Pub Date : 2026-01-31DOI: 10.1016/j.neuro.2026.103396
Intakhar Ahmad, Jacqueline Rocha, Zachary McDonald, Douglas L Feinstein
Previous studies showed that exposure to long-acting anticoagulant rodenticides (LAARs) can induce neuropathology in adult rats. In the current study we tested if the potent LAAR brodifacoum similarly promoted neuropathology in adult rabbits which provide a better model of human LAAR poisoning. Adult male New Zealand White rabbits were administered by gavage a single administration of brodifacoum at its LD50 dose (200 μg/kg), followed by daily injections of vitamin K1 to prevent mortality due to anti-coagulation. After 3 weeks, examination of the cerebellum revealed an increase in glial cell activation, and a decrease in myelin content. A targeted lipidomics analysis was carried out to determine if brodifacoum altered the relative abundance of lipids enriched in myelin. We observed brodifacoum-dependent decreases in several sulfatides which were associated with an increase in expression of arylsulfatase A which degrades sulfatides. Daily treatment with the bile sequestrant cholestyramine, which accelerates LAAR clearance from the body, ameliorated brodifacoum -induced damage. These findings confirm that, despite daily vitamin K1 treatment, LAARs such as brodifacoum can induce neuropathology in adult animals and support the use of agents such as bile sequestrants to ameliorate those consequences.
{"title":"The long-acting anticoagulant rodenticide brodifacoum induces neuropathology in adult New Zealand White rabbits and is reduced by the bile sequestrant cholestyramine.","authors":"Intakhar Ahmad, Jacqueline Rocha, Zachary McDonald, Douglas L Feinstein","doi":"10.1016/j.neuro.2026.103396","DOIUrl":"10.1016/j.neuro.2026.103396","url":null,"abstract":"<p><p>Previous studies showed that exposure to long-acting anticoagulant rodenticides (LAARs) can induce neuropathology in adult rats. In the current study we tested if the potent LAAR brodifacoum similarly promoted neuropathology in adult rabbits which provide a better model of human LAAR poisoning. Adult male New Zealand White rabbits were administered by gavage a single administration of brodifacoum at its LD<sub>50</sub> dose (200 μg/kg), followed by daily injections of vitamin K1 to prevent mortality due to anti-coagulation. After 3 weeks, examination of the cerebellum revealed an increase in glial cell activation, and a decrease in myelin content. A targeted lipidomics analysis was carried out to determine if brodifacoum altered the relative abundance of lipids enriched in myelin. We observed brodifacoum-dependent decreases in several sulfatides which were associated with an increase in expression of arylsulfatase A which degrades sulfatides. Daily treatment with the bile sequestrant cholestyramine, which accelerates LAAR clearance from the body, ameliorated brodifacoum -induced damage. These findings confirm that, despite daily vitamin K1 treatment, LAARs such as brodifacoum can induce neuropathology in adult animals and support the use of agents such as bile sequestrants to ameliorate those consequences.</p>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":" ","pages":"103396"},"PeriodicalIF":3.9,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1016/j.neuro.2026.103394
Anthony R White
Airborne combustion emissions from military burn pits, wildfires, and urban/industrial sources are increasingly recognized as a component of the neurotoxic exposome, with potential consequences extending beyond cardiopulmonary disease to brain health. These aerosols comprise heterogeneous mixtures of fine and ultrafine particulate matter (PM₂.₅/PM₀.₁), polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and reactive gases whose composition varies with fuel type, combustion efficiency, and atmospheric aging. Evidence from experimental models, epidemiology, and exposed human cohorts supports two principal routes by which inhaled pollutants may influence the central nervous system: (i) the lung-brain axis, where pulmonary oxidative injury and systemic immune activation promote endothelial dysfunction and compromise blood-brain barrier integrity; and (ii) the olfactory (nose-to-brain) pathway, in which ultrafine and lipophilic constituents interact with the olfactory neuroepithelium and are associated with early neuroimmune changes in olfactory-connected brain regions. At the cellular level, these exposures converge on microglial and astrocytic activation, TLR-NF-κB and inflammasome signaling, mitochondrial dysfunction, and lipid peroxidation, processes that can sustain chronic neuroinflammation and plausibly interact with 'second hits' such as traumatic brain injury, psychological stress, heat stress, sleep disruption, and cardiometabolic comorbidity. Veterans and wildland firefighters represent sentinel occupational groups for defining exposure-biomarker-outcome relationships. This review brings together current evidence linking combustion-derived aerosols to neuroinflammatory and neurodegeneration-relevant mechanisms, highlighting source-specific considerations for military operational exposure, and outlines translational strategies for exposure monitoring, multi-omic biomarker discovery (blood and nasal/olfactory sampling), and early risk stratification to enable targeted prevention in vulnerable populations.
{"title":"The Impact of Military Occupational Combustion Smoke Inhalation on Neuroinflammation and Brain Health.","authors":"Anthony R White","doi":"10.1016/j.neuro.2026.103394","DOIUrl":"https://doi.org/10.1016/j.neuro.2026.103394","url":null,"abstract":"<p><p>Airborne combustion emissions from military burn pits, wildfires, and urban/industrial sources are increasingly recognized as a component of the neurotoxic exposome, with potential consequences extending beyond cardiopulmonary disease to brain health. These aerosols comprise heterogeneous mixtures of fine and ultrafine particulate matter (PM₂.₅/PM₀.₁), polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and reactive gases whose composition varies with fuel type, combustion efficiency, and atmospheric aging. Evidence from experimental models, epidemiology, and exposed human cohorts supports two principal routes by which inhaled pollutants may influence the central nervous system: (i) the lung-brain axis, where pulmonary oxidative injury and systemic immune activation promote endothelial dysfunction and compromise blood-brain barrier integrity; and (ii) the olfactory (nose-to-brain) pathway, in which ultrafine and lipophilic constituents interact with the olfactory neuroepithelium and are associated with early neuroimmune changes in olfactory-connected brain regions. At the cellular level, these exposures converge on microglial and astrocytic activation, TLR-NF-κB and inflammasome signaling, mitochondrial dysfunction, and lipid peroxidation, processes that can sustain chronic neuroinflammation and plausibly interact with 'second hits' such as traumatic brain injury, psychological stress, heat stress, sleep disruption, and cardiometabolic comorbidity. Veterans and wildland firefighters represent sentinel occupational groups for defining exposure-biomarker-outcome relationships. This review brings together current evidence linking combustion-derived aerosols to neuroinflammatory and neurodegeneration-relevant mechanisms, highlighting source-specific considerations for military operational exposure, and outlines translational strategies for exposure monitoring, multi-omic biomarker discovery (blood and nasal/olfactory sampling), and early risk stratification to enable targeted prevention in vulnerable populations.</p>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":" ","pages":"103394"},"PeriodicalIF":3.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1016/j.neuro.2026.103395
Lamiaa M. Shawky , Ahmed A. Morsi , Nermine Beshara , Omar T. Abualnasr , Ghena Hamza , Lamia Asali , Faten Asali , Eman El Bana
Lead (Pb) toxicity is a great community health problem. Brain is the primary target organ of Pb intoxication. Ascorbic acid (AA) and Gallic acid (GA) have proven to show potential anti‑inflammatory and antioxidant properties during heavy metal intoxication. So, the current paper aimed to explore the possible protection of AA, GA, and their combination in the current model of Pb neurotoxicity. Fifty-six Wistar male albino rats were assigned into seven groups: control, AA alone (10 mg/kg, oral), GA alone (20 mg/kg, oral), Pb alone (40 mg/kg, intraperitoneal), AA/Pb, GA/Pb, and AA/GA/Pb combination groups. After one month of oral treatment, the animals were humanely killed, and brain cortical samples were extracted for biochemical measurement of the inflammatory and oxidative markers in the brain tissue homogenates. Moreover, the samples were subjected to structural and ultrastructural examinations using light and electron microscopic (EM) studies. Pb resulted in brain injury indicated by remarkable structural and ultrastructural changes evident by neuronal degeneration and reduction of healthy nerve cells. EM showed atrophic nerve cells with irregular outlines, swollen, rarefied mitochondria, and enlarged, fused electron-dense lysosomes indicating possible autophagic vacuoles. Also, a significant increase in the pro-inflammatory markers was noticed, as evident by the raised immunohistochemical expression of glial fibrillary acidic protein (GFAP), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α). In addition, the anti-inflammatory marker decreased, as denoted by the decline in superoxide dismutase (SOD) and catalase. All these alterations were lessened by AA and GA with great restoration in the AA/GA combination group, which showed almost normal histological, ultrastructural, and biochemical parameters. AA and GA are suggested to alleviate Pb‑induced neurotoxicity owing to the modulation of oxidative stress, inflammation, and apoptosis. However, the AA/GA combination shows the greatest effect as evidenced by biochemical, structural, and ultrastructural analyses.
{"title":"Gallic and ascorbic acids either alone or combined contribute to ameliorating lead-induced cerebral neurotoxicity in rats: A histological and immunohistochemical study","authors":"Lamiaa M. Shawky , Ahmed A. Morsi , Nermine Beshara , Omar T. Abualnasr , Ghena Hamza , Lamia Asali , Faten Asali , Eman El Bana","doi":"10.1016/j.neuro.2026.103395","DOIUrl":"10.1016/j.neuro.2026.103395","url":null,"abstract":"<div><div>Lead (Pb) toxicity is a great community health problem. Brain is the primary target organ of Pb intoxication. Ascorbic acid (AA) and Gallic acid (GA) have proven to show potential anti‑inflammatory and antioxidant properties during heavy metal intoxication. So, the current paper aimed to explore the possible protection of AA, GA, and their combination in the current model of Pb neurotoxicity. Fifty-six Wistar male albino rats were assigned into seven groups: control, AA alone (10 mg/kg, oral), GA alone (20 mg/kg, oral), Pb alone (40 mg/kg, intraperitoneal), AA/Pb, GA/Pb, and AA/GA/Pb combination groups. After one month of oral treatment, the animals were humanely killed, and brain cortical samples were extracted for biochemical measurement of the inflammatory and oxidative markers in the brain tissue homogenates. Moreover, the samples were subjected to structural and ultrastructural examinations using light and electron microscopic (EM) studies. Pb resulted in brain injury indicated by remarkable structural and ultrastructural changes evident by neuronal degeneration and reduction of healthy nerve cells. EM showed atrophic nerve cells with irregular outlines, swollen, rarefied mitochondria, and enlarged, fused electron-dense lysosomes indicating possible autophagic vacuoles. Also, a significant increase in the pro-inflammatory markers was noticed, as evident by the raised immunohistochemical expression of glial fibrillary acidic protein (GFAP), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α). In addition, the anti-inflammatory marker decreased, as denoted by the decline in superoxide dismutase (SOD) and catalase. All these alterations were lessened by AA and GA with great restoration in the AA/GA combination group, which showed almost normal histological, ultrastructural, and biochemical parameters. AA and GA are suggested to alleviate Pb‑induced neurotoxicity owing to the modulation of oxidative stress, inflammation, and apoptosis. However, the AA/GA combination shows the greatest effect as evidenced by biochemical, structural, and ultrastructural analyses.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103395"},"PeriodicalIF":3.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1016/j.neuro.2026.103393
Xueqi Tang , Priyanka Baloni , Michael Aschner , Aaron B. Bowman
Understanding manganese (Mn) neurotoxicity requires experimental models that realistically reflect human exposure scenarios. A key limitation of current in vitro paradigms is the reliance on acute, high-concentration exposures, which may not accurately capture the molecular consequences of long-term Mn accumulation. To address this, this study compared transcriptomic responses to acute (6-hour) and chronic (40-day) Mn exposures in SH-SY5Y cells, using Mn concentrations spanning near-physiological to sub-cytotoxic ranges. The 6-hour exposure design replicates a widely applied acute duration in the literature, while the 40-day duration was selected to mimic prolonged, low-level Mn burden reported in epidemiological and occupational studies. Bulk RNA sequencing revealed that chronic Mn exposure induced distinct and more extensive transcriptional alterations compared to acute exposure, independent of concentration. Pathway enrichment analyses indicated that cellular functions selectively perturbed under chronic conditions are highly relevant to neurodegenerative risks and aligns with independent Parkinson’s disease transcriptomic datasets. These pathways include axonal guidance signaling, amyloid fiber formation, extracellular matrix organization, and synaptic functioning. In contrast, acute exposures primarily disturbed intracellular ion homeostasis maintenance mechanisms. Protein kinase A signaling and metallothionein-mediated metal-binding pathway were the only two pathways that were shared between both applied durations exposed at Mn concentrations with reported adverse outcomes. Transcriptomic alterations in this study highlighted the contribution of mechanisms related to normal Mn-dependent cellular functions in the development of its neurotoxicity. Furthermore, these results emphasized that exposure duration is a critical determinant to be considered when evaluating long-term Mn overload-induced neurodegeneration via in vitro platforms.
{"title":"Prolonged duration induces divergent transcriptomic responses to manganese, distinct from concentration effects, in an SH-SY5Y neurotoxicity model","authors":"Xueqi Tang , Priyanka Baloni , Michael Aschner , Aaron B. Bowman","doi":"10.1016/j.neuro.2026.103393","DOIUrl":"10.1016/j.neuro.2026.103393","url":null,"abstract":"<div><div>Understanding manganese (Mn) neurotoxicity requires experimental models that realistically reflect human exposure scenarios. A key limitation of current <em>in vitro</em> paradigms is the reliance on acute, high-concentration exposures, which may not accurately capture the molecular consequences of long-term Mn accumulation. To address this, this study compared transcriptomic responses to acute (6-hour) and chronic (40-day) Mn exposures in SH-SY5Y cells, using Mn concentrations spanning near-physiological to sub-cytotoxic ranges. The 6-hour exposure design replicates a widely applied acute duration in the literature, while the 40-day duration was selected to mimic prolonged, low-level Mn burden reported in epidemiological and occupational studies. Bulk RNA sequencing revealed that chronic Mn exposure induced distinct and more extensive transcriptional alterations compared to acute exposure, independent of concentration. Pathway enrichment analyses indicated that cellular functions selectively perturbed under chronic conditions are highly relevant to neurodegenerative risks and aligns with independent Parkinson’s disease transcriptomic datasets. These pathways include axonal guidance signaling, amyloid fiber formation, extracellular matrix organization, and synaptic functioning. In contrast, acute exposures primarily disturbed intracellular ion homeostasis maintenance mechanisms. Protein kinase A signaling and metallothionein-mediated metal-binding pathway were the only two pathways that were shared between both applied durations exposed at Mn concentrations with reported adverse outcomes. Transcriptomic alterations in this study highlighted the contribution of mechanisms related to normal Mn-dependent cellular functions in the development of its neurotoxicity. Furthermore, these results emphasized that exposure duration is a critical determinant to be considered when evaluating long-term Mn overload-induced neurodegeneration via <em>in vitro</em> platforms.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103393"},"PeriodicalIF":3.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dimethylacetamide (DMAC) is a polar organic solvent widely used in the production of synthetic fibers and other industrial applications. Its hepatotoxic potential has been well documented in laboratory animals and occupationally exposed workers, establishing DMAC as a recognized industrial hazard. However, evidence regarding its neurological effects remains scarce. We report a clinical case of accidental DMAC inhalation associated with diffuse cortical hyperintensity on brain magnetic resonance imaging, raising concern for direct neurotoxicity. To address this knowledge gap, we investigated the neurotoxic potential of DMAC in a controlled rat model experiment. Animals subjected to repeated intraperitoneal DMAC administration exhibited cortical and subcortical histopathological alterations consistent with neurotoxicity, accompanied by significant hepatic and renal injury. These findings provide the first experimental evidence that DMAC toxicity extends beyond hepatotoxicity to involve the central nervous system and kidneys, highlighting its potential for multi-organ toxicity and reinforcing concerns regarding occupational exposure risks.
{"title":"From clinical observation to experimental validation: Investigating the neurotoxic impact of dimethylacetamide","authors":"Hizir Asliyuksek , Nihan Hande Akcakaya , Rumeysa Hekimoglu , Simay Bozkurt , Berna Yeniceri , Onder Huseyinbas , Sibel Atacan , Mukaddes Esrefoglu , Emrah Yucesan , Beyza Goncu","doi":"10.1016/j.neuro.2026.103392","DOIUrl":"10.1016/j.neuro.2026.103392","url":null,"abstract":"<div><div>Dimethylacetamide (DMAC) is a polar organic solvent widely used in the production of synthetic fibers and other industrial applications. Its hepatotoxic potential has been well documented in laboratory animals and occupationally exposed workers, establishing DMAC as a recognized industrial hazard. However, evidence regarding its neurological effects remains scarce. We report a clinical case of accidental DMAC inhalation associated with diffuse cortical hyperintensity on brain magnetic resonance imaging, raising concern for direct neurotoxicity. To address this knowledge gap, we investigated the neurotoxic potential of DMAC in a controlled rat model experiment. Animals subjected to repeated intraperitoneal DMAC administration exhibited cortical and subcortical histopathological alterations consistent with neurotoxicity, accompanied by significant hepatic and renal injury. These findings provide the first experimental evidence that DMAC toxicity extends beyond hepatotoxicity to involve the central nervous system and kidneys, highlighting its potential for multi-organ toxicity and reinforcing concerns regarding occupational exposure risks.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103392"},"PeriodicalIF":3.9,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.neuro.2026.103391
Martin Macháček , Markéta Bébarová
Synthetic cathinones and phenethylamines are increasingly prevalent novel psychoactive substances with stimulant and hallucinogenic properties. They are associated with acute symptomatic seizures, often with lethal outcomes. Current management is usually limited to symptomatic therapy, as serotonin and sympathomimetic toxidromes are widely regarded as the main seizure-inducing mechanisms. However, intoxications frequently involve severe organ toxicities or metabolic disturbances with high epileptogenic potential, which may be preventable or treatable. This review aimed to assess seizure mechanisms beyond central monoaminergic toxicity to identify additional factors and improve seizure management. A systematic search of PubMed and Web of Science (2003–2024) identified reports describing individual human cases of acute intoxication with synthetic cathinones or phenethylamines, published in English and providing detailed clinical data. Inclusion criteria were met by 42 cases from 34 reports. A descriptive synthesis was performed to summarize observed patterns across substance groups. Most seizures occurred in previously healthy young adults and resulted in death in nearly 50 % of cases, with higher fatality among cathinone users. Serotonin and sympathomimetic toxidromes were present in most cases, supporting a primary role in seizure generation. However, intracranial hemorrhage and cerebral edema (often precipitated by hypertensive crisis), hypoglycemia, and hyponatremia likely contributed to seizures in several cases. Based on these findings, we recommend that young adults presenting with seizures and signs of monoaminergic toxicity, in whom synthetic cathinone or phenethylamine intoxication is confirmed or suspected, should be promptly assessed for focal brain injury and metabolic disturbances to identify treatable causes and potentially improve outcomes.
合成卡西酮和苯乙胺是越来越普遍的新型精神活性物质，具有兴奋和致幻性质。它们与急性症状性癫痫发作有关，通常具有致命的后果。目前的治疗通常局限于对症治疗，因为5 -羟色胺和拟交感神经毒素被广泛认为是主要的癫痫诱发机制。然而，中毒通常涉及严重的器官毒性或具有高致痫潜能的代谢紊乱，这是可以预防或治疗的。本综述旨在评估除中枢单胺能毒性外的癫痫发作机制，以确定其他因素并改善癫痫发作管理。通过对PubMed和Web of Science（2003-2024）的系统搜索，发现了用英文发表并提供详细临床数据的报告，这些报告描述了人工合成卡西酮或苯乙胺急性中毒的个体病例。34例报告中有42例符合纳入标准。进行描述性综合，以总结在物质组中观察到的模式。大多数癫痫发作发生在以前健康的年轻人中，导致近50% %的病例死亡，卡西酮使用者的死亡率更高。5 -羟色胺和拟交感神经毒素在大多数病例中存在，支持癫痫发作的主要作用。然而，颅内出血和脑水肿（通常由高血压危象引起）、低血糖和低钠血症可能导致几例癫痫发作。基于这些发现，我们建议出现癫痫发作和单胺中毒症状的年轻人，如果确认或怀疑合成卡西酮或苯乙胺中毒，应及时评估局灶性脑损伤和代谢紊乱，以确定可治疗的原因，并可能改善结果。
{"title":"Triggers of highly lethal seizures induced by novel stimulants: A systematic review focused on synthetic cathinones and phenethylamines","authors":"Martin Macháček , Markéta Bébarová","doi":"10.1016/j.neuro.2026.103391","DOIUrl":"10.1016/j.neuro.2026.103391","url":null,"abstract":"<div><div>Synthetic cathinones and phenethylamines are increasingly prevalent novel psychoactive substances with stimulant and hallucinogenic properties. They are associated with acute symptomatic seizures, often with lethal outcomes. Current management is usually limited to symptomatic therapy, as serotonin and sympathomimetic toxidromes are widely regarded as the main seizure-inducing mechanisms. However, intoxications frequently involve severe organ toxicities or metabolic disturbances with high epileptogenic potential, which may be preventable or treatable. This review aimed to assess seizure mechanisms beyond central monoaminergic toxicity to identify additional factors and improve seizure management. A systematic search of PubMed and Web of Science (2003–2024) identified reports describing individual human cases of acute intoxication with synthetic cathinones or phenethylamines, published in English and providing detailed clinical data. Inclusion criteria were met by 42 cases from 34 reports. A descriptive synthesis was performed to summarize observed patterns across substance groups. Most seizures occurred in previously healthy young adults and resulted in death in nearly 50 % of cases, with higher fatality among cathinone users. Serotonin and sympathomimetic toxidromes were present in most cases, supporting a primary role in seizure generation. However, intracranial hemorrhage and cerebral edema (often precipitated by hypertensive crisis), hypoglycemia, and hyponatremia likely contributed to seizures in several cases. Based on these findings, we recommend that young adults presenting with seizures and signs of monoaminergic toxicity, in whom synthetic cathinone or phenethylamine intoxication is confirmed or suspected, should be promptly assessed for focal brain injury and metabolic disturbances to identify treatable causes and potentially improve outcomes.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103391"},"PeriodicalIF":3.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-10DOI: 10.1016/j.neuro.2026.103390
David Mateo , Marília Cristina Oliveira Souza , Nerea Carrión , Luis Heredia , Cristian Cabrera , Montse Marquès , Eva Forcadell-Ferreres , Maria Pino , Josep Zaragoza , José Luis Domingo , Fernando Barbosa , Margarita Torrente
Background
Gut microbiota (GMB) and metal exposure have both been implicated in cognitive impairment (CI), including amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). However, studies integrating these areas remain scarce.
Objective
This pilot study aimed to investigate whether exposure to metals modulates the relationship between GMB composition and clinical outcomes in individuals with CI.
Methods
Stool samples were collected from aMCI (n = 12), AD (n = 18), and cognitively healthy controls (HC, n = 30). Participants were categorized into CI (n = 30) and HC (n = 30). Gut microbial diversity was assessed using shotgun sequencing, and 25 metals were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive, neuropsychological, neuropsychiatric, and functional assessments were also conducted.
Results
No significant differences were observed between groups in microbial richness, alpha-diversity (Shannon index), or beta-diversity (Bray–Curtis). Likewise, microbial diversity measures were not associated with cognitive outcomes. In contrast, aMCI and AD participants exhibited significantly higher fecal concentrations of silver (Ag), lithium (Li), and platinum (Pt) compared to HC (all p < 0.001).
Conclusion
This multidimensional pilot study integrating microbiota profiling, metal exposure assessment, and cognitive evaluation, revealed elevated fecal excretion of Ag, Li, and Pt in participants with cognitive impairment, suggesting potential interactions between trace metals and neurodegenerative processes. While no significant differences in overall microbial diversity were observed between groups, these findings emphasize the need for larger, longitudinal investigations to elucidate the complex relationships among gut microbiota, metal homeostasis, and cognitive decline.
{"title":"Elevated fecal silver, lithium, and platinum in cognitive impairment: A pilot exploration of microbiota–metal interactions","authors":"David Mateo , Marília Cristina Oliveira Souza , Nerea Carrión , Luis Heredia , Cristian Cabrera , Montse Marquès , Eva Forcadell-Ferreres , Maria Pino , Josep Zaragoza , José Luis Domingo , Fernando Barbosa , Margarita Torrente","doi":"10.1016/j.neuro.2026.103390","DOIUrl":"10.1016/j.neuro.2026.103390","url":null,"abstract":"<div><h3>Background</h3><div>Gut microbiota (GMB) and metal exposure have both been implicated in cognitive impairment (CI), including amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). However, studies integrating these areas remain scarce.</div></div><div><h3>Objective</h3><div>This pilot study aimed to investigate whether exposure to metals modulates the relationship between GMB composition and clinical outcomes in individuals with CI.</div></div><div><h3>Methods</h3><div>Stool samples were collected from aMCI (n = 12), AD (n = 18), and cognitively healthy controls (HC, n = 30). Participants were categorized into CI (n = 30) and HC (n = 30). Gut microbial diversity was assessed using shotgun sequencing, and 25 metals were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive, neuropsychological, neuropsychiatric, and functional assessments were also conducted.</div></div><div><h3>Results</h3><div>No significant differences were observed between groups in microbial richness, alpha-diversity (Shannon index), or beta-diversity (Bray–Curtis). Likewise, microbial diversity measures were not associated with cognitive outcomes. In contrast, aMCI and AD participants exhibited significantly higher fecal concentrations of silver (Ag), lithium (Li), and platinum (Pt) compared to HC (all p < 0.001).</div></div><div><h3>Conclusion</h3><div>This multidimensional pilot study integrating microbiota profiling, metal exposure assessment, and cognitive evaluation, revealed elevated fecal excretion of Ag, Li, and Pt in participants with cognitive impairment, suggesting potential interactions between trace metals and neurodegenerative processes. While no significant differences in overall microbial diversity were observed between groups, these findings emphasize the need for larger, longitudinal investigations to elucidate the complex relationships among gut microbiota, metal homeostasis, and cognitive decline.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103390"},"PeriodicalIF":3.9,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.neuro.2026.103389
Yuxin Lin, Qian Jin, Yuanqing Chen, Jingyan Wang, Yi Zhang, Manzhu Cao, Jingjing Shi, Liqin Li
Exposure to organophosphorus nerve agents (OPNAs) like soman frequently develops status epilepticus (SE), leading to brain damage. Existing antiseizure medications (e.g., diazepam, DZP) often demonstrate insufficient efficacy. To develop more effective treatments for OPNA-induced seizures, this study evaluated the efficacy of glutamate receptor antagonists with distinct mechanisms of action in a soman-induced rat seizure model. After 5 min of subcutaneous exposure to 110 μg/kg soman, which induced SE, rats received intraperitoneal injections (10 mg/kg) of perampanel (PER), fanapanel (FNP), IEM-1925 (IEM), or DZP. The results showed that IEM significantly suppressed seizure activity and improved survival. The survival rate of the vehicle-treated control group was 31.25 %, whereas DZP, FNP, and IEM increased survival rates to 50 %, 43.75 %, and 56.25 % respectively. Electroencephalographic (EEG) recordings for 24 h indicated that both DZP and IEM controlled soman-induced SE. However, while DZP initially blocked the onset of seizures, they recurred after its transient anticonvulsant effect wore off. In contrast, IEM reduced behavioral convulsion intensity and total duration of SE. Histopathological examinations (HE, Nissl, immunohistochemistry, and immunofluorescence) showed that IEM attenuated hippocampal CA1, CA2, and DG neuronal damage. Behavioral tests (open field, novel object recognition, and Y maze) confirmed IEM outperformed DZP and the solvent-treated group in ameliorating soman-induced anxiety, cognitive dysfunction, and memory impairment. In conclusion, IEM demonstrates potent triple effects-antiseizure, neuroprotective, and cognitive improving in soman exposure model, providing a novel therapeutic strategy and candidate drug for the medical treatment of OPNAs poisoning.
{"title":"Targeting glutamate receptors with IEM-1925: A strategy against soman-induced status epilepticus and neurodegeneration","authors":"Yuxin Lin, Qian Jin, Yuanqing Chen, Jingyan Wang, Yi Zhang, Manzhu Cao, Jingjing Shi, Liqin Li","doi":"10.1016/j.neuro.2026.103389","DOIUrl":"10.1016/j.neuro.2026.103389","url":null,"abstract":"<div><div>Exposure to organophosphorus nerve agents (OPNAs) like soman frequently develops status epilepticus (SE), leading to brain damage. Existing antiseizure medications (e.g., diazepam, DZP) often demonstrate insufficient efficacy. To develop more effective treatments for OPNA-induced seizures, this study evaluated the efficacy of glutamate receptor antagonists with distinct mechanisms of action in a soman-induced rat seizure model. After 5 min of subcutaneous exposure to 110 μg/kg soman, which induced SE, rats received intraperitoneal injections (10 mg/kg) of perampanel (PER), fanapanel (FNP), IEM-1925 (IEM), or DZP. The results showed that IEM significantly suppressed seizure activity and improved survival. The survival rate of the vehicle-treated control group was 31.25 %, whereas DZP, FNP, and IEM increased survival rates to 50 %, 43.75 %, and 56.25 % respectively. Electroencephalographic (EEG) recordings for 24 h indicated that both DZP and IEM controlled soman-induced SE. However, while DZP initially blocked the onset of seizures, they recurred after its transient anticonvulsant effect wore off. In contrast, IEM reduced behavioral convulsion intensity and total duration of SE. Histopathological examinations (HE, Nissl, immunohistochemistry, and immunofluorescence) showed that IEM attenuated hippocampal CA1, CA2, and DG neuronal damage. Behavioral tests (open field, novel object recognition, and Y maze) confirmed IEM outperformed DZP and the solvent-treated group in ameliorating soman-induced anxiety, cognitive dysfunction, and memory impairment. In conclusion, IEM demonstrates potent triple effects-antiseizure, neuroprotective, and cognitive improving in soman exposure model, providing a novel therapeutic strategy and candidate drug for the medical treatment of OPNAs poisoning.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103389"},"PeriodicalIF":3.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.neuro.2026.103386
Courtney Hillman , James Kearn , Maciej Trznadel , Matthew J. Winter , Matthew O. Parker
The rapid emergence of novel psychoactive substances poses a growing neurotoxicological concern, characterised by poorly defined mechanisms, high potency, and escalating overdose fatalities. Effective treatments remain limited, highlighting the need for scalable in vivo systems capable of identifying hazardous pharmacological profiles before widespread harm occurs. Here, we evaluated larval zebrafish (Danio rerio) as a medium/high-throughput model for early hazard assessment of γ-aminobutyric acid (GABA)A positive allosteric modulators (PAMs) and N-methyl-D-aspartate (NMDA) receptor antagonists. Behavioural analysis of 4 days post-fertilisation (dpf) larvae revealed concentration-dependent locomotor effects consistent with mammalian pharmacodynamics, while whole-body bioanalysis confirmed compound uptake, revealing substance-specific differences in internal exposure. Notably, diazepam and tiletamine deviated from expected class profiles, highlighting the model’s sensitivity to compounds with distinctive neuropharmacological signatures. These findings demonstrate the translational value of larval zebrafish for rapid neurotoxicity screening and pharmacodynamic profiling, offering an ethically advantageous, 3Rs-aligned platform to inform overdose treatment development and prioritisation of emerging psychoactive threats.
新型精神活性物质的迅速出现引起了越来越多的神经毒理学关注，其特点是机制不明确，效力高，过量死亡人数不断上升。有效的治疗方法仍然有限，强调需要可扩展的体内系统，能够在广泛的伤害发生之前识别危险的药理学特征。本研究以斑马鱼幼鱼（Danio rerio）作为中/高通量模型，用于γ-氨基丁酸（GABA） a阳性变构调节剂（PAMs）和n -甲基- d -天门氨酸（NMDA）受体拮抗剂的早期危害评估。受精后4天（dpf）幼虫的行为分析显示了与哺乳动物药效学一致的浓度依赖性运动效应，而全身生物分析证实了化合物摄取，揭示了物质内部暴露的特异性差异。值得注意的是，地西泮和替乐胺偏离了预期的类概况，突出了模型对具有独特神经药理特征的化合物的敏感性。这些发现证明了斑马鱼幼虫在快速神经毒性筛查和药效学分析方面的转化价值，提供了一个具有伦理优势的、符合3rs的平台，为过量治疗的开发和新出现的精神活性威胁的优先级提供信息。
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Pub Date : 2026-01-01DOI: 10.1016/j.neuro.2025.103374
Hong Yang , Weihao Fan , Xinyu Yang , Ying Wei , Li Xiao , Hongkun Yang , Linzhi Jiang , Jian Li , Kaiting Shi , Shuang Zhao , Lin Yang , Yi Ye , Linchuan Liao
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits both therapeutic potential and abuse liability. However, the spatial distribution of ketamine across brain regions remains poorly characterized. Meanwhile, elucidating the mechanism underlying ketamine-induced psychiatric disorders through the investigation of metabolite alterations in the specific brain regions targeted by ketamine is of crucial significance. This study investigated the neurochemical effects of chronic ketamine administration in C57BL/6 mice using in situ mass spectrometry imaging (MSI) and metabolomics. Mice treated with ketamine (30 mg/kg daily for 15 days) exhibited increased anxiety-like behaviors without cognitive deficits. MSI revealed ketamine accumulation in the cerebral cortex, midbrain, and cerebellum, while the key neurotransmitter γ-aminobutyric acid (GABA) distribution shifted toward thalamic and striatum regions. The prefrontal cortex and cerebellum were selected as targeted brain regions for metabolomics analysis based on the MSI results. In metabolomics results, 73 and 134 differential metabolites in the prefrontal cortex and cerebellum were identified, respectively, predominantly linked to Alanine, aspartate, and glutamate metabolism, Estrogen signaling pathway, and GABAergic synapse pathways. This study integrated behavioral assessments, in situ MSI, and metabolomics to visually resolve and multidimensionally correlate ketamine's spatial distribution in the brain with region-specific metabolic changes in a ketamine-induced anxiety model. The findings reveal distinct neurochemical disruptions across brain regions and offer a groundwork for further elucidating the mechanisms of ketamine-related anxiety.
氯胺酮是一种n -甲基- d -天冬氨酸（NMDA）受体拮抗剂，具有治疗潜力和滥用危险。然而，氯胺酮在大脑区域的空间分布特征仍然很差。同时，通过研究氯胺酮靶向的特定脑区代谢物改变来阐明氯胺酮致精神障碍的机制具有重要意义。本研究采用原位质谱成像（MSI）和代谢组学方法研究慢性氯胺酮给药对C57BL/6小鼠神经化学的影响。氯胺酮（每天30mg/kg，连续15天）治疗的小鼠表现出焦虑样行为增加，但没有认知缺陷。MSI显示氯胺酮在大脑皮层、中脑和小脑积聚，而关键的神经递质γ-氨基丁酸（GABA）分布向丘脑和纹状体区域转移。根据MSI结果，选择前额叶皮层和小脑作为代谢组学分析的目标脑区。在代谢组学结果中，分别在前额叶皮层和小脑中鉴定出73种和134种差异代谢物，主要与丙氨酸、天冬氨酸和谷氨酸代谢、雌激素信号通路和gaba能突触通路有关。本研究综合了行为评估、原位MSI和代谢组学，在氯胺酮诱导的焦虑模型中，视觉分析氯胺酮在大脑中的空间分布与区域特异性代谢变化之间的多维关联。研究结果揭示了不同大脑区域的神经化学破坏，并为进一步阐明氯胺酮相关焦虑的机制提供了基础。
{"title":"Ketamine's brain spatial distribution and metabolic effects in a mouse model of anxiety: Insight into in situ mass spectrometry imaging and metabolomics methods","authors":"Hong Yang , Weihao Fan , Xinyu Yang , Ying Wei , Li Xiao , Hongkun Yang , Linzhi Jiang , Jian Li , Kaiting Shi , Shuang Zhao , Lin Yang , Yi Ye , Linchuan Liao","doi":"10.1016/j.neuro.2025.103374","DOIUrl":"10.1016/j.neuro.2025.103374","url":null,"abstract":"<div><div>Ketamine, an N-methyl-<span>D</span>-aspartate (NMDA) receptor antagonist, exhibits both therapeutic potential and abuse liability. However, the spatial distribution of ketamine across brain regions remains poorly characterized. Meanwhile, elucidating the mechanism underlying ketamine-induced psychiatric disorders through the investigation of metabolite alterations in the specific brain regions targeted by ketamine is of crucial significance. This study investigated the neurochemical effects of chronic ketamine administration in C57BL/6 mice using in situ mass spectrometry imaging (MSI) and metabolomics. Mice treated with ketamine (30 mg/kg daily for 15 days) exhibited increased anxiety-like behaviors without cognitive deficits. MSI revealed ketamine accumulation in the cerebral cortex, midbrain, and cerebellum, while the key neurotransmitter γ-aminobutyric acid (GABA) distribution shifted toward thalamic and striatum regions. The prefrontal cortex and cerebellum were selected as targeted brain regions for metabolomics analysis based on the MSI results. In metabolomics results, 73 and 134 differential metabolites in the prefrontal cortex and cerebellum were identified, respectively, predominantly linked to Alanine, aspartate, and glutamate metabolism, Estrogen signaling pathway, and GABAergic synapse pathways. This study integrated behavioral assessments, in situ MSI, and metabolomics to visually resolve and multidimensionally correlate ketamine's spatial distribution in the brain with region-specific metabolic changes in a ketamine-induced anxiety model. The findings reveal distinct neurochemical disruptions across brain regions and offer a groundwork for further elucidating the mechanisms of ketamine-related anxiety.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103374"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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