Pub Date : 2025-12-01Epub Date: 2025-09-05DOI: 10.1016/j.neuro.2025.103316
Natália Harumi Corrêa Kobayashi , Lucas Villar Pedrosa da Silva Pantoja , Brenda Costa da Conceição , Marta Eduarda Oliveira Barbosa , Sabrina de Carvalho Cartágenes , Pedro Iuri Castro da Silva , Jofre Jacob da Silva Freitas , Geanne Matos de Andrade , Enéas Andrade Fontes-Junior , Bruno Gonçalves Pinheiro , Cristiane do Socorro Ferraz Maia
Ketamine has been widely used as a recreational substance by adolescents and young adults in nightclubs and raves in an acute manner, especially during the weekend. Considering the scarcity of evidence on the harmful consequences of adolescent ketamine recreational use on the central nervous system, primarily related to motor function, this study aimed to investigate the behavioral, biochemical, and neurochemical consequences on motor function induced by ketamine use, evaluating the motor cortex, cerebellum, and striatum in early abstinence. Adolescent female Wistar rats (28 days old) received ketamine by intranasal route (10 mg/kg/day) for 3 consecutive days. Twenty-four hours following the ketamine protocol, the animals were subjected to behavioral tests in the open field, inclined plane, pole, and rotarod tests. After behavioral assays, the animals were anesthetized and euthanized for the collection of the motor cortex, cerebellum, and striatum for biochemical and monoamine evaluations. We found that ketamine exposure in early adolescence induced a reduction in spontaneous locomotion, motor imbalance, and bradykinesia associated with oxidative stress and a decrease in neurotransmitter levels, particularly dopamine, norepinephrine, and serotonin in the striatal region. These results demonstrate that ketamine recreational use in a binge pattern in the early adolescence period displays a widespread motor function impairment during the first periods of withdrawal, which oxidative damage in motor areas and neurotransmitter reduction in the striatum may contribute to the behavioral alteration observed.
{"title":"Monoamine depletion and oxidative imbalance underlie ketamine-induced motor deficits in adolescent rats","authors":"Natália Harumi Corrêa Kobayashi , Lucas Villar Pedrosa da Silva Pantoja , Brenda Costa da Conceição , Marta Eduarda Oliveira Barbosa , Sabrina de Carvalho Cartágenes , Pedro Iuri Castro da Silva , Jofre Jacob da Silva Freitas , Geanne Matos de Andrade , Enéas Andrade Fontes-Junior , Bruno Gonçalves Pinheiro , Cristiane do Socorro Ferraz Maia","doi":"10.1016/j.neuro.2025.103316","DOIUrl":"10.1016/j.neuro.2025.103316","url":null,"abstract":"<div><div>Ketamine has been widely used as a recreational substance by adolescents and young adults in nightclubs and raves in an acute manner, especially during the weekend. Considering the scarcity of evidence on the harmful consequences of adolescent ketamine recreational use on the central nervous system, primarily related to motor function, this study aimed to investigate the behavioral, biochemical, and neurochemical consequences on motor function induced by ketamine use, evaluating the motor cortex, cerebellum, and striatum in early abstinence. Adolescent female Wistar rats (28 days old) received ketamine by intranasal route (10 mg/kg/day) for 3 consecutive days. Twenty-four hours following the ketamine protocol, the animals were subjected to behavioral tests in the open field, inclined plane, pole, and rotarod tests. After behavioral assays, the animals were anesthetized and euthanized for the collection of the motor cortex, cerebellum, and striatum for biochemical and monoamine evaluations. We found that ketamine exposure in early adolescence induced a reduction in spontaneous locomotion, motor imbalance, and bradykinesia associated with oxidative stress and a decrease in neurotransmitter levels, particularly dopamine, norepinephrine, and serotonin in the striatal region. These results demonstrate that ketamine recreational use in a binge pattern in the early adolescence period displays a widespread motor function impairment during the first periods of withdrawal, which oxidative damage in motor areas and neurotransmitter reduction in the striatum may contribute to the behavioral alteration observed.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103316"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015827","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 : 2025-12-01Epub Date: 2025-11-19DOI: 10.1016/j.neuro.2025.103355
Chadni Patel , Christina Glytsou , Mi-Hyeon Jang , Peter D. Cole
Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these treatments are associated with detrimental side effects like chemotherapy-induced cognitive impairment (CICI), or “chemobrain.” Measurable deficits in cognitive function persist years after treatment. Specifically, doxorubicin (DOXO), a commonly used chemotherapeutic agent in curative regimens for children with cancer, plays a pivotal role in the development of CICI, even though it doesn’t cross the blood-brain barrier (BBB). Using a juvenile rat model, we found that DOXO compromises the BBB integrity. To further address the poorly understood mechanism of DOXO-related CICI, we utilized human cerebral microvascular endothelial cells (hCMEC/D3) to study the changes induced by DOXO in BBB integrity. RNA sequencing after DOXO exposure demonstrated changes in inflammatory pathways that may play a critical role in BBB integrity. Upon DOXO treatment, there was an increase in the secretion of proinflammatory cytokines including interleukin-6 (IL-6), regulated on activation, normal T cell expressed and secreted (RANTES) and granulocyte-macrophage colony stimulating factor (GM-CSF). DOXO induced the activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK1/2), and cAMP response element binding protein (CREB). Using xCELLigence Real Time Cell Analysis, we found that DOXO doesn’t immediately compromise the barrier in hCMEC/D3. Additionally, we found that DOXO treatment significantly decreases maximal respiration and the spare respiratory capacity in hCMEC/D3 cells, indicating mitochondrial bioenergetic defects. Our findings provide critical insights on how DOXO impacts the BBB and builds a foundation for developing preventative measures that may improve the quality of life for patients.
{"title":"The effects of doxorubicin on blood-brain barrier integrity in hCMEC/D3","authors":"Chadni Patel , Christina Glytsou , Mi-Hyeon Jang , Peter D. Cole","doi":"10.1016/j.neuro.2025.103355","DOIUrl":"10.1016/j.neuro.2025.103355","url":null,"abstract":"<div><div>Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these treatments are associated with detrimental side effects like chemotherapy-induced cognitive impairment (CICI), or “chemobrain.” Measurable deficits in cognitive function persist years after treatment. Specifically, doxorubicin (DOXO), a commonly used chemotherapeutic agent in curative regimens for children with cancer, plays a pivotal role in the development of CICI, even though it doesn’t cross the blood-brain barrier (BBB). Using a juvenile rat model, we found that DOXO compromises the BBB integrity. To further address the poorly understood mechanism of DOXO-related CICI, we utilized human cerebral microvascular endothelial cells (hCMEC/D3) to study the changes induced by DOXO in BBB integrity. RNA sequencing after DOXO exposure demonstrated changes in inflammatory pathways that may play a critical role in BBB integrity. Upon DOXO treatment, there was an increase in the secretion of proinflammatory cytokines including interleukin-6 (IL-6), regulated on activation, normal T cell expressed and secreted (RANTES) and granulocyte-macrophage colony stimulating factor (GM-CSF). DOXO induced the activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK1/2), and cAMP response element binding protein (CREB). Using xCELLigence Real Time Cell Analysis, we found that DOXO doesn’t immediately compromise the barrier in hCMEC/D3. Additionally, we found that DOXO treatment significantly decreases maximal respiration and the spare respiratory capacity in hCMEC/D3 cells, indicating mitochondrial bioenergetic defects. Our findings provide critical insights on how DOXO impacts the BBB and builds a foundation for developing preventative measures that may improve the quality of life for patients.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103355"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564743","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 : 2025-12-01Epub Date: 2025-10-01DOI: 10.1016/j.neuro.2025.103332
Ayang Zhao , Hongjiang Jin , Xiaofei Ma , Guibo Fan , Yueyue Gao , Yuting Rong , Siqi Sun , Ao Zhang , Sihua Qi
Background
Exposure to general anesthetics during early postnatal development is linked to enduring cognitive deficits in rodent and non-human primate models. However, the mechanisms by which inhaled anesthetics induce neuronal death and synaptic alterations remain unclear.
Methods
C. elegans and neonatal male mice were administered sevoflurane. Subsequently, their learning and memory capabilities were assessed, and the potential mechanisms influencing learning and memory in C. elegans and mice were explored.
Results
Early developmental exposure to sevoflurane resulted in learning and memory impairment in C. elegans. The eIF3l and ced-3 genes are critical for sevoflurane-induced developmental neurotoxicity in C. elegans. Endoplasmic reticulum stress is a possible mechanism underlying developmental neurotoxicity induced by sevoflurane in C. elegans. In neonatal mice, sevoflurane induced endoplasmic reticulum stress in hippocampal neurons independently of eIF3l, which was mitigated by TUDCA ( tauroursodeoxycholic acid, an ER stress inhibitor). Additionally, mature mice exposed to sevoflurane during the neonatal period exhibited decreased synaptic function in the hippocampus, which was alleviated by TUDCA. Persistent cognitive dysfunction was observed in adult mice exposed to sevoflurane during the neonatal period, which was alleviated by TUDCA.
Conclusion
Our findings demonstrate that early developmental exposure to sevoflurane induces endoplasmic reticulum stress, which may result in a decrease in memory and learning capabilities. TUDCA may alleviate these effects.
{"title":"Sevoflurane exposure in juvenile causes persistent learning and memory impairment via inducing endoplasmic reticulum stress in caenorhabditis elegans and mice","authors":"Ayang Zhao , Hongjiang Jin , Xiaofei Ma , Guibo Fan , Yueyue Gao , Yuting Rong , Siqi Sun , Ao Zhang , Sihua Qi","doi":"10.1016/j.neuro.2025.103332","DOIUrl":"10.1016/j.neuro.2025.103332","url":null,"abstract":"<div><h3>Background</h3><div>Exposure to general anesthetics during early postnatal development is linked to enduring cognitive deficits in rodent and non-human primate models. However, the mechanisms by which inhaled anesthetics induce neuronal death and synaptic alterations remain unclear.</div></div><div><h3>Methods</h3><div><em>C. elegans</em> and neonatal male mice were administered sevoflurane. Subsequently, their learning and memory capabilities were assessed, and the potential mechanisms influencing learning and memory in <em>C. elegans</em> and mice were explored<em>.</em></div></div><div><h3>Results</h3><div>Early developmental exposure to sevoflurane resulted in learning and memory impairment in <em>C. elegans.</em> The eIF3l and ced-3 genes are critical for sevoflurane-induced developmental neurotoxicity in <em>C. elegans</em>. Endoplasmic reticulum stress is a possible mechanism underlying developmental neurotoxicity induced by sevoflurane in <em>C. elegans</em>. In neonatal mice, sevoflurane induced endoplasmic reticulum stress in hippocampal neurons independently of eIF3l, which was mitigated by TUDCA ( tauroursodeoxycholic acid, an ER stress inhibitor). Additionally, mature mice exposed to sevoflurane during the neonatal period exhibited decreased synaptic function in the hippocampus, which was alleviated by TUDCA. Persistent cognitive dysfunction was observed in adult mice exposed to sevoflurane during the neonatal period, which was alleviated by TUDCA.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that early developmental exposure to sevoflurane induces endoplasmic reticulum stress, which may result in a decrease in memory and learning capabilities. TUDCA may alleviate these effects.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103332"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220441","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 : 2025-12-01Epub Date: 2025-08-30DOI: 10.1016/j.neuro.2025.103311
Aaron M. Kim , Lisa M. Barnhill , Marisol Arellano , Kazi Md Mahmudul Hasan , Sharon Li , Jeff M. Bronstein
Contributions of genetic heredity to neurodegenerative diseases have opened avenues of investigations into the interplay between environmental exposures and neurodegeneration. Epidemiological studies have identified some chlorinated solvents as potential modifiers of neurodegenerative disease risk, but not much is known about the molecular mechanisms underlying their neurotoxic potencies. To this end, we investigated how exposure to chlorinated solvents might induce neurotoxicity in wild-type and transgenic zebrafish. Chlorinated solvents were screened for neurotoxicity through a series of assays measuring changes in locomotion, neuron numbers, and autophagic flux. Decreased locomotion was observed in zebrafish larvae exposed to all chlorinated solvents and all but 1,2-dichloroethane (EDC) and 1,2-dichloropropane (PDC) led to monoaminergic neuron loss. Solvents that induced neuron loss, including carbon tetrachloride (Carbon Tet), dichloromethane (DCM), tetrachloroethylene (PCE), and trichloroethylene (TCE), also caused impairments in autophagic flux, as evidenced by decreased rates of autophagosome formation and increased p62 punctae. In summary, chlorinated methanes and ethenes induced neurotoxicity as evident by behavioral changes, neuronal loss, and reduced autophagic flux in the central nervous system, whereas chlorinated ethanes and propanes did not. This study lends further credence to the epidemiological associations connecting solvent exposure to neurodegenerative disease and highlights the importance of understanding mechanistic links that may cumulatively contribute to disease risk.
{"title":"Chlorinated solvents associated with neurodegenerative disease induce neurotoxicity and impair autophagic flux","authors":"Aaron M. Kim , Lisa M. Barnhill , Marisol Arellano , Kazi Md Mahmudul Hasan , Sharon Li , Jeff M. Bronstein","doi":"10.1016/j.neuro.2025.103311","DOIUrl":"10.1016/j.neuro.2025.103311","url":null,"abstract":"<div><div>Contributions of genetic heredity to neurodegenerative diseases have opened avenues of investigations into the interplay between environmental exposures and neurodegeneration. Epidemiological studies have identified some chlorinated solvents as potential modifiers of neurodegenerative disease risk, but not much is known about the molecular mechanisms underlying their neurotoxic potencies. To this end, we investigated how exposure to chlorinated solvents might induce neurotoxicity in wild-type and transgenic zebrafish. Chlorinated solvents were screened for neurotoxicity through a series of assays measuring changes in locomotion, neuron numbers, and autophagic flux. Decreased locomotion was observed in zebrafish larvae exposed to all chlorinated solvents and all but 1,2-dichloroethane (EDC) and 1,2-dichloropropane (PDC) led to monoaminergic neuron loss. Solvents that induced neuron loss, including carbon tetrachloride (Carbon Tet), dichloromethane (DCM), tetrachloroethylene (PCE), and trichloroethylene (TCE), also caused impairments in autophagic flux, as evidenced by decreased rates of autophagosome formation and increased p62 punctae. In summary, chlorinated methanes and ethenes induced neurotoxicity as evident by behavioral changes, neuronal loss, and reduced autophagic flux in the central nervous system, whereas chlorinated ethanes and propanes did not. This study lends further credence to the epidemiological associations connecting solvent exposure to neurodegenerative disease and highlights the importance of understanding mechanistic links that may cumulatively contribute to disease risk.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103311"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963068","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 : 2025-12-01Epub Date: 2025-11-06DOI: 10.1016/j.neuro.2025.103345
María Sancho-Alonso , Paula Izquierdo-Altarejos , Gergana Mincheva , Marta Llansola , Vicente Felipo
Hyperammonemia is a main contributor to cognitive impairment in patients with hepatic encephalopathy. Hyperammonemia-induced cognitive impairment is mediated by neuroinflammation and alteration of glutamatergic and GABAergic neurotransmission in hippocampus. Hyperammonemia enhances GABAergic neurotransmission in hippocampus but the role of neuroinflammation remains unknown. In cerebellum of hyperammonemic rats enhanced S1PR2-BDNF-TrkB pathway activation mediates enhancement of GABAergic neurotransmission. In hippocampus of hyperammonemic rats, the increase of IL-1β and Src kinase activation alters glutamatergic neurotransmission. The aims of this work were to assess if neuroinflammation is responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats and to identify the underlying mechanisms. We used ex vivo hippocampal slices from control and hyperammonemic male rats and assessed the effects of blocking the S1PR2, the IL-1 receptor, TrkB or of inhibiting the protein kinases Src or PI3K on glutamate decarboxylases and GABA content and on membrane expression of GABAA receptor, GABA transporters and chloride co-transporters. Blocking the S1PR2-IL-1β-Src-BDNF-TrkB-PI3K pathway at any of its steps reversed the reduced membrane expression of GABA transporters, which would increase extracellular GABA, and the increased membrane expression of most of the GABAA receptor subunits analyzed, which also enhances GABAergic neurotransmission. This would be mediated by increasing the content of gephyrin and phosphorylation of the β3 subunit of GABAA receptors. The identification of this pathway as the origin of the enhanced GABAergic neurotransmission provides several therapeutic targets to reverse cognitive impairment in hyperammonemia and hepatic encephalopathy and, likely, in other pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission.
{"title":"Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats","authors":"María Sancho-Alonso , Paula Izquierdo-Altarejos , Gergana Mincheva , Marta Llansola , Vicente Felipo","doi":"10.1016/j.neuro.2025.103345","DOIUrl":"10.1016/j.neuro.2025.103345","url":null,"abstract":"<div><div>Hyperammonemia is a main contributor to cognitive impairment in patients with hepatic encephalopathy. Hyperammonemia-induced cognitive impairment is mediated by neuroinflammation and alteration of glutamatergic and GABAergic neurotransmission in hippocampus. Hyperammonemia enhances GABAergic neurotransmission in hippocampus but the role of neuroinflammation remains unknown. In cerebellum of hyperammonemic rats enhanced S1PR2-BDNF-TrkB pathway activation mediates enhancement of GABAergic neurotransmission. In hippocampus of hyperammonemic rats, the increase of IL-1β and Src kinase activation alters glutamatergic neurotransmission. The aims of this work were to assess if neuroinflammation is responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats and to identify the underlying mechanisms. We used ex vivo hippocampal slices from control and hyperammonemic male rats and assessed the effects of blocking the S1PR2, the IL-1 receptor, TrkB or of inhibiting the protein kinases Src or PI3K on glutamate decarboxylases and GABA content and on membrane expression of GABA<sub>A</sub> receptor, GABA transporters and chloride co-transporters. Blocking the S1PR2-IL-1β-Src-BDNF-TrkB-PI3K pathway at any of its steps reversed the reduced membrane expression of GABA transporters, which would increase extracellular GABA, and the increased membrane expression of most of the GABA<sub>A</sub> receptor subunits analyzed, which also enhances GABAergic neurotransmission. This would be mediated by increasing the content of gephyrin and phosphorylation of the β3 subunit of GABA<sub>A</sub> receptors. The identification of this pathway as the origin of the enhanced GABAergic neurotransmission provides several therapeutic targets to reverse cognitive impairment in hyperammonemia and hepatic encephalopathy and, likely, in other pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103345"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465586","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 : 2025-12-01Epub Date: 2025-09-25DOI: 10.1016/j.neuro.2025.103329
Mao-Hsiang Hsiao , Kun‑Chieh Yeh , Ming-Yi Lee , Wei-Che Chiu , Su-Jane Wang
Thymoquinone (TQ), a natural compound derived from the oil of Nigella sativa seeds, has demonstrated neuroprotective properties. This study investigated the effects of TQ on glutamate release from rat cortical synaptosomes and explored the underlying mechanisms. TQ inhibited 4-aminopyridine (4-AP)-evoked glutamate release in a concentration-dependent manner, with an estimated IC50 of 8.1 μM. This inhibitory effect was absent under Ca2 + -free conditions and in the presence of bafilomycin A1, an inhibitor of vesicular glutamate transporter, indicating a Ca2+-dependent exocytotic mechanism. Consistently, TQ significantly reduced 4-AP-induced uptake of the synaptotagmin 1 luminal domain antibody (syt1-L ab), confirming suppression of synaptic vesicle exocytosis. Moreover, TQ attenuated the 4-AP-induced elevation of intraterminal Ca2+ without affecting synaptosomal membrane potential. Notably, the inhibitory effect of TQ on glutamate release was abolished by blockade of P/Q-type Ca2+ channels or inhibition of protein kinase C (PKC). Western blot analysis further revealed that TQ reduced 4-AP-induced phosphorylation of PKC, SNAP-25, and Munc18–1 in synaptosomes. Collectively, these findings suggest that TQ inhibits glutamate exocytosis from cortical synaptosomes by reducing Ca2+ influx through P/Q-type Ca2+ channels and subsequently downregulating the PKC/SNAP-25/Munc18–1 signaling cascade.
{"title":"Inhibitory regulation of glutamate release from rat cortical nerve terminals by thymoquinone","authors":"Mao-Hsiang Hsiao , Kun‑Chieh Yeh , Ming-Yi Lee , Wei-Che Chiu , Su-Jane Wang","doi":"10.1016/j.neuro.2025.103329","DOIUrl":"10.1016/j.neuro.2025.103329","url":null,"abstract":"<div><div>Thymoquinone (TQ), a natural compound derived from the oil of <em>Nigella sativa</em> seeds, has demonstrated neuroprotective properties. This study investigated the effects of TQ on glutamate release from rat cortical synaptosomes and explored the underlying mechanisms. TQ inhibited 4-aminopyridine (4-AP)-evoked glutamate release in a concentration-dependent manner, with an estimated IC<sub>50</sub> of 8.1 μM. This inhibitory effect was absent under Ca<sup>2 +</sup> -free conditions and in the presence of bafilomycin A1, an inhibitor of vesicular glutamate transporter, indicating a Ca<sup>2+</sup>-dependent exocytotic mechanism. Consistently, TQ significantly reduced 4-AP-induced uptake of the synaptotagmin 1 luminal domain antibody (syt1-L ab), confirming suppression of synaptic vesicle exocytosis. Moreover, TQ attenuated the 4-AP-induced elevation of intraterminal Ca<sup>2+</sup> without affecting synaptosomal membrane potential. Notably, the inhibitory effect of TQ on glutamate release was abolished by blockade of P/Q-type Ca<sup>2+</sup> channels or inhibition of protein kinase C (PKC). Western blot analysis further revealed that TQ reduced 4-AP-induced phosphorylation of PKC, SNAP-25, and Munc18–1 in synaptosomes. Collectively, these findings suggest that TQ inhibits glutamate exocytosis from cortical synaptosomes by reducing Ca<sup>2+</sup> influx through P/Q-type Ca<sup>2+</sup> channels and subsequently downregulating the PKC/SNAP-25/Munc18–1 signaling cascade.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103329"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182051","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}
Silver nanoparticles (AgNPs) are widely used in industrial and biomedical applications owing to their superior physicochemical properties, especially antimicrobial activity. However, their potential health risks raise concerns. Given that the central nervous system (CNS) is a major target of AgNPs, assessing their neurotoxic effects is critical for safety evaluation. Recent studies suggest that ferroptosis may play a pivotal role in AgNPs-induced neurotoxicity, yet the underlying molecular mechanisms remain unclear. This study is the first to investigate AgNPs-triggered ferroptosis in human microglial cells (HMC3) and explore the regulatory role of triggering receptor expressed on myeloid cells 2 (TREM2)-mediated inflammatory responses. Following exposure to AgNPs (0, 50, 100, and 200 μg/mL) for 48 h, HMC3 cells exhibited dose-dependent cytotoxicity. Further analyses revealed mitochondrial ultrastructural and functional damage, intracellular Fe²⁺ overload, elevated ROS levels, GSH depletion, and increased lipid peroxidation, accompanied by dysregulated expression of ferroptosis-related proteins. Inflammatory profiling demonstrated reduced TREM2 protein levels, elevated pro-inflammatory markers, and decreased anti-inflammatory markers, indicating AgNPs-induced inflammatory responses. Treatment with the TREM2 agonist COG 1410 (5 μg/mL) significantly upregulated TREM2 expression, attenuated pro-inflammatory factors, and enhanced anti-inflammatory factors. Moreover, TREM2 activation significantly inhibited AgNPs-induced ferroptosis in HMC3 cells, indicating that TREM2-mediated inflammation may play a key role in regulating this process. These findings offer new understanding of AgNPs neurotoxicity and potential therapeutic targets for reducing CNS damage from AgNPs exposure.
{"title":"TREM2-mediated neuroinflammatory response is involved in AgNPs-induced ferroptosis in HMC3 cells","authors":"Haitao Yang, Menghao Guo, Shuyan Niu, Chenyu Liu, Tianshu Wu, Mengjing Cui, Yuying Xue","doi":"10.1016/j.neuro.2025.103326","DOIUrl":"10.1016/j.neuro.2025.103326","url":null,"abstract":"<div><div>Silver nanoparticles (AgNPs) are widely used in industrial and biomedical applications owing to their superior physicochemical properties, especially antimicrobial activity. However, their potential health risks raise concerns. Given that the central nervous system (CNS) is a major target of AgNPs, assessing their neurotoxic effects is critical for safety evaluation. Recent studies suggest that ferroptosis may play a pivotal role in AgNPs-induced neurotoxicity, yet the underlying molecular mechanisms remain unclear. This study is the first to investigate AgNPs-triggered ferroptosis in human microglial cells (HMC3) and explore the regulatory role of triggering receptor expressed on myeloid cells 2 (TREM2)-mediated inflammatory responses. Following exposure to AgNPs (0, 50, 100, and 200 μg/mL) for 48 h, HMC3 cells exhibited dose-dependent cytotoxicity. Further analyses revealed mitochondrial ultrastructural and functional damage, intracellular Fe²⁺ overload, elevated ROS levels, GSH depletion, and increased lipid peroxidation, accompanied by dysregulated expression of ferroptosis-related proteins. Inflammatory profiling demonstrated reduced TREM2 protein levels, elevated pro-inflammatory markers, and decreased anti-inflammatory markers, indicating AgNPs-induced inflammatory responses. Treatment with the TREM2 agonist COG 1410 (5 μg/mL) significantly upregulated TREM2 expression, attenuated pro-inflammatory factors, and enhanced anti-inflammatory factors. Moreover, TREM2 activation significantly inhibited AgNPs-induced ferroptosis in HMC3 cells, indicating that TREM2-mediated inflammation may play a key role in regulating this process. These findings offer new understanding of AgNPs neurotoxicity and potential therapeutic targets for reducing CNS damage from AgNPs exposure.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103326"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149857","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 : 2025-12-01Epub Date: 2025-11-19DOI: 10.1016/j.neuro.2025.103354
Yujun Ma , Guangsen Feng , Shihui Guo , Jing Song , Linping Wang , Huifang Zhang , Jinzhu Yin , Xiaoting Lu
This study aimed to elucidate the associations among occupational aluminum exposure, plasma phosphorylated tau (P-tau), and cognitive function, with particular attention to the modulatory effects of key factors involved in tau protein synthesis and degradation. A total of 208 aluminum plant workers were enrolled, with assessments conducted for plasma aluminum concentrations, cognitive performance, levels of phosphorylated tau (P-tau181 and P-tau231), and biomarkers related to tau synthesis and degradation pathways. Elevated plasma aluminum levels were inversely associated with scores on cognitive assessments, including the MMSE, DSP, DSR, DS, FOM, and CDT, while showing positive associations with STRA and STRF scores. Higher plasma aluminum concentrations were also significantly associated with increased levels of P-tau181 and P-tau231. P-tau181 and P-tau 231 concentrations are negatively correlated with MMSE, DSP, DSR, DS, and FOM scores, and positively correlated with STRA, STRF, and CDT scores. Mediation analysis revealed that P-tau181 and P-tau231 were statistically consistent with mediating 16.6 % and 35.9 % of the association between aluminum exposure and MMSE scores, respectively, with P-tau231 demonstrating a stronger mediating effect. Moderated mediation analysis further indicated that factors regulating tau synthesis had a more pronounced influence on this mediating role than those involved in degradation[Δ(PP2A, CDK5)= 0.016 > Δ(CHIP, Ub)= 0; Δ(PP2A, CDK5)= 0.027 > Δ(CHIP, Ub)= 0], with PP2A-mediated regulation exerting a greater effect than CDK5[Δ(PP2A)= 0.021 > Δ(CDK5)= 0.006; Δ(PP2A)= 0.016 > Δ(CDK5)= 0.008]. These results are statistically consistent with the hypothesis that P-tau231 and PP2A are critical targets for early intervention and biomonitoring in the context of aluminum-related cognitive impairment, offering novel directions for occupational health risk management and protection.
{"title":"A moderated mediation of tau phosphorylated sites in the association between occupational aluminum exposure and cognitive function","authors":"Yujun Ma , Guangsen Feng , Shihui Guo , Jing Song , Linping Wang , Huifang Zhang , Jinzhu Yin , Xiaoting Lu","doi":"10.1016/j.neuro.2025.103354","DOIUrl":"10.1016/j.neuro.2025.103354","url":null,"abstract":"<div><div>This study aimed to elucidate the associations among occupational aluminum exposure, plasma phosphorylated tau (P-tau), and cognitive function, with particular attention to the modulatory effects of key factors involved in tau protein synthesis and degradation. A total of 208 aluminum plant workers were enrolled, with assessments conducted for plasma aluminum concentrations, cognitive performance, levels of phosphorylated tau (P-tau181 and P-tau231), and biomarkers related to tau synthesis and degradation pathways. Elevated plasma aluminum levels were inversely associated with scores on cognitive assessments, including the MMSE, DSP, DSR, DS, FOM, and CDT, while showing positive associations with STRA and STRF scores. Higher plasma aluminum concentrations were also significantly associated with increased levels of P-tau181 and P-tau231. P-tau181 and P-tau 231 concentrations are negatively correlated with MMSE, DSP, DSR, DS, and FOM scores, and positively correlated with STRA, STRF, and CDT scores. Mediation analysis revealed that P-tau181 and P-tau231 were statistically consistent with mediating 16.6 % and 35.9 % of the association between aluminum exposure and MMSE scores, respectively, with P-tau231 demonstrating a stronger mediating effect. Moderated mediation analysis further indicated that factors regulating tau synthesis had a more pronounced influence on this mediating role than those involved in degradation[Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A, CDK5)= 0.016 > Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CHIP, Ub)= 0; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A, CDK5)= 0.027 > Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CHIP, Ub)= 0], with PP2A-mediated regulation exerting a greater effect than CDK5[Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A)= 0.021 > Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CDK5)= 0.006; Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(PP2A)= 0.016 > Δ<span><math><msup><mrow><mi>R</mi></mrow><mrow><mn>2</mn></mrow></msup></math></span>(CDK5)= 0.008]. These results are statistically consistent with the hypothesis that P-tau231 and PP2A are critical targets for early intervention and biomonitoring in the context of aluminum-related cognitive impairment, offering novel directions for occupational health risk management and protection.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103354"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564750","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 : 2025-12-01Epub Date: 2025-09-03DOI: 10.1016/j.neuro.2025.103313
T. Noah Hutson , Susan Searles Nielsen , Natalie Senini , John O’Donnell , Hubert P. Flores , Tamara Hershey , Joel S. Perlmutter , Anil Kumar Soda , Stephen M. Moerlein , Zhude Tu , Michael Kasper , Lianne Sheppard , Brad A. Racette , Susan R. Criswell
Background and objective
Excessive exposure to manganese (Mn) produces a clinical syndrome of parkinsonism and cognitive impairment. However, our understanding of the mechanisms of Mn neurotoxicity remains limited. This study aimed to evaluate the relationships between Mn exposure, cholinergic function, and cognitive impairment in exposed workers.
Methods
We assessed brain cholinergic function using vesicular acetylcholine transporter (VAChT) radiotracer (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone (VAT) with positron emission tomography (PET) in 21 Mn-exposed workers. We estimated occupational Mn exposure from work histories and the MRI pallidal index. A cognitive control battery consisting of the Verbal Fluency (VF), Letter Number Sequencing (LNS), Two-Back Letter Task (2B), Go-No-Go (GnG), and Simon Task assessed cognitive function. We applied generalized linear models to Mn exposure, voxel-based cholinergic PET, and cognitive control measures, estimating coefficients for cholinergic-mediated associations between Mn and cognitive function. We utilized bootstrapping techniques to validate the mediation coefficients.
Results
Both Mn exposure metrics were associated with low cholinergic VAT binding in the caudate and cortical regions including the precuneus, pars triangularis, pars opercularis, middle temporal lobe, and entorhinal cortex. Regional cholinergic function mediated the relationship between Mn exposure and both the composite cognitive control score (mean of the 5 cognitive tests) [β = -0.661, 90 % confidence interval (CI) −2.130, −0.032] and the individual VF assessment (β = −0.944, 90 % CI −2.157, −0.065).
Discussion
Higher Mn exposure is associated with lower cholinergic activity in multiple brain regions. Cholinergic function also mediates a portion of the relationship between Mn exposure and cognitive control performance. Caudate and cortical cholinergic activity may be a biomarker of early Mn neurotoxicity and represent an important mechanism of cognitive dysfunction in parkinsonian syndromes.
{"title":"Cholinergic dysfunction in occupational manganese exposure","authors":"T. Noah Hutson , Susan Searles Nielsen , Natalie Senini , John O’Donnell , Hubert P. Flores , Tamara Hershey , Joel S. Perlmutter , Anil Kumar Soda , Stephen M. Moerlein , Zhude Tu , Michael Kasper , Lianne Sheppard , Brad A. Racette , Susan R. Criswell","doi":"10.1016/j.neuro.2025.103313","DOIUrl":"10.1016/j.neuro.2025.103313","url":null,"abstract":"<div><h3>Background and objective</h3><div>Excessive exposure to manganese (Mn) produces a clinical syndrome of parkinsonism and cognitive impairment. However, our understanding of the mechanisms of Mn neurotoxicity remains limited. This study aimed to evaluate the relationships between Mn exposure, cholinergic function, and cognitive impairment in exposed workers.</div></div><div><h3>Methods</h3><div>We assessed brain cholinergic function using vesicular acetylcholine transporter (VAChT) radiotracer (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone (VAT) with positron emission tomography (PET) in 21 Mn-exposed workers. We estimated occupational Mn exposure from work histories and the MRI pallidal index. A cognitive control battery consisting of the Verbal Fluency (VF), Letter Number Sequencing (LNS), Two-Back Letter Task (2B), Go-No-Go (GnG), and Simon Task assessed cognitive function. We applied generalized linear models to Mn exposure, voxel-based cholinergic PET, and cognitive control measures, estimating coefficients for cholinergic-mediated associations between Mn and cognitive function. We utilized bootstrapping techniques to validate the mediation coefficients.</div></div><div><h3>Results</h3><div>Both Mn exposure metrics were associated with low cholinergic VAT binding in the caudate and cortical regions including the precuneus, pars triangularis, pars opercularis, middle temporal lobe, and entorhinal cortex. Regional cholinergic function mediated the relationship between Mn exposure and both the composite cognitive control score (mean of the 5 cognitive tests) [β = -0.661, 90 % confidence interval (CI) −2.130, −0.032] and the individual VF assessment (β = −0.944, 90 % CI −2.157, −0.065).</div></div><div><h3>Discussion</h3><div>Higher Mn exposure is associated with lower cholinergic activity in multiple brain regions. Cholinergic function also mediates a portion of the relationship between Mn exposure and cognitive control performance. Caudate and cortical cholinergic activity may be a biomarker of early Mn neurotoxicity and represent an important mechanism of cognitive dysfunction in parkinsonian syndromes.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103313"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006383","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 : 2025-12-01Epub Date: 2025-09-30DOI: 10.1016/j.neuro.2025.103331
Jingjing Gao , Jinghua Shen , Lu Gao , Dongying Yan , Ying Wang , Jia Meng , Dawei Chen , Hong Li , Jie Wu
Brominated flame retardants polybrominated diphenyl ethers (PBDEs) have posed threat to ecosystems and human health, especially on neurodevelopment, while the mechanisms remain obscure. Here, we assessed recognition memory for new object and spontaneous behavior of adolescent male rats after perinatal BDE-209 exposure. Considering that the miR-34 family is linked to spines morphology and memory formation and mediates neuroprotective role of melatonin through Sirtuin1 (SIRT1), we investigated the role of miR-34 in developmental neurotoxicity of BDE-209 of rats with or without melatonin pretreatment. We analyzed dendritic arborisation and spines density of pyramidal neurons in both prefrontal cortex (PFC) and hippocampal CA1 region via Golgi-staining and Sholl tools; then conducted miRNA sequencing and verified differentially expressed miRNAs and their targets. Our findings indicated that miR-34c and miR-134 were significantly up-regulated in the hippocampus and PFC of maternal BDE-209-exposed rats, as a target of miR-34c simultaneously upstream regulator for miR-134, neuronal SIRT1 level was decreased correspondingly. Furthermore, miR-134 targeted LIMK1/cofilin and CREB/BDNF pathway contributing to changes in dendritic morphology. Melatonin pretreatment restored synaptic morphological plasticity especially spines density in hippocampal and cortical neurons, partially through elevating SIRT1 expression, and alleviated BDE-209-caused memory deficits, providing a potential neuroprotective intervention.
{"title":"Melatonin improves synaptic morphological plasticity of adolescent male rats after perinatal BDE-209 exposure via SIRT1-mediated LIMK1 and CREB signaling","authors":"Jingjing Gao , Jinghua Shen , Lu Gao , Dongying Yan , Ying Wang , Jia Meng , Dawei Chen , Hong Li , Jie Wu","doi":"10.1016/j.neuro.2025.103331","DOIUrl":"10.1016/j.neuro.2025.103331","url":null,"abstract":"<div><div>Brominated flame retardants polybrominated diphenyl ethers (PBDEs) have posed threat to ecosystems and human health, especially on neurodevelopment, while the mechanisms remain obscure. Here, we assessed recognition memory for new object and spontaneous behavior of adolescent male rats after perinatal BDE-209 exposure. Considering that the miR-34 family is linked to spines morphology and memory formation and mediates neuroprotective role of melatonin through Sirtuin1 (SIRT1), we investigated the role of miR-34 in developmental neurotoxicity of BDE-209 of rats with or without melatonin pretreatment. We analyzed dendritic arborisation and spines density of pyramidal neurons in both prefrontal cortex (PFC) and hippocampal CA1 region via Golgi-staining and Sholl tools; then conducted miRNA sequencing and verified differentially expressed miRNAs and their targets. Our findings indicated that miR-34c and miR-134 were significantly up-regulated in the hippocampus and PFC of maternal BDE-209-exposed rats, as a target of miR-34c simultaneously upstream regulator for miR-134, neuronal SIRT1 level was decreased correspondingly. Furthermore, miR-134 targeted LIMK1/cofilin and CREB/BDNF pathway contributing to changes in dendritic morphology. Melatonin pretreatment restored synaptic morphological plasticity especially spines density in hippocampal and cortical neurons, partially through elevating SIRT1 expression, and alleviated BDE-209-caused memory deficits, providing a potential neuroprotective intervention.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103331"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206976","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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