Chelation Therapy	DMSA (dimercaptosuccinic acid)	Chelates metals such as lead, mercury, and arsenic, forming water-soluble complexes for renal excretion.	FDA-approved; effective against lead, mercury, and arsenic.	Poor CNS penetration; risk of depleting essential metals like zinc and copper.	[450]
	EDTA (ethylenediaminetetraacetic acid)	Chelates lead by forming stable, excretable complexes.	Widely used; effective in reducing systemic lead burden.	Limited CNS detoxification; nephrotoxicity risk.	[451]
	Deferoxamine	Chelates free iron, reducing oxidative damage caused by iron overload.	Effective for iron overload conditions.	Low BBB penetration; may require adjunctive therapies for CNS iron overload.	[450]
Antioxidant Therapy	N-acetylcysteine (NAC)	Enhances glutathione synthesis, scavenges ROS, and reduces oxidative stress.	Protects glial and neuronal cells; boosts antioxidant defense mechanisms.	Limited bioavailability; adjunct therapies often needed for significant CNS effects.	[452]
	Vitamin E	Neutralizes ROS and protects against lipid peroxidation.	Readily available; reduces oxidative stress in metal neurotoxicity.	Requires high doses for CNS effects; limited direct metal interaction.	[462,463,464]
	Melatonin	Scavenges free radicals and reduces mitochondrial oxidative stress.	BBB-permeable; protects neurons and glia.	Short half-life; adjunct therapies needed for severe neurotoxicity.	[452]
Anti-inflammatory	Minocycline	Reduces microglial activation and pro-inflammatory cytokine production.	Mitigates neuroinflammation; well-tolerated.	Does not address metal load; adjunct therapy needed.	[358]
	NSAIDs	Inhibit cyclooxygenase enzymes, reducing pro-inflammatory cytokine production.	Broadly available; reduces inflammation-driven neurotoxicity.	Long-term use associated with side effects (e.g., gastrointestinal issues).	[358]
Nanotechnology-Based	Lipid nanoparticles	Deliver chelators and antioxidants directly to CNS, bypassing BBB limitations.	Enhances targeted drug delivery and efficacy.	High cost; requires further research for clinical applications.	[465,466]
Gene Therapy	SOD/GPX modulation	Upregulates antioxidant enzymes to counteract ROS generation.	Addresses underlying oxidative stress; potential for long-term benefits.	Limited by current delivery technologies and regulatory hurdles.	[467]
Stem Cell Therapy	Mesenchymal stem cells (MSCs)	Replace damaged glial cells and modulate inflammatory and oxidative stress responses in the CNS.	Potential to repair CNS damage and restore function.	High cost; requires extensive research and clinical trials.	[468,469,470]
Nutritional Therapy	Curcumin	Acts as an antioxidant and chelator, reducing oxidative stress and binding metals.	Readily available; dual action as antioxidant and chelator.	Limited bioavailability; often requires adjunct therapy for effective CNS action.	[471,472,473,474]

Table 2. Summary of current and potential therapies for metal neurotoxicity.

Therapy Type	Drug/Approach	Mechanism of Action	Benefits	Limitations	References
Chelation Therapy	DMSA (dimercaptosuccinic acid)	Chelates metals such as lead, mercury, and arsenic, forming water-soluble complexes for renal excretion.	FDA-approved; effective against lead, mercury, and arsenic.	Poor CNS penetration; risk of depleting essential metals like zinc and copper.	[450]
	EDTA (ethylenediaminetetraacetic acid)	Chelates lead by forming stable, excretable complexes.	Widely used; effective in reducing systemic lead burden.	Limited CNS detoxification; nephrotoxicity risk.	[451]
	Deferoxamine	Chelates free iron, reducing oxidative damage caused by iron overload.	Effective for iron overload conditions.	Low BBB penetration; may require adjunctive therapies for CNS iron overload.	[450]
Antioxidant Therapy	N-acetylcysteine (NAC)	Enhances glutathione synthesis, scavenges ROS, and reduces oxidative stress.	Protects glial and neuronal cells; boosts antioxidant defense mechanisms.	Limited bioavailability; adjunct therapies often needed for significant CNS effects.	[452]
	Vitamin E	Neutralizes ROS and protects against lipid peroxidation.	Readily available; reduces oxidative stress in metal neurotoxicity.	Requires high doses for CNS effects; limited direct metal interaction.	[462,463,464]
	Melatonin	Scavenges free radicals and reduces mitochondrial oxidative stress.	BBB-permeable; protects neurons and glia.	Short half-life; adjunct therapies needed for severe neurotoxicity.	[452]
Anti-inflammatory	Minocycline	Reduces microglial activation and pro-inflammatory cytokine production.	Mitigates neuroinflammation; well-tolerated.	Does not address metal load; adjunct therapy needed.	[358]
	NSAIDs	Inhibit cyclooxygenase enzymes, reducing pro-inflammatory cytokine production.	Broadly available; reduces inflammation-driven neurotoxicity.	Long-term use associated with side effects (e.g., gastrointestinal issues).	[358]
Nanotechnology-Based	Lipid nanoparticles	Deliver chelators and antioxidants directly to CNS, bypassing BBB limitations.	Enhances targeted drug delivery and efficacy.	High cost; requires further research for clinical applications.	[465,466]
Gene Therapy	SOD/GPX modulation	Upregulates antioxidant enzymes to counteract ROS generation.	Addresses underlying oxidative stress; potential for long-term benefits.	Limited by current delivery technologies and regulatory hurdles.	[467]
Stem Cell Therapy	Mesenchymal stem cells (MSCs)	Replace damaged glial cells and modulate inflammatory and oxidative stress responses in the CNS.	Potential to repair CNS damage and restore function.	High cost; requires extensive research and clinical trials.	[468,469,470]
Nutritional Therapy	Curcumin	Acts as an antioxidant and chelator, reducing oxidative stress and binding metals.	Readily available; dual action as antioxidant and chelator.	Limited bioavailability; often requires adjunct therapy for effective CNS action.	[471,472,473,474]

8. Future Directions/Conclusions

The effects of different neurotoxic metals such as Pb, Hg, Ni, As, Cd, Al, Fe, and Mn disrupt the functionality of glial cells and are linked to various issues of neurological disorders have been discussed. These metals have toxic effects on glial cells, including astrocytes, microglia, and oligodendrocytes, through various processes, including inflammation, oxidative stress, cell death through apoptosis, alterations of calcium balance, and inhibition of other important biochemical reactions. Astrocytes are the most sensitive cell type under metal toxicity, and their effects include disturbed calcium homeostasis, blocked glutamate transport, oxidative stress, and weakened antioxidant protection. When cells are exposed to metal ions, microglia become more inflammatory and release higher levels of neurotoxic products. Oligodendrocytes undergo demyelination and suppress myelin protein synthesis, resulting in the breakdown of myelin and altering neuronal functioning. All of these glial alterations are significant because they precipitate the course of several neurological diseases. Likewise, metals significantly contribute to the progression of AD, PD, ASD, and ADHD, among others. In these conditions of public health concerns, the glial dysfunctions are worsened, suggesting that it is important to gain insights into metal neurotoxicity for their treatment and management. The specific molecular pathways through which various metals cause changes in glial functions, such as pathways of entry into the brain and biochemical interactions with glial cells leading to disruption of the overall cellular and systemic homeostasis, have been highlighted.

Future directions include identifying specific and sensitive biomarkers of glial damage caused by metals in cases of neurological disorders, which will help to enhance prognosis, early detection, and the course of treatment. Further studies should be concentrated on identifying individual-specific biomarkers that can be used to predict glial activation caused by metal exposure. Likewise, therapeutic interventions and prevention of metal-induced glial dysfunction are also crucial. This can be accomplished by utilizing antioxidants that would help in dealing with the issues arising due to oxidative stress or free radical damage, anti-inflammatory agents to help in controlling neuroinflammation, and chelating agents to help in getting rid of toxic metals from the brain. Public health strategies could include minimizing the overall use of metals by the population. Environmental concerns such as setting more rigid policies on emissions from industries, enhancing safety measures in workplaces where metal content is present, and promoting general education about metal neurotoxicity could be utilized. Furthermore, cross-disciplinary research should be encouraged. Collaborations between researchers in the neurotoxicology, neuropharmacology, epidemiology, and public health sectors can provide a broader perspective of the impact of metal toxicity on brain health and identify potential prevention and treatment strategies.

Potential therapeutic interventions can include the use of new and improved chelating agents with an enhanced ability to concentrate and function on neurotoxic metals in the brain without causing other complications. The use of antioxidant therapies such as NAC, coenzyme Q10, and curcumin could be exploited for their ability to displace oxidative stress. Likewise, considering that inflammation mediates metal neurotoxicity, anti-inflammatory formulations might aid in alleviating glial activation alongside neuropathological inflammation. Preventative measures and nutritional support in the form of dietary supplements and foods with antioxidant/anti-inflammatory properties might also be used for minimizing metal-related neurotoxicity.