Neurotoxicology最新文献_第2页

Neuroprotection via IGF-1 neuronal signaling activation by melatonin and edaravone synergy in methylmercury-induced ALS-like neurotoxicity: Comprehensive analysis of brain regions, spinal cord, CSF, and blood plasma 褪黑激素和依达拉奉协同作用激活IGF-1神经元信号对甲基汞诱导的als样神经毒性的神经保护：脑区、脊髓、脑脊液和血浆的综合分析

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-04 DOI: 10.1016/j.neuro.2026.103398

Gurudev Singh Raina , Sidharth Mehan , Ghanshyam Das Gupta

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5 mg/kg (MLT5) and 10 mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.

肌萎缩性侧索硬化症（ALS）是一种进行性神经退行性疾病，以运动神经元变性、氧化应激、神经炎症和神经递质失衡为特征。本研究探讨了褪黑激素（MLT）单独或联合依达拉奉（EDR）在甲基汞（MEME）诱导的ALS大鼠模型中的神经保护作用。MEME暴露有效地复制了ALS病理，导致行为缺陷、氧化应激、神经炎症、细胞凋亡以及大脑关键区域和脊髓的广泛结构损伤。5mg/kg （MLT5）和10mg/kg （MLT10）的MLT以剂量依赖的方式显著减轻了meme诱导的神经毒性。MLT改善运动功能，减少抑郁样行为，恢复体重。生物化学方面，MLT增强抗氧化防御，包括超氧化物歧化酶（SOD）和过氧化氢酶（CAT），减少促炎细胞因子，白细胞介素-1β (IL-1β)，增加抗炎细胞因子，白细胞介素-10 (IL-10)，并恢复神经递质平衡，如多巴胺和γ -氨基丁酸（GABA）。在机制上，MLT激活IGF-1信号通路，促进神经元存活，减少凋亡（Caspase-3表达）。组织病理学分析证实，MLT保留了神经元和胶质的完整性，减少了脱髓鞘，并恢复了脑和脑脊液中的髓鞘碱性蛋白（MBP）水平。MLT和EDR联合治疗显示出协同的神经保护作用，在减少氧化应激、炎症和神经元损伤方面优于单独治疗。行为和生化改善与全身恢复并行，血液参数正常化和脑组织甲基汞积累减少证明了这一点。这些发现强调了MLT，特别是与EDR联合，作为ALS的有效治疗药物，提供多靶点神经保护。未来的研究应探索其在临床治疗神经退行性疾病的转化潜力。

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引用次数: 0

Beta-caryophyllene restores liver–brain axis integrity in thioacetamide-induced hepatic encephalopathy: Behavioral and molecular insights -石竹烯恢复肝-脑轴完整性在硫乙酰胺诱导的肝性脑病：行为和分子的见解。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-05 DOI: 10.1016/j.neuro.2026.103400

Samet Tekin , Merve Bolat , İsmail Bolat , Ömercan Alat , Burak Batuhan Laçin , Burak Çınar , Aslıhan Atasever , Mehmet Emin Kanat , Emin Şengül , Mohamad Warda , Ahmet Hacımüftüoğlu

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver dysfunction, driven by hyperammonemia, oxidative stress, neuroinflammation, apoptosis, and endoplasmic reticulum (ER) stress, which disrupt the hepato-encephalic axis and impair cognition and motor functions. Despite its clinical burden, effective therapies that target this multi-organ pathology remain limited. β-Caryophyllene (BCP), an antioxidant and anti-inflammatory dietary sesquiterpene, has not been evaluated for its ability to modulate liver–brain crosstalk in HE. This study investigated the hepatoprotective and neuroprotective effects of BCP in a rat model of thioacetamide (TAA)-induced HE. Rats received TAA (200 mg/kg, i.p.) for three days, followed by BCP (100–400 mg/kg) for 14 days. A comprehensive evaluation included serum biochemistry, oxidative stress indices, inflammatory cytokines, apoptosis-related proteins, neurotrophic factors (BDNF), astroglial activation marker (GFAP), ER stress regulators (GRP78, IRE1, XBP1, PERK, CHOP, ATF6), histopathology, and behavioral outcomes. TAA caused severe hepatic and cerebral injury with elevated liver enzymes, oxidative and inflammatory mediators, ER stress dysregulation, pro-apoptotic signaling, reduced BDNF and GFAP, and impaired motor and exploratory behaviors. BCP treatment dose-dependently restored biochemical and molecular parameters, suppressed oxidative stress and neuroinflammation, normalized ER stress signaling, promoted anti-apoptotic pathways, preserved BDNF and maintained astroglial status as reflected by GFAP, and improved histoarchitecture. Importantly, moderate to high doses fully restored locomotor and exploratory activity, indicating coordinated protection across the hepato-encephalic axis. Here, for the first time, the BCP concurrently mitigates hepatic and cerebral pathology via oxidative, inflammatory, apoptotic, and ER stress pathways, supporting its translational potential as a dual hepatoprotective and neuroprotective candidate for xenobiotic-induced HE and related liver–brain disorders.

肝性脑病（HE）是一种严重的肝功能紊乱的神经精神并发症，由高氨血症、氧化应激、神经炎症、细胞凋亡和内质网（ER）应激驱动，破坏肝脑轴，损害认知和运动功能。尽管有临床负担，针对这种多器官病理的有效治疗仍然有限。β-石竹烯（BCP）是一种抗氧化和抗炎的膳食倍半萜，尚未对其调节HE中肝脑串扰的能力进行评估。本研究探讨了BCP对大鼠硫乙酰胺（TAA）诱导的HE模型的肝保护和神经保护作用。大鼠给予TAA (200mg/kg, ig) 3 d, BCP (100-400mg/kg) 14 d。综合评价包括血清生化、氧化应激指标、炎症因子、凋亡相关蛋白、神经营养因子（BDNF）、星形胶质细胞激活标志物（GFAP）、内质网应激调节因子（GRP78、IRE1、XBP1、PERK、CHOP、ATF6）、组织病理学和行为结果。TAA引起严重的肝和脑损伤，肝酶、氧化和炎症介质升高，内质网络应激失调，促凋亡信号传导，BDNF和GFAP降低，运动和探索行为受损。BCP治疗以剂量依赖性恢复生化和分子参数，抑制氧化应激和神经炎症，使内质网应激信号正常化，促进抗凋亡途径，保存BDNF，维持GFAP反映的星形胶质细胞状态，改善组织结构。重要的是，中等至高剂量完全恢复运动和探索活动，表明肝-脑轴协调保护。在这里，BCP首次通过氧化、炎症、凋亡和内质网应激途径同时缓解肝脏和大脑病理，支持其作为外源性HE和相关肝脑疾病的双重肝保护和神经保护候选物的翻译潜力。

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引用次数: 0

Synthetic cannabidiol analogues exhibit lower toxicity than cannabidiol and protect against ethanol-induced apoptosis in SH-SY5Y cells 合成大麻二酚类似物表现出比大麻二酚更低的毒性，并保护SH-SY5Y细胞免受乙醇诱导的凋亡。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-17 DOI: 10.1016/j.neuro.2026.103411

Carolina Aparecida Faria Almeida , Gabriela Salles , Vitor Bruno , Jessyca Milene Ribeiro , Alessandra Oliveira Silva , Giulia de Assis Braz , Felype Valentim Duarte Castelhano , Graziella dos Reis Rosa Franco , Cláudio Viegas Jr. , Tania Marcourakis , Larissa Helena Lobo Torres , Raphael Caio Tamborelli Garcia

Cannabidiol (CBD) shows therapeutic potential for treating alcohol use disorder (AUD); however, its neurotoxicological profile remains insufficiently characterized, especially when compared with emerging synthetic analogues designed to improve safety. This study compares the neurotoxic and mechanistic profiles of CBD and two synthetic derivatives, PQM-242 and PQM-249, and evaluates their ability to attenuate ethanol-induced cellular injury. Human SH-SY5Y neuroblastoma cells were exposed to increasing concentrations (0.1–1000 µM) to generate concentration-response curves, estimate no-observed-adverse-effect levels (NOAELs), and determine cytotoxicity thresholds. Cell viability (MTT), apoptosis (annexin V/propidium iodide), and Bax and Bcl-2 expression (western blot) were assessed after 48 h of exposure. CBD showed an LC50 of 44 µM, whereas PQM-242 and PQM-249 displayed LC50 values > 600 µM, indicating markedly lower intrinsic toxicity in the proposed study model. The NOAELs for PQM-242 and PQM-249 were 100 µM, compared with 10 µM for CBD. For co-exposure studies, 10 µM was selected to enable direct comparison under ethanol challenge (250 mM). All compounds reduced ethanol-induced loss of viability and apoptosis, and PQM-242 additionally prevented ethanol-mediated Bax upregulation. Overall, PQM-242 and PQM-249 demonstrated enhanced cellular safety and maintained protective activity, supporting their further investigation as candidate molecules for AUD.

大麻二酚（CBD）显示出治疗酒精使用障碍（AUD）的治疗潜力；然而，其神经毒理学特征仍然不够充分，特别是与旨在提高安全性的新兴合成类似物相比。本研究比较了CBD和两种合成衍生物PQM-242和PQM-249的神经毒性和机制，并评估了它们减轻乙醇诱导的细胞损伤的能力。将人SH-SY5Y神经母细胞瘤细胞暴露于增加浓度（0.1-1000µM）以产生浓度-反应曲线，估计未观察到的不良反应水平（NOAELs），并确定细胞毒性阈值。暴露48h后检测细胞活力（MTT）、凋亡（膜联蛋白V/碘化丙啶）、Bax和Bcl-2表达（western blot）。CBD的LC50值为44µM，而PQM-242和PQM-249的LC50值为60µM，表明该研究模型的内在毒性明显较低。PQM-242和PQM-249的NOAELs为100µM，而CBD为10µM。对于共暴露研究，选择10µM，以便在乙醇激发（250mM）下进行直接比较。所有化合物都能降低乙醇诱导的细胞活力丧失和细胞凋亡，PQM-242还能阻止乙醇介导的Bax上调。总体而言，PQM-242和PQM-249表现出增强的细胞安全性和保护活性，支持它们作为AUD候选分子的进一步研究。

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引用次数: 0

Prolonged duration induces divergent transcriptomic responses to manganese, distinct from concentration effects, in an SH-SY5Y neurotoxicity model 在SH-SY5Y神经毒性模型中，与浓度效应不同，持续时间延长可诱导对锰的不同转录组反应。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-01-24 DOI: 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.

理解锰（Mn）的神经毒性需要实验模型真实地反映人类暴露的情况。目前体外试验的一个关键限制是依赖于急性高浓度暴露，这可能无法准确捕捉长期Mn积累的分子后果。为了解决这个问题，本研究比较了SH-SY5Y细胞对急性（6小时）和慢性（40天）锰暴露的转录组反应，使用锰浓度范围从接近生理到亚细胞毒性。6小时暴露设计重复了文献中广泛应用的急性持续时间，而选择40天暴露时间模拟流行病学和职业研究中报告的长时间低水平锰负荷。大量RNA测序显示，与急性暴露相比，慢性锰暴露诱导了明显且更广泛的转录改变，与浓度无关。通路富集分析表明，慢性疾病下选择性干扰的细胞功能与神经退行性风险高度相关，并与独立的帕金森病转录组数据集一致。这些途径包括轴突引导信号、淀粉样纤维形成、细胞外基质组织和突触功能。相反，急性暴露主要干扰细胞内离子稳态维持机制。蛋白激酶A信号通路和金属硫蛋白介导的金属结合途径是在锰浓度暴露的两个应用时间之间唯一共享的两条途径，并报道了不良后果。本研究中的转录组学改变强调了与正常mn依赖性细胞功能相关的机制在其神经毒性发展中的贡献。此外，这些结果强调暴露时间是通过体外平台评估长期锰超载诱导的神经变性时需要考虑的关键决定因素。

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引用次数: 0

From clinical observation to experimental validation: Investigating the neurotoxic impact of dimethylacetamide 从临床观察到实验验证：研究二甲基乙酰胺的神经毒性作用。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI: 10.1016/j.neuro.2026.103392

Hizir Asliyuksek , Nihan Hande Akcakaya , Rumeysa Hekimoglu , Simay Bozkurt , Berna Yeniceri , Onder Huseyinbas , Sibel Atacan , Mukaddes Esrefoglu , Emrah Yucesan , Beyza Goncu

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.

二甲基乙酰胺（DMAC）是一种极性有机溶剂，广泛用于合成纤维的生产和其他工业应用。其潜在的肝毒性已在实验动物和职业暴露工人中得到充分证明，使DMAC成为公认的工业危害。然而，关于其神经效应的证据仍然很少。我们报告了一个意外吸入DMAC与脑磁共振成像弥漫性皮质高强度相关的临床病例，引起了对直接神经毒性的关注。为了解决这一知识空白，我们在对照大鼠模型实验中研究了DMAC的神经毒性潜力。反复腹腔注射DMAC的动物表现出与神经毒性一致的皮层和皮层下组织病理学改变，并伴有明显的肝和肾损伤。这些发现提供了第一个实验证据，证明DMAC毒性超出肝毒性，涉及中枢神经系统和肾脏，突出了其多器官毒性的潜力，并加强了对职业暴露风险的关注。

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引用次数: 0

Microglia as a key mediator in rosuvastatin-associated cognitive impairment 小胶质细胞是瑞舒伐他汀相关认知障碍的关键中介。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-12 DOI: 10.1016/j.neuro.2026.103405

Xianzheng Sang , Yichao Ye , Chengzi Yang , Xiaoxiang Hou , Yangu Guo , Hantong Shi , Chunhui Wang , Wen Chen , Danfeng Zhang , Lijun Hou

Background

Hydroxymethylglutaryl-coenzyme A (HMGCR) inhibitors, known as statins, as first-line lipid-lowering therapies for cardiovascular diseases. Despite their widespread use, concerns persist regarding potential cognitive adverse effects, although a definitive causal relationship remains elusive.

Methods

To investigate the underlying mechanisms, this study integrated network toxicology, in vitro experiments, public RNA-sequencing data, computational simulations, and Mendelian randomization analysis. Rosuvastatin was chosen as a representative statin, with human as the focused species and the HMC3 human microglial cell line as the in vitro model.

Results

Network toxicology initially identified microglia as a critically involved cell type. A multi-method approach then demonstrated that rosuvastatin alters microglial functions—including cell viability, migration, phagocytosis, and inflammatory responses—potentially by the JAK-STAT signaling pathway.

Conclusions

These findings suggest that rosuvastatin-induced disruption of microglial function may contribute to cognitive impairment. Our study elucidates potential pathways for this adverse effect and provides novel insights for developing preventive and therapeutic strategies.

背景：羟甲基戊二酰辅酶A （HMGCR）抑制剂，被称为他汀类药物，是心血管疾病的一线降脂疗法。尽管它们被广泛使用，但对潜在的认知不良影响的担忧仍然存在，尽管明确的因果关系仍然难以捉摸。方法：结合网络毒理学、体外实验、公开rna测序数据、计算模拟和孟德尔随机化分析，探讨其潜在机制。选择瑞舒伐他汀作为他汀类药物的代表，以人为重点物种，以HMC3人小胶质细胞系为体外模型。结果：网络毒理学初步确定小胶质细胞是一种关键参与的细胞类型。一项多方法研究表明瑞舒伐他汀可能通过JAK-STAT信号通路改变小胶质细胞功能，包括细胞活力、迁移、吞噬和炎症反应。结论：这些发现提示瑞舒伐他汀诱导的小胶质细胞功能破坏可能导致认知障碍。我们的研究阐明了这种不良反应的潜在途径，并为制定预防和治疗策略提供了新的见解。

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引用次数: 0

Taurine modulates gut microbiota and attenuates inﬂammation in a rotenone-induced mouse model of Parkinson's disease 在鱼藤酮诱导的帕金森病小鼠模型中，牛磺酸调节肠道微生物群并减轻炎症

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-06 DOI: 10.1016/j.neuro.2026.103401

Yunbo Zhu , Shuo Wang , Shuang Zhao , Yujia Zeng , Jing Li , Pingyue Wang , Zhijie Dou , Tianjun Wang

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder in which gut microbiota play a critical role in pathogenesis through the gut–brain axis. Taurine has been reported to exhibit neuroprotective properties. In this study, we employed a rotenone-induced mouse model of PD to investigate the protective effects of taurine and elucidate its underlying mechanisms. PD model mice exhibited weight loss and impaired motor function, both of which were significantly ameliorated by taurine treatment. These mice also showed a marked reduction in dopaminergic neurons alongside increased microglial and astrocyte activation in the substantia nigra. Taurine preserved dopaminergic neuron numbers and suppressed glial activation. Elevated plasma levels of LPS, IL-1β, IL-6, and TNF-α were detected in the PD model group, accompanied by intestinal barrier dysfunction, blood–brain barrier disruption, and gastrointestinal impairment. Taurine administration significantly reduced pro-inflammatory cytokine levels, improved gastrointestinal motility, and preserved the integrity of both the intestinal and blood–brain barriers. Fecal microbiota analysis revealed significant compositional alterations in PD mice. Both α- and β-diversity analyses indicated profound microbial dysbiosis in the model group, which was effectively mitigated by taurine.

帕金森病（PD）是一种常见的神经退行性疾病，其中肠道微生物群通过肠-脑轴在发病机制中起关键作用。据报道牛磺酸具有神经保护作用。在这项研究中，我们采用鱼藤酮诱导的PD小鼠模型来研究牛磺酸的保护作用并阐明其潜在机制。PD模型小鼠表现出体重减轻和运动功能受损，牛磺酸治疗显著改善了这两种情况。这些小鼠还表现出多巴胺能神经元的显著减少，同时黑质中小胶质细胞和星形胶质细胞的激活增加。牛磺酸保留了多巴胺能神经元的数量，抑制了神经胶质的激活。PD模型组大鼠血浆LPS、IL-1β、IL-6、TNF-α水平升高，伴肠屏障功能障碍、血脑屏障破坏、胃肠道损伤。牛磺酸给药显著降低促炎细胞因子水平，改善胃肠运动，并保持肠道和血脑屏障的完整性。粪便微生物群分析显示PD小鼠的组成发生了显著变化。α-和β-多样性分析表明，模型组存在严重的微生物生态失调，牛磺酸有效地缓解了这种失调。

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引用次数: 0

The long-acting anticoagulant rodenticide brodifacoum induces neuropathology in adult New Zealand White rabbits and is reduced by the bile sequestrant cholestyramine 长效抗凝血灭鼠剂溴二磷在成年新西兰大白兔中引起神经病变，并被胆汁隔离胆胺所减少。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-01-31 DOI: 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.

先前的研究表明，暴露于长效抗凝血灭鼠剂（LAARs）可诱导成年大鼠神经病变。在目前的研究中，我们测试了强效的LAAR brodifacoum是否同样促进了成年兔子的神经病理，这为人类LAAR中毒提供了更好的模型。用200 ug/kg的LD50剂量给成年雄性新西兰大白兔灌胃单次给药，然后每天注射维生素K1以预防抗凝死亡。3周后，小脑检查显示神经胶质细胞活化增加，髓磷脂含量减少。进行了一项针对性的脂质组学分析，以确定brodifacoum是否改变了髓磷脂中富集的脂质的相对丰度。我们观察到几种硫脂的溴二苯醚依赖性下降，这与降解硫脂的芳基硫脂酶A的表达增加有关。每日使用胆汁隔离剂胆甾胺治疗，可加速体内LAAR的清除，改善溴化钠引起的损伤。这些发现证实，尽管每天服用维生素K1，如brodifacoum等LAARs仍可诱发成年动物的神经病理，并支持使用胆汁隔离剂等药物来改善这些后果。

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引用次数: 0

Linking particulate matter exposure and neurological disorders: Evidence from epidemiology, biomarkers and mechanistic studies 将颗粒物暴露与神经系统疾病联系起来：来自流行病学、生物标志物和机制研究的证据。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2025-12-31 DOI: 10.1016/j.neuro.2025.103375

Saiyami Bhardwaj , Abhishek Bharti , Radhey Shyam Sharma , Santosh Kumar Mishra , Pankaj Kumar , Abdul S. Ethayathulla , Atinderpal Singh , Vandana Mishra

Exposure to particulate matter (PM) including fine (PM₂.₅), coarse (PM₁₀), and ultrafine particles (UFPM) has emerged as a critical environmental determinant of neurological disorders, including Alzheimer’s and Parkinson’s diseases, neurodevelopmental impairments, and cognitive decline. This review integrates evidence from 129 research articles (2002–2025) to elucidate the mechanistic, biomarker-based, and public health dimensions of PM-induced neurotoxicity. Mechanistic pathways include oxidative stress, neuroinflammation, mitochondrial dysfunction, and blood–brain barrier disruption, with documented structural and functional damage in brain regions such as the hippocampus and prefrontal cortex. PM₂.₅ serves as a carrier of neurotoxic metals (e.g., lead, cadmium, vanadium) and understudied organic toxicants (e.g., PAHs, pesticides), amplifying its pathogenic potential. Exposure occurs through the olfactory route, systemic circulation, and gut–brain axis, highlighting multiple entry points into the central nervous system. Biomarkers such as Aβ₄₂, phosphorylated tau (p-tau), and α-synuclein are elevated in experimental models, but require greater validation in human PM-exposed populations. Children and older adults represent the most vulnerable groups due to developmental sensitivity and cumulative neuroinflammatory burden, yet remain underrepresented in cohort studies. Geographic disparities further limit generalizability, with low- and middle-income countries underrepresented despite experiencing the highest PM burdens. Future research must advance longitudinal, cohort and life-course studies, multi-omics biomarker discovery, and real-world mixture toxicology to identify intervention targets. These findings call for urgent integration of air pollution control into public health strategies targeting neurological diseases, emphasizing prevention through regulation, early detection, and equity-focused research frameworks.

暴露于颗粒物质（PM），包括细颗粒物（PM 2）。₅)，粗（PM₁₀）和超细颗粒（UFPM）已成为神经系统疾病的关键环境决定因素，包括阿尔茨海默病和帕金森病，神经发育障碍和认知能力下降。本综述整合了来自129篇研究文章（2002-2025）的证据，以阐明pm诱导的神经毒性的机制、基于生物标志物和公共卫生层面。机制途径包括氧化应激、神经炎症、线粒体功能障碍和血脑屏障破坏，在海马和前额皮质等大脑区域有记录的结构和功能损伤。点₂。₅是神经毒性金属（如铅、镉、钒）和未充分研究的有机毒物（如多环芳烃、农药）的载体，放大了其致病潜力。暴露通过嗅觉途径、体循环和肠脑轴发生，突出了进入中枢神经系统的多个入口点。生物标志物如β₄2，磷酸化tau （p-tau）和α-突触核蛋白在实验模型中升高，但需要在pm暴露的人类人群中进行更大的验证。由于发育敏感性和累积神经炎症负担，儿童和老年人是最脆弱的群体，但在队列研究中仍未得到充分代表。地域差异进一步限制了普遍性，低收入和中等收入国家尽管经历了最高的PM负担，但代表性不足。未来的研究必须推进纵向、队列和生命过程研究、多组学生物标志物发现和现实世界混合毒理学，以确定干预目标。这些发现呼吁紧急将空气污染控制纳入针对神经系统疾病的公共卫生战略，强调通过监管、早期发现和以公平为重点的研究框架进行预防。

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引用次数: 0

Single-cell transcriptomics reveals the mechanism of long-term neurodevelopmental toxicity following sevoflurane anesthesia 单细胞转录组学揭示七氟醚麻醉后长期神经发育毒性的机制。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2026-03-01 Epub Date: 2026-02-11 DOI: 10.1016/j.neuro.2026.103402

Jinnan Xu , Ziyu Wang , Hao Wang , Hongbo Wen , Zhirou Wen , Longying Chen , Yanyong Cheng , Jia Yan , Hong Jiang

Prolonged exposure to general anesthetics during early development has been associated with neurobehavioral deficits. Sevoflurane, a commonly used pediatric anesthetic, may disrupt cortical maturation, particularly in the prefrontal cortex (PFC) which plays a critical integrative and regulatory role in cognitive and motor functions. In this study, the long-term effects of neonatal sevoflurane exposure were examined using a mouse model, complemented by analysis of single-cell RNA sequencing data from human embryonic PFC (GSE196239). Behavioral assays showed that mice exposed to sevoflurane at postnatal day 7 exhibited persistent impairments in fine motor ability and spatial memory in adulthood. Transcriptomic analysis showed that sevoflurane induced widespread gene expression alterations without changing the major cell-type composition. Through enrichment analysis, dysregulation of pathways related to cell shape was identified. Consistent with these transcriptomic findings, reduced dendritic complexity was observed in sevoflurane-treated neurons by immunofluorescence. Notably, microtubule-associated protein 2 (MAP2), a key structural protein in dendrites, was significantly reduced at the protein level without a corresponding decrease in mRNA expression, suggesting the involvement of post-transcriptional regulation. Together, these findings suggest that prolonged neonatal sevoflurane exposure may impair neuronal maturation and dendritic architecture, and provide molecular insights into the long-term cognitive and motor alterations associated with neonatal sevoflurane exposure.

在发育早期长期暴露于全身麻醉剂与神经行为缺陷有关。七氟醚是一种常用的儿科麻醉剂，可能会破坏皮层的成熟，特别是在前额叶皮层（PFC），它在认知和运动功能中起着关键的整合和调节作用。在这项研究中，通过对人类胚胎PFC （GSE196239）单细胞RNA测序数据的分析，利用小鼠模型研究了新生儿七氟醚暴露的长期影响。行为分析显示，在出生后第7天暴露于七氟醚的小鼠在成年期的精细运动能力和空间记忆方面表现出持续的损伤。转录组学分析表明，七氟醚在不改变主要细胞类型组成的情况下诱导了广泛的基因表达改变。通过富集分析，发现了与细胞形状相关的通路失调。与这些转录组学发现一致，免疫荧光观察到七氟醚处理的神经元树突复杂性降低。值得注意的是，树突的关键结构蛋白微管相关蛋白2 （MAP2）在蛋白水平上显著降低，但mRNA的表达并未相应减少，这表明参与了转录后调控。总之，这些发现表明，新生儿长时间暴露于七氟醚可能损害神经元成熟和树突结构，并为新生儿暴露于七氟醚相关的长期认知和运动改变提供了分子见解。

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引用次数: 0