Neurotoxicity Research最新文献

{"title":"Evaluation of Methylmercury-Induced Motor Dysfunction and Proteomic Analysis of Cerebrospinal Fluid in Common Marmosets (Callithrix jacchus).","authors":"Chisato Kataoka, Yingxi Li, Zoran Minic, Takashi Inoue, Terumi Yurimoto, Erika Sasaki, Yoshihiro Komohara, Komyo Eto, Naomichi Ogihara, Masaaki Nakamura, Hing Man Chan, Megumi Yamamoto","doi":"10.1007/s12640-026-00832-z","DOIUrl":"https://doi.org/10.1007/s12640-026-00832-z","url":null,"abstract":"<p><p>Methylmercury (MeHg) poisoning can lead to Minamata disease, often manifesting as motor dysfunction. We aimed to establish a quantitative evaluation method for MeHg exposure-associated motor dysfunction in the common marmoset (Callithrix jacchus). Three male marmosets were orally administered MeHg (1.5 mg Hg/kg/day) for 2 weeks, followed by a 2-week non-treatment period; three control marmosets received vehicle. Walking and spontaneous behavior were recorded weekly. After marking body segments, bounding gait videos were analyzed to assess locomotion speed, hip joint position, knee angle, dorsal neck-to-torso angle, and spontaneous behavior. In Hg-1 (MeHg-exposed marmoset with earliest symptom onset), locomotion speed and stride length decreased, while stride time increased. In Hg-2 (second marmoset to exhibit symptom onset), hip joint position and knee angle initially showed relatively normal fluctuations during bounding gait. However, their lower limits decreased following MeHg administration, and the dorsal neck-to-torso angle shifted from negative to positive. Spontaneous activity of Hg-1 and Hg-2 significantly decreased after MeHg administration. These results indicate that MeHg exposure-associated motor dysfunction in marmosets can be detected using our method, with particularly prominent lower-limb abnormalities. Furthermore, cerebrospinal fluid proteomic profiling revealed coordinated disruptions converging on three pathological axes-neuronal injury and neuroprotective responses, neuronal metabolic failure and cytosolic enzyme leakage, and impaired transport and homeostatic regulation-identifying nine proteins as candidate biomarkers. Proteomic alterations were consistent with the observed neuronal injury, neuroinflammation, metabolic dysfunction, and impaired homeostatic regulation in affected motor pathways. These findings establish the marmoset as a translational primate model for neurotoxicological assessments and biomarker discovery.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 6","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224694","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}

{"title":"Aerobic Interval Training and Hesperidin Attenuate Paclitaxel-Induced Memory Impairment in Rats: Roles of Inflammation and Oxidative Stress.","authors":"Mahdieh Hojjat Panah, Hanieh Gholamalizadeh, Vafa Baradaran Rahimi, Roya Askari, Zahra Stiri, Marzieh Sadat Azarniveh, Bahram Sadeghi, Matteo Pusceddu, Vahid Reza Askari","doi":"10.1007/s12640-026-00831-0","DOIUrl":"10.1007/s12640-026-00831-0","url":null,"abstract":"<p><p>Paclitaxel (PTX) is an effective antineoplastic agent used against various types of cancer. However, its use is limited in many patients due to intolerable side effects, including neurotoxicity. This study examined the effects of aerobic interval training and/or hesperidin (HES) on neuroinflammation and memory impairment caused by PTX in rats. Thirty male Wistar rats were randomly divided into five groups: Sham (SH), PTX, PTX + exercise (EX), PTX + HES, and PTX + EX + HES. To induce PTX toxicity, 2 mg/kg of PTX was injected intraperitoneally into the rats on days 1, 3, 5, 7, and 9. The aerobic exercise program involved five treadmill interval training sessions per week for seven weeks, with each session consisting of 2-minute running intervals. In the first week, the rats completed six repetitions, increasing by one each week until reaching 12 in the final week. Exercise intensity gradually increased from 60% of maximum speed in the first week to 75% in the last week. Between intervals, active rest lasted one minute at 40-45% of maximum speed. HES (100 mg/kg) was administered orally one hour before exercise starting on the tenth day after PTX injection. The Shuttle box and Morris water maze tests assessed changes in avoidance and spatial memory. Animals were finally sacrificed, and hippocampal tissue samples were collected to evaluate inflammatory and oxidative stress markers, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF). Avoidance and spatial memory significantly improved in the exercise and supplement groups compared to the PTX group (P < 0.05), with the most notable improvement in spatial memory observed in the PTX + EX + HES group. The PTX group showed a significant increase in TNF-α, IL-6, and MDA levels compared to the other groups (p˂0.05 - 0.001). Conversely, IL-10 and BDNF levels were significantly lower in the PTX group compared to other groups (p ˂ 0.05 - 0.001). Our results demonstrate that PTX impairs memory and learning ability; however, aerobic interval training and HES supplementation increase BDNF levels and enhance avoidance and spatial memory. Thus, these treatments may help mitigate chemotherapy side effects. Further research is necessary to determine safe and effective dosages.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183345","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}

{"title":"Exploring the Potential Neurotoxic Links Between 6PPD/6PPD-Q and Parkinson's Disease Through Network Toxicology and Multi-Dimensional Bioinformatics Analysis.","authors":"Lijuan Zhang, Bowen Peng, Daiping Hua, Qiaoyu Xuan, Lanting Sun, Wenming Yang, Han Wang","doi":"10.1007/s12640-026-00830-1","DOIUrl":"10.1007/s12640-026-00830-1","url":null,"abstract":"<p><p>N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product 6PPD-Q are emerging tire-derived environmental contaminants that have been detected in human biological samples; however, their neurotoxic mechanisms remain unclear. This study employed network toxicology, transcriptomic analysis, and machine learning to explore the potential neurotoxic associations between 6PPD/6PPD-Q and Parkinson's disease (PD). By integrating four target prediction platforms and three disease databases, a total of 260 potential toxic targets associated with 6PPD/6PPD-Q-related PD were identified. Eighty-two differentially expressed genes were identified from GEO datasets, and five candidate genes were obtained through intersection analysis. Among the five candidate genes, KCND3, PSEN2, and SLC18A2 were consistently selected by three machine-learning algorithms (LASSO, SVM-RFE, and Boruta). Validation analysis showed that all core genes were significantly downregulated in the substantia nigra tissues of PD patients, with area under the curve (AUC) values of 0.917 for KCND3, 0.757 for PSEN2, and 0.819 for SLC18A2. Mendelian randomization analysis provided preliminary genetic evidence consistent with a causal association between elevated SLC18A2 expression levels and reduced PD risk (OR = 0.488, 95% CI: 0.273-0.870, P = 0.015). Molecular docking analysis showed favorable predicted binding scores between 6PPD/6PPD-Q and the three target proteins. Exploratory immune analysis suggested alterations in activated dendritic cells and γδ T cells in PD. Collectively, these findings suggest potential neurotoxic relevance of 6PPD/6PPD-Q to PD and provide a basis for further experimental investigation.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112790","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}

{"title":"Retraction Note: Quercetin Exhibits α7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents.","authors":"Niraj Kumar Singh, Debapriya Garabadu","doi":"10.1007/s12640-026-00829-8","DOIUrl":"10.1007/s12640-026-00829-8","url":null,"abstract":"","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063173","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}

{"title":"Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.","authors":"Tanveera Rounaque Sarhadi, Neha Joshi, Atchaya Raveendran, Janhavee Shirish Panse, Shirisha Nagotu","doi":"10.1007/s12640-026-00827-w","DOIUrl":"10.1007/s12640-026-00827-w","url":null,"abstract":"<p><p>Parkinson's disease is a complex neurodegenerative disorder that results from the interplay of genetic, environmental, and age-associated factors. The characteristic pathological feature of the disease is the presence of aggregated forms of the intrinsically disordered protein α-synuclein. Protein aggregates eventually form Lewy bodies, which are associated with the death of dopaminergic neurons. Elevated expression, mutations in the coding sequence, increased misfolding, and decreased degradation contribute to the aggregation of α-synuclein, associated with the disease. Mutations in the SNCA gene, which encodes α-synuclein, are predominantly associated with the familial form of the disease. The majority of the identified mutations are located in the N-terminal region of the protein and are associated with either early- or late-onset of the disease. Studies using model organisms, cell lines, and animal models identified several cellular effects associated with mutated forms of the protein. In addition, the clinical phenotypes of the disease in patients with different mutations vary in intensity. Interestingly, although each mutation is associated with the disease, the resulting α-synuclein aggregation rate and effect on cellular pathways are variable. In this review, we aim to summarize these interesting alterations in the protein and the associated pathophysiology of the disease following a single amino acid change.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955238","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}

{"title":"Atorvastatin Shows Limited Disease-Modifying Effects in an A53T α-Synuclein Mouse Model of Parkinson's Disease.","authors":"Lijian Wei, Junkai Hua, Shuangfeng Tang, Jianming Lei, Guozhi Li, LiWei Wei, MingShu Mo","doi":"10.1007/s12640-026-00825-y","DOIUrl":"10.1007/s12640-026-00825-y","url":null,"abstract":"<p><p>Neuroprotective effects of statins in Parkinson's disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-Dependent Effects of Neonatal Methamphetamine Exposure on Catecholamines but Not Oxidative Stress in the Hippocampus and Striatum of Male Rats.","authors":"Čechová Barbora, Jurčovičová Jana, Zorad Štefan, Vaculín Šimon, Šandera Štěpán, Šlamberová Romana","doi":"10.1007/s12640-026-00828-9","DOIUrl":"10.1007/s12640-026-00828-9","url":null,"abstract":"<p><p>Methamphetamine (MA) is a widely abused psychostimulant known to affect monoaminergic systems, with neurotoxic effects often associated with oxidative stress. The present study investigated the early effects of repeated neonatal MA exposure on dopamine (DA), noradrenaline (NA), and selected markers of oxidative status in the hippocampus and striatum of male rats. MA (5 mg/kg/day, s.c.; PND 1-12) significantly reduced DA levels in both brain regions on PND 12, while lipid peroxidation (TBARS) and antioxidant capacity remained unchanged. By PND 28, the early reduction in DA was no longer detectable, and neonatal MA exposure did not significantly affect body weight within either exposure paradigm. In the indirect-exposure paradigm, post-weaning isolation was associated with increased noradrenaline concentrations, whereas no corresponding housing effect was detected in the direct-injection paradigm; however, treatment × housing interactions were not significantThese findings indicate that early postnatal MA exposure induces transient alterations in dopaminergic neurotransmission without detectable changes in markers of lipid peroxidation, suggesting a normalization of DA levels during early adolescence. Overall, under the present experimental conditions, lipid peroxidation does not appear to be a major contributing mechanism to the observed neurochemical changes.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920374","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}

{"title":"TRIM14 Knockdown is Associated with Attenuated Sevoflurane-Induced Ferroptosis and Mitochondrial Dysfunction in Hippocampal Neurons.","authors":"Chun Wang, Enjun Yan, Dongchao Qu","doi":"10.1007/s12640-026-00821-2","DOIUrl":"10.1007/s12640-026-00821-2","url":null,"abstract":"<p><p>Sevoflurane (SEV) is widely used in clinical anesthesia, but its exposure is increasingly being linked to neurocognitive dysfunction, particularly in hippocampal neurons. TRIM14, an E3 ubiquitin ligase, is essential for regulating inflammation, apoptosis, and mitochondrial function; however, its involvement in SEV-induced neuronal damage remains unclear. In this study, we investigated the role of TRIM14 in SEV-induced hippocampal neuronal damage, focusing on mitochondrial dysfunction, iron homeostasis, and inflammation. The results show that TRIM14 knockdown significantly increased cell viability, restrained apoptosis, and suppressed inflammatory cytokines in SEV-treated neurons. However, it also alleviated mitochondrial dysfunction, mitigated ferroptosis, and regulated iron homeostasis. Furthermore, silencing TRIM14 suppressed the NF-κB and STAT3 axis. These findings suggest that TRIM14 contributes to SEV-induced neuronal damage.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892337","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}

{"title":"Targeting Gasdermins for Therapeutic Interventions in Central Nervous System Injury.","authors":"Yonghui Lv, Hongchao Zhang, Mengting Zhu, Can Liang, Feng Wei, Wenshuang Yan, Cheng Ma, Muya Shu, Jianwu Dai, He Shen","doi":"10.1007/s12640-026-00824-z","DOIUrl":"10.1007/s12640-026-00824-z","url":null,"abstract":"<p><p>Central nervous system (CNS) injuries are the leading cause of permanent disability and premature death in adults worldwide, with their incidence continuing to rise amid social development. These injuries not only severely impair the quality of life but also impose a heavy burden on the global public health system. Current clinical interventions, such as decompression and thrombolysis, can alleviate primary injury but fail to effectively reverse the secondary neuroinflammatory damage. Traditional anti-inflammatory therapies, which cannot block the upstream source of the inflammatory cascade, have led to repeated failures in global clinical translation research over the past decades. Gasdermins were first characterized in studies of systemic inflammatory diseases. These proteins form transmembrane pores to drive the release of proinflammatory factors and inflammatory cell death, serving as key mediators of host innate immunity. Recent studies have revealed that gasdermins play critical roles in regulating the initiation and amplification of neuroinflammation following CNS injury. To clarify the therapeutic potential of gasdermins as targets for injury repair, this review systematically summarizes the structure and function of gasdermins, as well as their cell-specific activation and regulatory mechanisms. We further elaborate on their pathological roles in these injuries and the corresponding therapeutic strategies, aiming to provide a theoretical reference for basic research and clinical translation in this field.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874999","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}

{"title":"Differential Effects of Cannabidiol and Cannabigerol on Cognition, Neuroinflammation, and Blood-Brain Barrier Integrity in a Rat Model of Iron Overload.","authors":"Layza Kowalski, Anna C M Colucci, Juliana B Dos Santos, Beatriz W Vuaden, Alice L Herlinger, Jaime E C Hallak, Antônio W Zuardi, José A S Crippa, Maria N M de Lima, Nadja Schröder","doi":"10.1007/s12640-026-00826-x","DOIUrl":"10.1007/s12640-026-00826-x","url":null,"abstract":"<p><p>Iron is an essential micronutrient for brain development, participating in mitochondrial respiration, myelination, and neurotransmitter synthesis. However, previous studies have demonstrated that excessive iron during early postnatal life induces oxidative reactions, leading to mitochondrial dysfunction and synaptic failure. These alterations compromise energy metabolism and neuronal integrity, contributing to long-lasting cognitive dysfunction and increased brain vulnerability later in life. This study evaluated the effects of cannabidiol (CBD) and cannabigerol (CBG) on behavioral, neuroinflammatory, and blood-brain barrier (BBB) outcomes in rats exposed to early-life iron overload. Male Wistar rats received iron carbonyl (30 mg/kg, intragastrically) from postnatal day 12 to 14. At three months of age, they were treated intraperitoneally with CBD, CBG (both at 10 mg/kg), or vehicle for 21 days. Cognitive performance was assessed in the open field and object recognition tasks. We examined hippocampal levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), as proinflammatory markers, and occludin, a protein known to regulate BBB permeability. Iron-exposed animals showed impaired recognition memory, with elevated TNF-α and IL-1β, while CBD reversed memory deficits and reduced IL-1β in iron-treated animals, without affecting TNF-α. CBG restored memory, decreased IL-1β in both iron-treated and controls, and increased TNF-α in controls. Also, iron overload reduced occludin expression in vehicle-treated rats which was reversed by both CBD and CBG. These findings highlight inflammation and BBB disruption as mediators of iron-induced cognitive dysfunction and show that both phytocannabinoids act through distinct but complementary mechanisms, supporting their therapeutic potential in neuroinflammation linked to iron overload.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 5","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13524965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}