Neurotoxicology最新文献_第5页

Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats 神经炎症调节高氨血症大鼠海马gaba能神经传递的机制

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-06 DOI: 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 GABA_A 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_A 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_A 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.

高氨血症是肝性脑病患者认知功能障碍的主要原因。高氨血症引起的认知障碍是由神经炎症和海马谷氨酸能和氨基丁酸能神经传递的改变介导的。高氨血症增强海马gaba能神经传递，但神经炎症的作用尚不清楚。高氨血症大鼠小脑中S1PR2-BDNF-TrkB通路激活增强介导gaba能神经传递。在高氨血症大鼠海马中，IL-1β和Src激酶激活的增加改变了谷氨酸能神经传递。本研究的目的是评估神经炎症是否与高氨血症大鼠海马gaba能神经传递增强有关，并确定其潜在机制。我们使用对照和高氨血症雄性大鼠的离体海马切片，评估阻断S1PR2、IL-1受体、TrkB或抑制蛋白激酶Src或PI3K对谷氨酸脱羧酶和GABA含量的影响，以及对GABAA受体、GABA转运体和氯化物共转运体膜表达的影响。阻断S1PR2-IL-1β-Src-BDNF-TrkB-PI3K通路的任何一个步骤都可以逆转GABA转运体的膜表达减少，从而增加细胞外GABA，并且分析的大多数GABAA受体亚基的膜表达增加，这也增强了GABA能神经传递。这可能是通过增加gephyrin的含量和GABAA受体β3亚基的磷酸化来介导的。这一途径作为gabaergy神经传递增强的起源，为逆转高氨血症和肝性脑病的认知障碍提供了几个治疗靶点，也可能是与神经炎症和gabaergy神经传递增强相关的其他病理。

{"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":"2025-11-06","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}

引用次数: 0

Metal and metalloid exposure and cognitive function among copper mine workers: A three-year longitudinal study 铜矿工人的金属和类金属接触与认知功能：一项为期三年的纵向研究

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-06 DOI: 10.1016/j.neuro.2025.103349

Narjes Soltani , Tabandeh Sadeghi , Majid Saadloo , Mohammad Reza Baneshi , Soghra Akbari Chermahini , Ali Shamsizade

Occupational exposure to heavy metals is increasingly recognized as a threat to neurological health. This three-year longitudinal study investigated the relationship between heavy metal exposure and cognitive performance among 69 copper miners and 74 non-miner controls. Blood concentrations of heavy metals were determined using atomic absorption spectrophotometry, while cognitive performance was assessed with standardized neuropsychological tests, including the Mini-Mental State Examination (MMSE), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), Psychomotor Vigilance Task (PVT), creativity measures, and the Beck Depression Inventory. The results demonstrated significantly higher blood levels of arsenic and lead in miners compared with controls, whereas copper levels showed no meaningful group difference. Elevated arsenic concentrations were strongly associated with reduced performance on the oral SDMT, reflecting impairments in information processing speed and working memory. Longitudinal analyses confirmed persistent group differences in neurocognitive outcomes, with age and education exerting notable modifying effects. Interestingly, miners consistently exhibited lower depression scores across the study period, despite greater exposure to toxic metals. These findings indicate that chronic occupational exposure to arsenic and lead contributes to subtle but measurable cognitive deficits in copper miners, particularly in domains of working memory and processing speed.

越来越多的人认识到职业性接触重金属是对神经系统健康的威胁。这项为期三年的纵向研究调查了69名铜矿工人和74名非矿工的重金属暴露与认知表现之间的关系。使用原子吸收分光光度法测定血液中重金属浓度，同时使用标准化的神经心理学测试评估认知能力，包括迷你精神状态检查（MMSE）、符号数字模态测试（SDMT）、节奏性听觉序列加法测试（PASAT）、精神运动警惕性任务（PVT）、创造力测量和贝克抑郁量表。结果显示，与对照组相比，矿工血液中砷和铅的含量明显较高，而铜的含量则没有明显的组间差异。砷浓度升高与口服SDMT的表现下降密切相关，反映了信息处理速度和工作记忆的损伤。纵向分析证实了神经认知结果的持续组差异，年龄和教育发挥了显着的调节作用。有趣的是，矿工在整个研究期间一直表现出较低的抑郁得分，尽管他们更多地接触有毒金属。这些发现表明，长期职业性接触砷和铅会导致铜矿工人的认知缺陷，尤其是在工作记忆和处理速度方面。

{"title":"Metal and metalloid exposure and cognitive function among copper mine workers: A three-year longitudinal study","authors":"Narjes Soltani , Tabandeh Sadeghi , Majid Saadloo , Mohammad Reza Baneshi , Soghra Akbari Chermahini , Ali Shamsizade","doi":"10.1016/j.neuro.2025.103349","DOIUrl":"10.1016/j.neuro.2025.103349","url":null,"abstract":"<div><div>Occupational exposure to heavy metals is increasingly recognized as a threat to neurological health. This three-year longitudinal study investigated the relationship between heavy metal exposure and cognitive performance among 69 copper miners and 74 non-miner controls. Blood concentrations of heavy metals were determined using atomic absorption spectrophotometry, while cognitive performance was assessed with standardized neuropsychological tests, including the Mini-Mental State Examination (MMSE), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), Psychomotor Vigilance Task (PVT), creativity measures, and the Beck Depression Inventory. The results demonstrated significantly higher blood levels of arsenic and lead in miners compared with controls, whereas copper levels showed no meaningful group difference. Elevated arsenic concentrations were strongly associated with reduced performance on the oral SDMT, reflecting impairments in information processing speed and working memory. Longitudinal analyses confirmed persistent group differences in neurocognitive outcomes, with age and education exerting notable modifying effects. Interestingly, miners consistently exhibited lower depression scores across the study period, despite greater exposure to toxic metals. These findings indicate that chronic occupational exposure to arsenic and lead contributes to subtle but measurable cognitive deficits in copper miners, particularly in domains of working memory and processing speed.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103349"},"PeriodicalIF":3.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465587","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}

引用次数: 0

Subchronic Residual Oil Fly Ash (ROFA) exposure induces oxidative stress in brain, lung, and cardiac tissues and promotes neuroinflammation, with partial attenuation by taurine 亚慢性残油粉煤灰（ROFA）暴露可诱导脑、肺和心脏组织的氧化应激，并促进神经炎症，牛磺酸可部分减弱。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-06 DOI: 10.1016/j.neuro.2025.103347

Gedaias Noronha da Silva , Bruna Marmett , Mateus Belmonte Macedo , Gilson Pires Dorneles , Dora Athaydes Saul , Pedro Roosevelt Torres Romão , Eliane Dallegrave

Background

Exposure to particulate matter (PM₂.₅), including Residual Oil Fly Ash (ROFA), triggers oxidative stress and inflammation. Taurine, an antioxidant amino acid, may protect against these effects, but its efficacy against subchronic ROFA exposure is unclear. This study evaluated taurine’s protective role in ROFA-induced multi-organ damage and neurobehavioral changes.

Methods

Male Wistar rats received ROFA (250 µg/day, intranasally) for six weeks, with or without taurine (400 mg/kg/day). Oxidative markers (CAT, SOD, TBARS) were measured in the brain, lungs, heart, and liver. Cytokines (TNF-α, IL-1β) were assessed in plasma and brain. Behavior was tested using Open Field, Elevated Plus Maze, and Novel Object Recognition.

Results

ROFA increased oxidative stress, reducing catalase in the brain and lungs and raising TBARS. Neuroinflammation was evident via elevated TNF-α and IL-1β and confirmed by histopathology, which revealed Gitter cells and endothelial hypertrophy. ROFA also raised urea levels and caused pulmonary damage. Behaviorally, ROFA increased locomotion (distance traveled and line crossings) without altering anxiety or memory. Taurine attenuated oxidative stress in the liver and kidneys. While taurine treatment alone increased vertical exploratory behavior (rearing), it did not significantly reverse the behavioral or neuropathological changes induced by ROFA exposure.

Conclusions

Subchronic ROFA exposure causes multi-organ damage, predominantly in the brain and lungs. Histopathological evidence confirmed significant neuroinflammation. Taurine provides partial, organ-specific protection against oxidative stress but has limited efficacy against neuroinflammation. These findings suggest taurine's benefits are context-dependent, highlighting the need for further research into its mechanisms and potential in combating air pollution-related health effects.

背景：暴露于颗粒物（PM₂）。₅)，包括残油飞灰（ROFA），会引发氧化应激和炎症。牛磺酸是一种抗氧化氨基酸，可以防止这些影响，但其对亚慢性ROFA暴露的功效尚不清楚。本研究评估了牛磺酸在rofa诱导的多器官损伤和神经行为改变中的保护作用。方法：雄性Wistar大鼠给予ROFA（250µg/天，鼻内），加或不加牛磺酸（400mg/kg/天），持续6周。在脑、肺、心和肝中测量氧化标志物（CAT、SOD、TBARS）。测定血浆和脑组织中细胞因子（TNF-α、IL-1β）。行为测试采用开放场地，高架加迷宫和新物体识别。结果：ROFA增加氧化应激，降低脑和肺过氧化氢酶，提高TBARS。神经炎症通过TNF-α和IL-1β升高而明显，组织病理学证实为闪烁细胞和内皮细胞肥大。ROFA还会提高尿素水平，造成肺损伤。在行为上，ROFA增加了运动（行进距离和过线），但没有改变焦虑或记忆。牛磺酸可以减轻肝脏和肾脏的氧化应激。虽然单独的牛磺酸治疗增加了垂直探索行为（饲养），但它并没有显著逆转ROFA暴露引起的行为或神经病理改变。结论：亚慢性ROFA暴露导致多器官损伤，主要是脑和肺。组织病理学证实有明显的神经炎症。牛磺酸提供部分的、器官特异性的抗氧化应激保护，但对神经炎症的作用有限。这些发现表明牛磺酸的益处取决于环境，强调需要进一步研究其机制和对抗空气污染相关健康影响的潜力。

{"title":"Subchronic Residual Oil Fly Ash (ROFA) exposure induces oxidative stress in brain, lung, and cardiac tissues and promotes neuroinflammation, with partial attenuation by taurine","authors":"Gedaias Noronha da Silva , Bruna Marmett , Mateus Belmonte Macedo , Gilson Pires Dorneles , Dora Athaydes Saul , Pedro Roosevelt Torres Romão , Eliane Dallegrave","doi":"10.1016/j.neuro.2025.103347","DOIUrl":"10.1016/j.neuro.2025.103347","url":null,"abstract":"<div><h3>Background</h3><div>Exposure to particulate matter (PM₂.₅), including Residual Oil Fly Ash (ROFA), triggers oxidative stress and inflammation. Taurine, an antioxidant amino acid, may protect against these effects, but its efficacy against subchronic ROFA exposure is unclear. This study evaluated taurine’s protective role in ROFA-induced multi-organ damage and neurobehavioral changes.</div></div><div><h3>Methods</h3><div>Male Wistar rats received ROFA (250 µg/day, intranasally) for six weeks, with or without taurine (400 mg/kg/day). Oxidative markers (CAT, SOD, TBARS) were measured in the brain, lungs, heart, and liver. Cytokines (TNF-α, IL-1β) were assessed in plasma and brain. Behavior was tested using Open Field, Elevated Plus Maze, and Novel Object Recognition.</div></div><div><h3>Results</h3><div>ROFA increased oxidative stress, reducing catalase in the brain and lungs and raising TBARS. Neuroinflammation was evident via elevated TNF-α and IL-1β and confirmed by histopathology, which revealed Gitter cells and endothelial hypertrophy. ROFA also raised urea levels and caused pulmonary damage. Behaviorally, ROFA increased locomotion (distance traveled and line crossings) without altering anxiety or memory. Taurine attenuated oxidative stress in the liver and kidneys. While taurine treatment alone increased vertical exploratory behavior (rearing), it did not significantly reverse the behavioral or neuropathological changes induced by ROFA exposure.</div></div><div><h3>Conclusions</h3><div>Subchronic ROFA exposure causes multi-organ damage, predominantly in the brain and lungs. Histopathological evidence confirmed significant neuroinflammation. Taurine provides partial, organ-specific protection against oxidative stress but has limited efficacy against neuroinflammation. These findings suggest taurine's benefits are context-dependent, highlighting the need for further research into its mechanisms and potential in combating air pollution-related health effects.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103347"},"PeriodicalIF":3.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477032","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}

引用次数: 0

Dapagliflozin ameliorates cisplatin-induced cognitive impairments in rats: Cross-talk between miRNA-21/p-ERK/p-38 MAPK and wnt/β-catenin signaling pathways 达格列净改善大鼠顺铂诱导的认知障碍：miRNA-21/p-ERK/p-38 MAPK和wnt/β-catenin信号通路的交叉对话

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-06 DOI: 10.1016/j.neuro.2025.103348

Abeer M. Shaheen , Rabab H. Sayed , Gouda K. Helal , Mohammed F. El-Yamany , Mohamed I. Fahmy

Cisplatin is a well-known, highly potent, and efficient anticancer drug frequently used for the treatment of a range of malignant tumors; nevertheless, it is associated with an undefined phenomenon termed chemobrain. Chemobrain is an extensive impairment in memory, learning abilities, and cognitive functions brought on by inflammation, apoptosis, and oxidative stress in the brain tissue, which negatively affects cancer survivors’ quality of life. Dapagliflozin (DAPA), a sodium-glucose transporter-2 inhibitor, has shown remarkable neuroprotective effects in different preclinical studies; nonetheless, it has not been studied in a chemobrain model. The current research aimed to assess the potential neuroprotective effect of DAPA in mitigating the cognitive impairment induced by cisplatin and the possible underlying mechanism of action. Forty male Wistar albino rats were allocated into four groups and treated for 4 weeks as follows: control, DAPA (1 mg/kg/day, p.o) group, cisplatin (5 mg/kg/week, i.p.) group, and cisplatin + DAPA group. The results proved that DAPA treatment alleviates cognitive dysfunction induced by cisplatin, as evidenced by behavioral tests, namely novel object recognition, Morris water maze, and Y-maze tests. Moreover, DAPA attenuated oxidative stress, inflammation, and apoptotic pathways. DAPA also downregulated the expression of miRNA-2, extracellular regulated kinase (p-ERK), and p-38 mitogen-activated protein kinase (p-38 MAPK). Along with that, DAPA restored neurogenesis and neuronal survival via promoting the wingless-related integration site (Wnt), β-catenin, accompanied by a reduction in glycogen synthase kinase-3 beta (GSK-3β). In conclusion, our findings postulated that DAPA may have a promising neuroprotective activity against cisplatin-induced cognitive impairments.

顺铂是一种众所周知的、高效的抗癌药物，经常用于治疗一系列恶性肿瘤；然而，它与一种被称为化学脑的未定义现象有关。化学脑是一种记忆、学习能力和认知功能的广泛损伤，由脑组织中的炎症、细胞凋亡和氧化应激引起，对癌症幸存者的生活质量产生负面影响。Dapagliflozin （DAPA）是一种钠-葡萄糖转运蛋白-2抑制剂，在不同的临床前研究中显示出显著的神经保护作用；尽管如此，它还没有在化学脑模型中进行过研究。本研究旨在评估DAPA在减轻顺铂所致认知功能障碍中的潜在神经保护作用及其可能的作用机制。将40只雄性Wistar白化大鼠分为4组，分别为对照组、DAPA（1 mg/kg/d，口服）组、顺铂（5 mg/kg/ d，口服）组、顺铂+ DAPA组，治疗4周。结果证明，DAPA治疗可以缓解顺铂所致的认知功能障碍，行为测试，即新物体识别，Morris水迷宫和y迷宫测试证明了这一点。此外，DAPA还能减弱氧化应激、炎症和凋亡途径。DAPA还下调了miRNA-2、细胞外调节激酶（p-ERK）和p-38丝裂原活化蛋白激酶（p-38 MAPK）的表达。与此同时，DAPA通过促进无翅相关整合位点(Wnt) β-连环蛋白（β-catenin），并伴随着糖原合成酶激酶-3β (GSK-3β)的减少，恢复神经发生和神经元存活。综上所述，我们的研究结果假设DAPA可能对顺铂诱导的认知障碍具有很好的神经保护作用。

{"title":"Dapagliflozin ameliorates cisplatin-induced cognitive impairments in rats: Cross-talk between miRNA-21/p-ERK/p-38 MAPK and wnt/β-catenin signaling pathways","authors":"Abeer M. Shaheen , Rabab H. Sayed , Gouda K. Helal , Mohammed F. El-Yamany , Mohamed I. Fahmy","doi":"10.1016/j.neuro.2025.103348","DOIUrl":"10.1016/j.neuro.2025.103348","url":null,"abstract":"<div><div>Cisplatin is a well-known, highly potent, and efficient anticancer drug frequently used for the treatment of a range of malignant tumors; nevertheless, it is associated with an undefined phenomenon termed chemobrain. Chemobrain is an extensive impairment in memory, learning abilities, and cognitive functions brought on by inflammation, apoptosis, and oxidative stress in the brain tissue, which negatively affects cancer survivors’ quality of life. Dapagliflozin (DAPA), a sodium-glucose transporter-2 inhibitor, has shown remarkable neuroprotective effects in different preclinical studies; nonetheless, it has not been studied in a chemobrain model. The current research aimed to assess the potential neuroprotective effect of DAPA in mitigating the cognitive impairment induced by cisplatin and the possible underlying mechanism of action. Forty male Wistar albino rats were allocated into four groups and treated for 4 weeks as follows: control, DAPA (1 mg/kg/day, p.o) group, cisplatin (5 mg/kg/week, i.p.) group, and cisplatin + DAPA group. The results proved that DAPA treatment alleviates cognitive dysfunction induced by cisplatin, as evidenced by behavioral tests, namely novel object recognition, Morris water maze, and Y-maze tests. Moreover, DAPA attenuated oxidative stress, inflammation, and apoptotic pathways. DAPA also downregulated the expression of miRNA-2, extracellular regulated kinase (p-ERK), and p-38 mitogen-activated protein kinase (p-38 MAPK). Along with that, DAPA restored neurogenesis and neuronal survival via promoting the wingless-related integration site (Wnt), β-catenin, accompanied by a reduction in glycogen synthase kinase-3 beta (GSK-3β). In conclusion, our findings postulated that DAPA may have a promising neuroprotective activity against cisplatin-induced cognitive impairments.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103348"},"PeriodicalIF":3.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465585","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}

引用次数: 0

Oxidative stress and retinal damage induced by cobalt chloride in Drosophila melanogaster: Insights into cone cell susceptibility and stress gene responses 氯化钴诱导黑腹果蝇的氧化应激和视网膜损伤：锥细胞易感性和应激基因反应的见解。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-05 DOI: 10.1016/j.neuro.2025.103346

Puja Karmakar , Janmejaya Bag , Seekha Naik , Monalisa Mishra

Oxidative stress is a critical factor of neurotoxicity and retinal disorders, yet the early cellular mechanisms underlying glial involvement remain poorly understood. In this study, we used Drosophila melanogaster to understand the toxic effects of cobalt chloride (CoCl₂)-induced oxidative stress on retinal development, focusing on glial-like cone (semper) cells. CoCl₂ exposure resulted in reduced pupal yield, indicating developmental neurotoxicity. Acridine orange and propidium iodide staining of eye-imaginal discs showed reduced fluorescence intensity in treated tissues due to widespread cellular degeneration. Phalloidin and 4′,6-diamidino-2-phenylindole staining revealed early cytoskeletal fragmentation in cone cells of pupae and adult CoCl₂-trated eye samples, preceding widespread photoreceptor disruption. Functionally, CoCl₂-treatment impaired larval crawling, adult climbing, and phototactic behaviour, accompanied by elevated ROS levels at the larval stage, reduced body weight, and decreased adult survival. Biochemical assays showed delayed Superoxide Dismutase and catalase activity, and increased glutathione peroxidase activity. SDS-PAGE and qPCR confirmed heat shock response activation, with significant upregulation of Hsp22, Hsp23, Hsp27, and Hsp70, while Hsp26 remained unchanged. These findings indicate that cone cells as early neurotoxic targets of oxidative stress and establish Drosophila as a valuable oxidative retinopathy model for studying glia-neuron interactions and redox-induced neurodegeneration.

氧化应激是神经毒性和视网膜疾病的关键因素，但神经胶质参与的早期细胞机制仍然知之甚少。在这项研究中，我们使用果蝇来了解氯化钴（CoCl₂）诱导的氧化应激对视网膜发育的毒性作用，重点是胶质样锥体（semper）细胞。coc2暴露导致蛹产量降低，表明发育神经毒性。眼影像盘的吖啶橙（AO）和碘化丙啶（PI）染色显示，由于广泛的细胞变性，处理组织的荧光强度降低。Phalloidin和4'，6-二氨基-2-苯基吲哚（DAPI）染色显示，CoCl 2处理过的蛹和成体眼睛样本的视锥细胞早期出现细胞骨架断裂，随后广泛发生光感受器破坏。在功能上，CoCl 2处理会损害幼虫爬行、成虫攀爬和光致行为，并伴有幼虫期ROS水平升高、体重减轻和成虫存活率降低。生化检测结果显示超氧化物歧化酶（SOD）和过氧化氢酶活性延迟，谷胱甘肽过氧化物酶（GPx）活性升高。SDS-PAGE和qPCR证实热休克反应激活，Hsp22、Hsp23、Hsp27和Hsp70显著上调，而Hsp26保持不变。这些发现表明，视锥细胞是氧化应激的早期神经毒性靶点，并使果蝇成为研究胶质-神经元相互作用和氧化还原诱导的神经变性的有价值的氧化性视网膜病变模型。

{"title":"Oxidative stress and retinal damage induced by cobalt chloride in Drosophila melanogaster: Insights into cone cell susceptibility and stress gene responses","authors":"Puja Karmakar , Janmejaya Bag , Seekha Naik , Monalisa Mishra","doi":"10.1016/j.neuro.2025.103346","DOIUrl":"10.1016/j.neuro.2025.103346","url":null,"abstract":"<div><div>Oxidative stress is a critical factor of neurotoxicity and retinal disorders, yet the early cellular mechanisms underlying glial involvement remain poorly understood. In this study, we used <em>Drosophila melanogaster</em> to understand the toxic effects of cobalt chloride (CoCl₂)-induced oxidative stress on retinal development, focusing on glial-like cone (semper) cells. CoCl₂ exposure resulted in reduced pupal yield, indicating developmental neurotoxicity. Acridine orange and propidium iodide staining of eye-imaginal discs showed reduced fluorescence intensity in treated tissues due to widespread cellular degeneration. Phalloidin and 4′,6-diamidino-2-phenylindole staining revealed early cytoskeletal fragmentation in cone cells of pupae and adult CoCl₂-trated eye samples, preceding widespread photoreceptor disruption. Functionally, CoCl₂-treatment impaired larval crawling, adult climbing, and phototactic behaviour, accompanied by elevated ROS levels at the larval stage, reduced body weight, and decreased adult survival. Biochemical assays showed delayed Superoxide Dismutase and catalase activity, and increased glutathione peroxidase activity. SDS-PAGE and qPCR confirmed heat shock response activation, with significant upregulation of <em>Hsp22</em>, <em>Hsp23, Hsp27</em>, and <em>Hsp70</em>, while <em>Hsp26</em> remained unchanged. These findings indicate that cone cells as early neurotoxic targets of oxidative stress and establish <em>Drosophila</em> as a valuable oxidative retinopathy model for studying glia-neuron interactions and redox-induced neurodegeneration.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103346"},"PeriodicalIF":3.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471516","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}

引用次数: 0

Prenatal nicotine exposure affects hippocampal development and behavior in mouse offspring 产前尼古丁暴露影响小鼠后代海马发育和行为。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.neuro.2025.103342

Si-Jing Fan , Yu Qi Zhou , Lian Liu , Qun Liu

To investigate the association between prenatal nicotine exposure (PNE) induced behavioral abnormalities in offspring and multiple classes of neuronal cell changes in the hippocampus at different developmental stages after birth, pregnant mice were injected subcutaneously with nicotine (1.5 mg/kg) from gestational day (GD) 9 until parturition. Multimodal histological analyses (Golgi staining, and immunohistochemistry) were performed on hippocampal DG, CA1, and CA3 regions at postnatal day (PD) 1, 7, 14, 21, and 90. Behavioral assessment (open field, tail suspension, forced swimming, sucrose preference, novel object recognition, and morris water maze tests) was conducted from PD56 to PD90. The results showed that PNE induced stage-specific alterations in hippocampal development, characterized by enhanced neuronal proliferation during early postnatal stages (PD1–7) and suppressed dendritic arborization during middle postnatal phases (PD14–21); persistent neurogenesis deficits were observed in the DG region, coupled with sustained reduction in dendritic spine density in CA1 pyramidal neurons throughout adulthood; the CA1 region demonstrated transient microglial depletion alongside persistent GABAergic interneuron deficiency; behavioral assessments revealed significant deficits in spatial learning and memory retention, as well as heightened anxiety- and depression-like phenotypes in adult PNE offspring.

为了研究产前尼古丁暴露（PNE）诱导的后代行为异常与出生后不同发育阶段海马多类神经元细胞变化之间的关系，从妊娠第9天（GD）至分娩期间，对怀孕小鼠皮下注射尼古丁（1.5mg/kg）。在出生后第1、7、14、21和90天对海马DG、CA1和CA3区进行多模式组织学分析（高尔基染色和免疫组织化学）。从PD56到PD90进行行为评估（开放场地、悬尾、强迫游泳、蔗糖偏好、新物体识别和morris水迷宫测试）。结果表明，PNE诱导海马发育的阶段特异性改变，其特征是在出生后早期（PD1-7）增强神经元增殖，在出生后中期（PD14-21）抑制树突状树突生长；在DG区观察到持续的神经发生缺陷，伴随着CA1锥体神经元持续的树突棘密度降低；CA1区表现出短暂的小胶质细胞耗竭和持续的gaba能中间神经元缺乏；行为评估显示，PNE后代在空间学习和记忆保留方面存在显著缺陷，并且焦虑和抑郁样表型增加。

{"title":"Prenatal nicotine exposure affects hippocampal development and behavior in mouse offspring","authors":"Si-Jing Fan , Yu Qi Zhou , Lian Liu , Qun Liu","doi":"10.1016/j.neuro.2025.103342","DOIUrl":"10.1016/j.neuro.2025.103342","url":null,"abstract":"<div><div>To investigate the association between prenatal nicotine exposure (PNE) induced behavioral abnormalities in offspring and multiple classes of neuronal cell changes in the hippocampus at different developmental stages after birth, pregnant mice were injected subcutaneously with nicotine (1.5 mg/kg) from gestational day (GD) 9 until parturition. Multimodal histological analyses (Golgi staining, and immunohistochemistry) were performed on hippocampal DG, CA1, and CA3 regions at postnatal day (PD) 1, 7, 14, 21, and 90. Behavioral assessment (open field, tail suspension, forced swimming, sucrose preference, novel object recognition, and morris water maze tests) was conducted from PD56 to PD90. The results showed that PNE induced stage-specific alterations in hippocampal development, characterized by enhanced neuronal proliferation during early postnatal stages (PD1–7) and suppressed dendritic arborization during middle postnatal phases (PD14–21); persistent neurogenesis deficits were observed in the DG region, coupled with sustained reduction in dendritic spine density in CA1 pyramidal neurons throughout adulthood; the CA1 region demonstrated transient microglial depletion alongside persistent GABAergic interneuron deficiency; behavioral assessments revealed significant deficits in spatial learning and memory retention, as well as heightened anxiety- and depression-like phenotypes in adult PNE offspring.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103342"},"PeriodicalIF":3.9,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459345","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}

引用次数: 0

Protective effects of oleuropein against monosodium glutamate-induced toxicity in aged rats 橄榄苦苷对谷氨酸钠致老龄大鼠毒性的保护作用。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.neuro.2025.103344

Gurkan Baytar , Aslı Okan Oflamaz , zuleyha Doganyi̇gi̇t , Serdar Aktas , Tuncer Kutlu , Aylin Ates , Serdal Ogut

The research aimed to investigate the adverse responses of the aged organism to monosodium glutamate (MSG) exposure and to evaluate the potential protective effects of oleuropein (OLE) against these responses.

A total of 48 aged rats were allocated into four distinct experimental groups. Control, MSG, OLE, and MSG+OLE. Treatments were administered via oral gavage for 28 days. Biochemical markers (e.g., TAC, TOC, MDA, ALT, AST) and histopathological analyses of liver, heart and brain tissues were performed. Immunohistochemical evaluations assessed glutamate receptor (GluR) and Kir4.1 expression levels. Statistical analyses included ANOVA and post-hoc tests.

MSG administration significantly increased oxidative stress markers (MDA, NO, TOC) and liver enzymes (ALT, AST), while reducing antioxidant levels (TAC, TTL). Histopathological findings revealed liver damage (hemorrhage, sinusoidal dilation) and neuronal degeneration in the prefrontal cortex. OLE co-administration mitigated these effects, reducing oxidative damage and improving liver histology. Immunohistochemical results showed MSG upregulated GluR-1, GluR-2, and mGluR-5 in heart tissue, while OLE restored Kir4.1 expression in the brainstem.

OLE demonstrated hepatoprotective and neuroprotective effects against MSG-induced toxicity by reducing oxidative stress and preserving tissue integrity. These findings highlight OLE’s potential as a therapeutic agent, however, additional research is required to clarify its underlying molecular pathways. The research supports the consumption of OLE-rich foods to counteract food additive-related toxicity.

本研究旨在探讨老年机体对味精（MSG）暴露的不良反应，并评价橄榄苦苷（OLE）对这些不良反应的潜在保护作用。将48只老龄大鼠分为4个实验组。Control、MSG、OLE和MSG+OLE。经灌胃治疗28 d。进行肝、心、脑组织生化指标（如TAC、TOC、MDA、ALT、AST）和组织病理学分析。免疫组化评价谷氨酸受体（GluR）和Kir4.1的表达水平。统计分析包括方差分析和事后检验。味精处理显著增加了氧化应激标志物（MDA、NO、TOC）和肝酶（ALT、AST），降低了抗氧化剂水平（TAC、TTL）。组织病理学结果显示肝损伤（出血，窦扩张）和前额皮质神经元变性。OLE联合用药减轻了这些影响，减少了氧化损伤，改善了肝脏组织学。免疫组化结果显示，MSG上调了心脏组织中GluR-1、GluR-2和mGluR-5的表达，OLE恢复了脑干中Kir4.1的表达。OLE通过减少氧化应激和保持组织完整性，对味精诱导的毒性具有肝保护和神经保护作用。这些发现突出了OLE作为一种治疗剂的潜力，然而，需要进一步的研究来阐明其潜在的分子途径。这项研究支持食用富含ole的食物来抵消与食品添加剂相关的毒性。

{"title":"Protective effects of oleuropein against monosodium glutamate-induced toxicity in aged rats","authors":"Gurkan Baytar , Aslı Okan Oflamaz , zuleyha Doganyi̇gi̇t , Serdar Aktas , Tuncer Kutlu , Aylin Ates , Serdal Ogut","doi":"10.1016/j.neuro.2025.103344","DOIUrl":"10.1016/j.neuro.2025.103344","url":null,"abstract":"<div><div>The research aimed to investigate the adverse responses of the aged organism to monosodium glutamate (MSG) exposure and to evaluate the potential protective effects of oleuropein (OLE) against these responses.</div><div>A total of 48 aged rats were allocated into four distinct experimental groups. Control, MSG, OLE, and MSG+OLE. Treatments were administered via oral gavage for 28 days. Biochemical markers (e.g., TAC, TOC, MDA, ALT, AST) and histopathological analyses of liver, heart and brain tissues were performed. Immunohistochemical evaluations assessed glutamate receptor (GluR) and Kir4.1 expression levels. Statistical analyses included ANOVA and post-hoc tests.</div><div>MSG administration significantly increased oxidative stress markers (MDA, NO, TOC) and liver enzymes (ALT, AST), while reducing antioxidant levels (TAC, TTL). Histopathological findings revealed liver damage (hemorrhage, sinusoidal dilation) and neuronal degeneration in the prefrontal cortex. OLE co-administration mitigated these effects, reducing oxidative damage and improving liver histology. Immunohistochemical results showed MSG upregulated GluR-1, GluR-2, and mGluR-5 in heart tissue, while OLE restored Kir4.1 expression in the brainstem.</div><div>OLE demonstrated hepatoprotective and neuroprotective effects against MSG-induced toxicity by reducing oxidative stress and preserving tissue integrity. These findings highlight OLE’s potential as a therapeutic agent, however, additional research is required to clarify its underlying molecular pathways. The research supports the consumption of OLE-rich foods to counteract food additive-related toxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103344"},"PeriodicalIF":3.9,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459348","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}

引用次数: 0

DDT exposure induces microglial activation and disease-associated microglial signatures: Relevance to mechanisms of Alzheimer’s disease DDT暴露诱导小胶质细胞激活和疾病相关的小胶质细胞特征：与阿尔茨海默病的机制相关。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-11-02 DOI: 10.1016/j.neuro.2025.103343

Isha Mhatre-Winters , Aseel Eid , Nicole Blum , Yoonhee Han , Ferass M. Sammoura , Long-Jun Wu , Jason R. Richardson

Background

Alzheimer’s disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.

Objective

Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.

Methods

DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, 4–5-month-old C57BL/6J mice received a single oral dose of 30 mg/kg DDT for 24 h, and the hippocampal and frontal cortical expression of proinflammatory and DAM genes was measured.

Results

PMG exposed to DDT (0.5–5.0 µM) elicited a concentration-dependent upregulation in Il-1b, Il-6, Nos2, and Tnfa mRNA levels. These effects were blocked by TTX, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. C57BL/6J mice exposed to DDT demonstrated significantly increased Nos2, Il-1b, and Il-6 mRNA in the frontal cortex (1.5–2.3-fold), and Nos2, Il-1b, and Tnfa (1.5–1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes were downregulated, while stage-1 DAM genes were upregulated both in vitro and in vivo. Notably, Apoe and Trem2 were only upregulated in the females.

Conclusion

These data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.

背景：阿尔茨海默病（AD）的特点是存在淀粉样蛋白-β斑块、神经原纤维缠结和神经炎症。此前，我们报道了与年龄匹配的对照组相比，AD患者血清中农药二氯二苯三氯乙烷（DDT）的主要代谢物二氯二苯二氯乙烯（DDE）水平明显更高，并且在动物模型中，DDT暴露加重了AD病理。目的：研究DDT对小鼠原代小胶质细胞（PMG）和C57BL/6J小鼠神经炎症的影响。方法：在钠通道拮抗剂河豚毒素（TTX）预处理和不预处理的情况下，采用qPCR和免疫细胞化学方法检测ddt诱导的PMG炎症和疾病相关小胶质细胞（DAM）基因表达。此外，4-5月龄C57BL/6J小鼠单次口服滴滴涕30mg/kg，持续24h，测量海马和额叶皮质促炎和DAM基因的表达。结果：暴露于DDT（0.5-5.0µM）的PMG引起Il-1b、Il-6、Nos2和Tnfa mRNA水平的浓度依赖性上调。这些作用被TTX阻断，证明ddt -小胶质钠通道相互作用在介导这种反应中的作用。DDT暴露的C57BL/6J小鼠额叶皮质Nos2、Il-1b和Il-6 mRNA显著增加（1.5-2.3倍），海马Nos2、Il-1b和Tnfa显著增加（1.5-1.8倍）。此外，小胶质细胞内稳态基因下调，而1期DAM基因在体外和体内均上调。值得注意的是，Apoe和Trem2仅在雌性中上调。结论：这些数据表明DDT增加神经炎症，这可能是由DDT对小胶质细胞的直接作用引起的，这为DDT可能增加AD风险提供了一种新的途径。

{"title":"DDT exposure induces microglial activation and disease-associated microglial signatures: Relevance to mechanisms of Alzheimer’s disease","authors":"Isha Mhatre-Winters , Aseel Eid , Nicole Blum , Yoonhee Han , Ferass M. Sammoura , Long-Jun Wu , Jason R. Richardson","doi":"10.1016/j.neuro.2025.103343","DOIUrl":"10.1016/j.neuro.2025.103343","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.</div></div><div><h3>Objective</h3><div>Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.</div></div><div><h3>Methods</h3><div>DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, 4–5-month-old C57BL/6J mice received a single oral dose of 30 mg/kg DDT for 24 h, and the hippocampal and frontal cortical expression of proinflammatory and DAM genes was measured.</div></div><div><h3>Results</h3><div>PMG exposed to DDT (0.5–5.0 µM) elicited a concentration-dependent upregulation in <em>Il-1b, Il-6, Nos2,</em> and <em>Tnfa</em> mRNA levels. These effects were blocked by TTX, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. C57BL/6J mice exposed to DDT demonstrated significantly increased <em>Nos2</em>, <em>Il-1b</em>, and <em>Il-6</em> mRNA in the frontal cortex (1.5–2.3-fold), and <em>Nos2</em>, <em>Il-1b,</em> and <em>Tnfa</em> (1.5–1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes were downregulated, while stage-1 DAM genes were upregulated both <em>in vitro</em> and <em>in vivo</em>. Notably, <em>Apoe</em> and <em>Trem2</em> were only upregulated in the females.</div></div><div><h3>Conclusion</h3><div>These data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103343"},"PeriodicalIF":3.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445676","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}

引用次数: 0

A hyperpolarization-activated cyclic nucleotide-gated channel inhibitor mitigates brain mitochondrial oxidative stress, but does not affect other neuropathological 超极化激活的环核苷酸门控通道抑制剂减轻脑线粒体氧化应激，但不影响其他神经病理。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-10-28 DOI: 10.1016/j.neuro.2025.103341

Hiranya Pintana , Nattayaporn Apaijai , Adivitch Sripusanapan , Titikorn Chunchai , Damrongsak Jinarat , Aphisek Kongkaew , Nipon Chattipakorn , Siriporn C. Chattipakorn

Background

The effects of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, on doxorubicin-induced chemobrain remain unclear. This study aimed to investigate whether ivabradine mitigates doxorubicin-induced chemobrain by improving cognitive function, hippocampal synaptic plasticity, and mitochondrial function, while reducing oxidative stress, inflammation, and blood-brain barrier (BBB) disruption in male rats.

Methods

Twenty-four male rats were randomly assigned to one of four groups: control-vehicle treated, control-ivabradine treated, doxorubicin-vehicle treated, and doxorubicin-ivabradine treated. Control-rats received normal saline, while doxorubicin-treated rats were given doxorubicin (3 mg/kg/day) intraperitoneally on days 0, 4, 8, 15, 22, and 29. Ivabradine (10 mg/kg) was given orally from day 0 to day 29. On day 30, cognitive function was evaluated using the novel object location (NOL) test. Following euthanasia, hippocampal synaptic plasticity, mitochondrial function, BBB integrity, brain oxidative stress and inflammation were assessed.

Results

Doxorubicin treatment led to impaired performance in the NOL test, reduced hippocampal synaptic plasticity, disruption of mitochondrial function and BBB integrity, alongside increased oxidative stress and inflammation in the brain. Ivabradine reduced the level of mitochondrial reactive oxygen species (ROS), but did not significantly improve NOL performance or synaptic plasticity in doxorubicin-treated rats. However, ivabradine partially restored hippocampal dendritic spine morphology and reduced oxidative stress and inflammation in the brain.

Conclusion

Doxorubicin-induced chemobrain resulted in cognitive impairment and brain pathologies. Ivabradine reduced mitochondrial ROS and alleviated oxidative stress and inflammation in the brain, but did not improve cognitive function or synaptic plasticity. Higher doses of ivabradine may be required for more effective neuroprotection in chemobrain.

背景：伊瓦布雷定（一种超极化激活的环核苷酸门控通道阻滞剂）对阿霉素诱导的化学脑的影响尚不清楚。本研究旨在探讨伊伐布雷定是否通过改善雄性大鼠的认知功能、海马突触可塑性和线粒体功能，同时减少氧化应激、炎症和血脑屏障（BBB）破坏，来减轻阿霉素诱导的化学脑。方法：将24只雄性大鼠随机分为4组：对照组、对照组伊瓦布雷定组、阿霉素组和阿霉素-伊瓦布雷定组。对照组大鼠给予生理盐水，阿霉素治疗组大鼠于第0、4、8、15、22、29天腹腔注射阿霉素3mg/kg/天。从第0天至第29天口服伊伐布雷定（10mg/kg）。第30天，采用新目标定位（NOL）测试评估认知功能。安乐死后，评估海马突触可塑性、线粒体功能、血脑屏障完整性、脑氧化应激和炎症。结果：阿霉素治疗导致NOL测试表现受损，海马突触可塑性降低，线粒体功能和血脑屏障完整性破坏，同时大脑氧化应激和炎症增加。伊伐布雷定降低了阿霉素处理大鼠线粒体活性氧（ROS）水平，但没有显著改善NOL性能或突触可塑性。然而，伊伐布雷定部分恢复海马树突棘形态，减少大脑氧化应激和炎症。结论：阿霉素诱导的化学脑导致认知功能障碍和脑病理。伊伐布雷定降低了线粒体ROS，减轻了大脑的氧化应激和炎症，但没有改善认知功能或突触可塑性。在化学脑中，更高剂量的伊伐布雷定可能需要更有效的神经保护。

{"title":"A hyperpolarization-activated cyclic nucleotide-gated channel inhibitor mitigates brain mitochondrial oxidative stress, but does not affect other neuropathological","authors":"Hiranya Pintana , Nattayaporn Apaijai , Adivitch Sripusanapan , Titikorn Chunchai , Damrongsak Jinarat , Aphisek Kongkaew , Nipon Chattipakorn , Siriporn C. Chattipakorn","doi":"10.1016/j.neuro.2025.103341","DOIUrl":"10.1016/j.neuro.2025.103341","url":null,"abstract":"<div><h3>Background</h3><div>The effects of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, on doxorubicin-induced chemobrain remain unclear. This study aimed to investigate whether ivabradine mitigates doxorubicin-induced chemobrain by improving cognitive function, hippocampal synaptic plasticity, and mitochondrial function, while reducing oxidative stress, inflammation, and blood-brain barrier (BBB) disruption in male rats.</div></div><div><h3>Methods</h3><div>Twenty-four male rats were randomly assigned to one of four groups: control-vehicle treated, control-ivabradine treated, doxorubicin-vehicle treated, and doxorubicin-ivabradine treated. Control-rats received normal saline, while doxorubicin-treated rats were given doxorubicin (3 mg/kg/day) intraperitoneally on days 0, 4, 8, 15, 22, and 29. Ivabradine (10 mg/kg) was given orally from day 0 to day 29. On day 30, cognitive function was evaluated using the novel object location (NOL) test. Following euthanasia, hippocampal synaptic plasticity, mitochondrial function, BBB integrity, brain oxidative stress and inflammation were assessed.</div></div><div><h3>Results</h3><div>Doxorubicin treatment led to impaired performance in the NOL test, reduced hippocampal synaptic plasticity, disruption of mitochondrial function and BBB integrity, alongside increased oxidative stress and inflammation in the brain. Ivabradine reduced the level of mitochondrial reactive oxygen species (ROS), but did not significantly improve NOL performance or synaptic plasticity in doxorubicin-treated rats. However, ivabradine partially restored hippocampal dendritic spine morphology and reduced oxidative stress and inflammation in the brain.</div></div><div><h3>Conclusion</h3><div>Doxorubicin-induced chemobrain resulted in cognitive impairment and brain pathologies. Ivabradine reduced mitochondrial ROS and alleviated oxidative stress and inflammation in the brain, but did not improve cognitive function or synaptic plasticity. Higher doses of ivabradine may be required for more effective neuroprotection in chemobrain.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103341"},"PeriodicalIF":3.9,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409687","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}

引用次数: 0

The role of ER/ERK/CREB pathway mediated mitophagy in bisphenol F-induced cognitive function changes in young female rats ER/ERK/CREB通路介导的线粒体自噬在双酚f诱导的年轻雌性大鼠认知功能改变中的作用

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-10-28 DOI: 10.1016/j.neuro.2025.103340

Wenhe Wang, Zeqin Peng, Xinyi Feng, Zixuan Chen, Jie Zhang, Tianwenjing Huang, Qin Zhang, Dan Wu, Qin Liu

Bisphenol F (BPF) is a widespread industrial chemical and suspected neurotoxicant, yet its effects on cognitive function and the underlying mechanisms remain unclear. This study aimed to investigate whether BPF exposure induced cognitive function changes in young female rats were associated with ER/ERK/CREB pathway and subsequent mitophagy. 4-week-old Sprague-Dawley female rats received BPF via oral gavage (25 or 250 μg/kg bw/d) for 4 weeks. Cognitive function was evaluated using the Morris water maze and novel object recognition test during the last week of exposure. Hippocampal tissue was analysed for histomorphology, ER/ERK/CREB pathway changes, mitophagy and apoptosis. In this study, spatial learning in rats was transiently impaired, whereas long-term spatial memory remained unchanged in rats following BPF exposure. The recognition capability was improved as the dose increased. At the molecular level, the protein related to ER/ERK/CREB pathway, mitophagy and apoptosis were downregulated. Moreover, the mitophagy was downregulated in hippocampal CA1 region. These findings suggested that BPF exposure affected cognitive functions in young female rats, which was associated with the alterations of mitophagy mediated by ER/ERK/CREB pathway.

双酚F （BPF）是一种广泛使用的工业化学品和疑似神经毒物，但其对认知功能的影响及其潜在机制尚不清楚。本研究旨在探讨BPF暴露诱导的年轻雌性大鼠认知功能改变是否与ER/ERK/CREB通路及其后的有丝分裂有关。4周龄Sprague-Dawley雌性大鼠灌胃BPF(25或250μg/kg bw/d) 4周。在暴露的最后一周，使用Morris水迷宫和新物体识别测试评估认知功能。分析海马组织形态学、ER/ERK/CREB通路变化、线粒体自噬和细胞凋亡情况。在本研究中，暴露于BPF后，大鼠的空间学习功能短暂受损，而长期空间记忆功能保持不变。随着剂量的增加，识别能力有所提高。在分子水平上，与ER/ERK/CREB通路、线粒体自噬和细胞凋亡相关的蛋白下调。海马CA1区有丝分裂下调。这些结果表明，BPF暴露影响了年轻雌性大鼠的认知功能，这与ER/ERK/CREB途径介导的线粒体自噬改变有关。

{"title":"The role of ER/ERK/CREB pathway mediated mitophagy in bisphenol F-induced cognitive function changes in young female rats","authors":"Wenhe Wang, Zeqin Peng, Xinyi Feng, Zixuan Chen, Jie Zhang, Tianwenjing Huang, Qin Zhang, Dan Wu, Qin Liu","doi":"10.1016/j.neuro.2025.103340","DOIUrl":"10.1016/j.neuro.2025.103340","url":null,"abstract":"<div><div>Bisphenol F (BPF) is a widespread industrial chemical and suspected neurotoxicant, yet its effects on cognitive function and the underlying mechanisms remain unclear. This study aimed to investigate whether BPF exposure induced cognitive function changes in young female rats were associated with ER/ERK/CREB pathway and subsequent mitophagy. 4-week-old Sprague-Dawley female rats received BPF via oral gavage (25 or 250 μg/kg bw/d) for 4 weeks. Cognitive function was evaluated using the Morris water maze and novel object recognition test during the last week of exposure. Hippocampal tissue was analysed for histomorphology, ER/ERK/CREB pathway changes, mitophagy and apoptosis. In this study, spatial learning in rats was transiently impaired, whereas long-term spatial memory remained unchanged in rats following BPF exposure. The recognition capability was improved as the dose increased. At the molecular level, the protein related to ER/ERK/CREB pathway, mitophagy and apoptosis were downregulated. Moreover, the mitophagy was downregulated in hippocampal CA1 region. These findings suggested that BPF exposure affected cognitive functions in young female rats, which was associated with the alterations of mitophagy mediated by ER/ERK/CREB pathway.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103340"},"PeriodicalIF":3.9,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409707","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}

引用次数: 0