Search Results (58)

Intravenous use of methcathinone synthesized at home from over-the-counter medications containing pseudoephedrine or ephedrine poses significant health risks, including neurotoxicity, severe infections, and, in some cases, fatal outcomes. This study explores the public health implications of this hazardous practice. Post-mortem femoral blood and vitreous humor samples were analyzed using UHPLC-QqQ-MS/MS. The method enabled differentiation of ephedrine (a metabolite of methcathinone in this context) from pseudoephedrine (a precursor), along with the identification of relevant metabolites. A literature review was also conducted to contextualize associated health risks. The validated method accurately quantified methcathinone, pseudoephedrine, ephedrine, and identified their metabolites. The simultaneous detection of the final product and unreacted precursor supported the hypothesis of chronic intravenous use of homemade methcathinone. Literature data emphasized the risks of manganese-induced encephalopathy, injection-related infections, and the harmful effects of intravenously administered tablet excipients. These issues disproportionately affect marginalized and high-risk populations. This case highlights the diagnostic value of the method and its importance for monitoring the health impacts of illicit stimulant use. Effective responses should include public education, harm reduction strategies, surveillance of emerging drug trends, and, above all, the application of advanced analytical methods capable of comprehensive evaluation in such cases. Full article

Elevated exposure to manganese (Mn) has been linked to a broad spectrum of neurological disorders, including motor dysfunction. Neuroinflammation with excessively activated astrocytes plays a critical role in the pathogenesis and progression of neurodegenerative diseases. Astrocyte-mediated neuroinflammation plays a dual role due to distinct astrocyte phenotypes, including deleterious A1 and neuroprotective A2. Our previous studies have confirmed that Mn induces activation of astrocytes in the central nervous system, and endoplasmic reticulum (ER) stress has been verified to regulate A1 activation; however, the molecular mechanisms underlying Mn-induced neurotoxicity remain incompletely understood. We establish in vivo and in vitro Mn exposure models and observed that Mn induced A1 activation of astrocytes in both models, with upregulation of A1-specific markers. Sub-cellular morphological analysis showed Mn-induced ER stress in A1-type astrocytes. We found that EIF2α-PERK signaling pathways are activated in astrocytes and drive ER stress and mitochondrial impairment. Suppression of astrocytic PERK, using either ISRIB or GSK2606414, alleviates Mn-induced ER stress and A1 activation, which in turn mitigates the motor deficits induced by Mn exposure. These findings reveal that inhibition of PERK can ameliorate Mn-induced neurotoxicity by suppressing astrocyte activation and preserving organelle homeostasis, offering a potential therapeutic strategy to mitigate the harmful effects of Mn toxicity. Full article

Background and objective: Environmental and occupational exposure to toxic metals poses a significant risk to neurological health, particularly affecting motor-related brain structures. Essential metals like manganese, copper, and iron become neurotoxic when homeostasis is disrupted, while non-essential metals such as lead, mercury, and cadmium are inherently toxic, even at low exposure levels. We aimed to investigate the state of the art on neuroimaging evidence of the effects of exposure to toxic metals on motor related brain structures and functions. Methods: PRISMA guidelines were followed. We included studies that reported neuroimaging studies exploring the link between metal exposure and neural changes in motor areas. Results: We identified 518 papers, but only 20 articles were included. Our findings indicate that manganese is the most extensively studied metal in relation to the motor system using neuroimaging, but studies have also investigated the effects of other metals, including lead, mercury, and copper. Across these studies, the brain regions most consistently affected by metal exposure include the globus pallidus, caudate nucleus, frontal cortex, and cerebellum. Some studies exhibit structural or functional reductions in these areas that correlate with increased levels of metal exposure, suggesting a dose-dependent neurotoxic effect. Conclusions: This review synthesizes current neuroimaging evidence on metal-induced neurotoxicity, emphasizing its impact on motor function and highlighting critical gaps to guide future research and public health strategies. Full article

Background: Manganese (Mn) is an essential trace element for humans. It has been recognized as a potential occupational toxin, but its danger as a toxin in patients under parenteral nutrition is often forgotten. Case Presentation: A 73-year-old man was logged for 210 days in the intensive care unit (ICU), receiving parenteral nutrition (PN) for a month, and was then transferred, first, to the internal medicine ward and, then, to the rehabilitation hospital, and 223 days after discharge from the ICU, he had current disease, chorea-type movements in the head and neck, and left hemibody. Diagnostic tests: The magnetic resonance imaging findings suggested manganese deposits, with a total blood manganese concentration of 34 µg·L⁻¹ (reference range: less than 13 µg·L⁻¹). Discussion: Abnormal movements can be caused by manganese poisoning due to parenteral nutrition and are associated with liver failure in the ICU. Our patient showed toxic Mn concentrations in whole blood after 31 days of receiving 300 μg·d⁻¹ of Mn in PN, a shorter duration than typically reported. Neurotoxicity was observed several months later (223 days). Factors such as liver dysfunction and iron deficiency can modulate neurotoxicity. Age may also be a susceptibility factor due to increased expression of Mn transport proteins. Magnetic resonance imaging (MRI) intensity in the globus pallidus is useful for detecting brain Mn accumulation, but it is not feasible for routine clinical practice. Conclusions: In this case, choreiform movements were attributed to manganese (Mn) accumulation in the basal ganglia. It is essential to monitor patients receiving parenteral nutrition (PN) solutions containing Mn, especially in those who have biomarkers of susceptibility, even if they have not yet shown neurological signs, and routinely measure whole-blood Mn concentrations, iron levels, age, and liver function. If Mn intoxication is suspected, a brain MRI examination should be conducted. Full article

Manganese (Mn) is an essential trace element and a cofactor for several key enzymes, such as mitochondrial superoxide dismutase. Consequently, it plays an important defense role against reactive oxygen species. Despite this, Mn chronic overexposure can result in a neurological disorder referred to as manganism, which shares some similarities with Parkinson’s disease. Mn levels seem regulated by many transporters responsible for its uptake and efflux. These transporters play an established role in many inherited disorders of Mn metabolism and neurotoxicity. Some inherited Mn metabolism disorders, caused by mutations of SLC30A10 and SLC39A14, assume crucial importance since earlier treatment results in a better prognosis. Physicians should be familiar with the clinical presentation of these disorders as the underlying cause of dystonia/parkinsonism and look for other accompanying features, such as liver disease and polycythemia, which are typically associated with SLC30A10 mutations. This review aims to highlight the currently known Mn transporters, Mn-related neurotoxicity, and its consequences, and it provides an overview of inherited and acquired disorders of Mn metabolism. Currently available treatments are also discussed, focusing on the most frequently encountered presentations. Full article

Chronic overexposure to manganese (Mn) can occur in occupational settings, such as welding, leading to increased Mn levels in the brain. Excess brain Mn accumulation may result in neurotoxicity, which is characterized by Parkinsonian-like symptoms including motor and cognitive dysfunctions. In this work, we demonstrate a novel methodology for personalized diagnosis and spatial characterization of abnormal Magnetic Resonance Imaging R1 (R1 = 1/T1) relaxation rates arising from excessive Mn accumulation in welders’ brains. Utilizing voxel-wise population-derived norms based on a frequency age-matched non-exposed group (n = 25), we demonstrate the ability to conduct subject-specific assessments and mapping of Mn exposure using MRI relaxometry. Our results show elevated R1 in multiple brain regions in individual welders, but also extreme between-subject variability in Mn accumulation, debasing the concept that high exposures correlate with uniformly high Mn deposition in the brain. Consequently, the presented personalized methodology serves as a counterpart to group-based comparison, which allows for understanding the level of individual exposure and the toxicokinetics of Mn accumulation. This work lays a foundation for improved occupational health assessments and preventive measures against neurotoxic metal exposure. Full article

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. Full article

This study assessed PM_2.5 concentrations and heavy metal composition in blacksmith workshops located in Mekarmaju village, Bandung Regency, Indonesia. The PM_2.5 levels measured across seven workshops showed significantly elevated concentrations, ranging from 166.88 µg/m³ to 513.80 µg/m³, greatly exceeding the indoor air quality recommended by the World Health Organization (WHO). Chemical analysis revealed toxic heavy metals within PM_2.5, including iron (Fe), chromium (Cr), nickel (Ni), manganese (Mn), zinc (Zn), and lead (Pb), with total heavy metal concentrations varying significantly between workshops. The highest concentration was recorded in workshop B (61.8 µg/m³), while the lowest was in workshop F (6.1 µg/m³). These metals are associated with severe health risks such as respiratory and cardiovascular diseases, neurotoxicity, and increased cancer risk with prolonged exposure. Strong correlations between PM_2.5 and metals such as Fe, Cr, and Mn indicate that emissions from metalworking processes are primary sources of indoor pollution. Although this pilot study provides crucial baseline data, limitations such as a short sampling duration and a small sample size suggest the need for further research. Future studies should include long-term, continuous monitoring and detailed chemical speciation to enhance our understanding of occupational health risks. Full article

Excessive exposure to manganese (Mn) increases the risk of chronic neurological diseases, including Parkinson’s disease (PD) and other related Parkinsonisms. Aggregated α-synuclein (αSyn), a hallmark of PD, can spread to neighboring cells by exosomal release from neurons. We previously discovered that Mn enhances its spread, triggering neuroinflammatory and neurodegenerative processes. To better understand the Mn-induced release of exosomal αSyn, we examined the effect of Mn on endosomal trafficking and misfolded protein degradation. Exposing MN9D dopaminergic neuronal cells stably expressing human wild-type (WT) αSyn to 300 μM Mn for 24 h significantly suppressed protein and mRNA expression of Rab11a, thereby downregulating endosomal recycling, forcing late endosomes to mature into multivesicular bodies (MVBs). Ectopic expression of WT Rab11a significantly mitigated exosome release, whereas ectopic mutant Rab11a (S25N) increased it. Our in vitro and in vivo studies reveal that Mn exposure upregulated (1) mRNA and protein levels of endosomal Rab27a, which mediates the fusion of MVBs with the plasma membrane; and (2) expression of the autophagosomal markers Beclin-1 and p62, but downregulated the lysosomal marker LAMP2, thereby impairing autophagolysosome formation as confirmed by LysoTracker, cathepsin, and acridine orange assays. Our novel findings demonstrate that Mn promotes the exosomal release of misfolded αSyn by impairing endosomal trafficking and protein degradation. Full article

High levels of heavy metal contamination in soil present substantial threats to human health and the environment, leading to severe health problems such as neurotoxicity, cancer, kidney issues, chronic obstructive pulmonary disease, and reduced life expectancy. This research aims to identify and analyze heavy metals in soil samples collected from Superfund sites in North Birmingham, Alabama, specifically in affected areas with zip codes 35207 and 35217 and control area 35214. These affected areas were previously used for mining, coal-fired power plants, coke furnaces, smelting, and other potential sources of heavy metal pollution. Laser-induced breakdown spectroscopy (LIBS) was employed to study 60 soil samples systematically collected from affected and control areas. We found that by using LIBS, we could detect arsenic (As), lead (Pb), and manganese (Mn) in all soil samples from the affected areas. The limit of detection (LoD) was 29.5 mg/kg for Pb, 95.5 mg/kg for As, and 327 mg/kg for Mn using specific parameters of the detection system and/or argon gas purging at atmospheric pressure. The results were compared with ICP-MS measurements to validate the accuracy of the LIBS findings. The data showed good linearity for all calibration data at relatively low concentrations and a good correlation with ICP-MS measurements. Full article

Ovalbumin (OVA), a protein vital for chick embryo nutrition, hydration, and antimicrobial protection, together with other egg-white proteins, migrates to the amniotic fluid and is orally absorbed by the embryo during embryogenesis. Recently, it has been shown that for optimal eggshell quality, the hen diet can be supplemented with manganese. Although essential for embryonic development, manganese in excess causes neurotoxicity. This study investigates whether OVA may be involved in the regulation of manganese levels. The binding of Mn(II) to OVA was investigated using electron paramagnetic resonance (EPR) spectroscopy. The results show that OVA binds a maximum of two Mn(II) ions, one with slightly weaker affinity, even in a 10-fold excess, suggesting it may have a protective role from Mn(II) overload. It seems that the binding of Mn(II), or the presence of excess Mn(II), does not affect OVA’s tertiary structure, as evidenced from fluorescence and UV/vis measurements. Comparative analysis with bovine and human serum albumins revealed that they exhibit higher affinities for Mn(II) than OVA, most likely due to their essentially different physiological roles. These findings suggest that OVA does not play a role in the transport and storage of manganese; however, it may be involved in embryo protection from manganese-induced toxicity. Full article

Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to Mn exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at p < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate Mn-induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, Mn activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated Mn-losses of viability in SH-SY5Y cells. We discuss Mn as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. Mn induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc. Full article

Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V₂O₅) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl₂, V₂O_5, and MnCl₂-V₂O₅ co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl₂ (252 µg) alone, V₂O₅ (182 µg) alone, or a mixture of MnCl₂ (252 µg) and V₂O₅ (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism. Full article

Manganese (Mn), a cofactor for various enzyme classes, is an essential trace metal for all organisms. However, overexposure to Mn causes neurotoxicity. Here, we evaluated the effects of exposure to Mn chloride (MnCl₂) on viability, morphology, synapse function (based on neurogranin expression) and behavior of zebrafish larvae. MnCl₂ exposure from 2.5 h post fertilization led to reduced survival (60%) at 5 days post fertilization. Phenotypical changes affected body length, eye and olfactory organ size, and visual background adaptation. This was accompanied by a decrease in both the fluorescence intensity of neurogranin immunostaining and expression levels of the neurogranin-encoding genes nrgna and nrgnb, suggesting the presence of synaptic alterations. Furthermore, overexposure to MnCl₂ resulted in larvae exhibiting postural defects, reduction in motor activity and impaired preference for light environments. Following the removal of MnCl₂ from the fish water, zebrafish larvae recovered their pigmentation pattern and normalized their locomotor behavior, indicating that some aspects of Mn neurotoxicity are reversible. In summary, our results demonstrate that Mn overexposure leads to pronounced morphological alterations, changes in neurogranin expression and behavioral impairments in zebrafish larvae. Full article

Changes in trace element concentrations are being wildly considered when it comes to neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. This study aims to present the role that trace elements play in the central nervous system. Moreover, we reviewed the mechanisms involved in their neurotoxicity. Low zinc concentrations, as well as high levels of copper, manganese, and iron, activate the signalling pathways of the inflammatory, oxidative and nitrosative stress response. Neurodegeneration occurs due to the association between metals and proteins, which is then followed by aggregate formation, mitochondrial disorder, and, ultimately, cell death. In Alzheimer’s disease, low Zn levels suppress the neurotoxicity induced by β-amyloid through the selective precipitation of aggregation intermediates. High concentrations of copper, iron and manganese cause the aggregation of intracellular α-synuclein, which results in synaptic dysfunction and axonal transport disruption. Parkinson’s disease is caused by the accumulation of Fe in the midbrain dopaminergic nucleus, and the pathogenesis of multiple sclerosis derives from Zn deficiency, leading to an imbalance between T cell functions. Aluminium disturbs the homeostasis of other metals through a rise in the production of oxygen reactive forms, which then leads to cellular death. Selenium, in association with iron, plays a distinct role in the process of ferroptosis. Outlining the influence that metals have on oxidoreduction processes is crucial to recognising the pathophysiology of neurodegenerative diseases and may provide possible new methods for both their avoidance and therapy. Full article