Neurotoxicity Research最新文献

{"title":"Carbamazepine-Induced Paroxysmal Dysarthria and Ataxia in an Elderly Patient: A Case Report and Clinical Considerations.","authors":"Fayuan Ji, Dongmei Wu, Chao He, Yang Si, Hongbin Sun","doi":"10.1007/s12640-026-00803-4","DOIUrl":"10.1007/s12640-026-00803-4","url":null,"abstract":"<p><p>To report a case of carbamazepine-induced neurotoxicity presenting as paroxysmal dysarthria with ataxia, and to highlight clinical risk factors and diagnostic challenges. This case mimicked a transient ischemic attack (TIA), representing a significant diagnostic pitfall. We present the case of a 71-year-old woman who developed acute paroxysmal dysarthria and ataxia after initiating carbamazepine for otoneuralgia. Differential diagnoses considered included TIA, seizure, drug-induced neurotoxicity, and vestibular disorders. Diagnosis was established through medication review, temporal correlation, and a positive rechallenge test. The Naranjo Adverse Drug Reaction Probability Scale was applied. Symptoms resolved completely upon drug withdrawal and recurred immediately after re-exposure (the patient self-administered a single 100 mg dose on day 4, with immediate symptom recurrence, confirming causality). Serum drug levels were not measured due to limitations of our hospital's laboratory facilities; the Naranjo score was 5 (probable ADR). This case illustrates that carbamazepine may induce specific neurotoxicity even at standard doses in susceptible elderly patients. Paroxysmal dysarthria is a rare but underrecognized adverse reaction. Key clinical take-home points include vigilant clinical assessment, caution with potential drug-drug interactions, therapeutic drug monitoring, and pharmacogenetic profiling when indicated- all of which may aid in prevention and risk reduction.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278198","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":"Impact of Chronic Mild Stress on Neurotrophic and Hypothalamic-Pituitary-Adrenal Factors in the Brain of Rats Submitted to Sepsis.","authors":"Jefté Peper-Nascimento, Taise Possamai-Della, Thais Gois-Carvalho, Jorge M Aguiar-Geraldo, Bruna Pescador, João Quevedo, Felipe Dal-Pizzol, Samira S Valvassori","doi":"10.1007/s12640-026-00801-6","DOIUrl":"10.1007/s12640-026-00801-6","url":null,"abstract":"<p><p>The present study aimed to investigate the effects of chronic mild stress (CMS) on neurotrophic factors in the brains of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. After 30 days of the CLP procedure, the animals were subjected to CMS. Twenty-four hours after the last stressor, the animals were euthanized, their blood was collected, and their brains were dissected in the frontal cortex and hippocampus. Then, the levels of brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, nerve growth factor, and glial cell line-derived neurotrophic factor were evaluated in the brain structures. The levels of adrenocorticotropic hormone and corticosterone were evaluated in the serum of the rats. The four experimental groups of the present study were: (1) Sham + Non-stressed; (2) Sepsis + Non-stressed; (3) Sham + CMS; (4) Sepsis + CMS. CMS increased adrenocorticotropic hormone and corticosterone levels, whereas sepsis alone did not significantly alter these hormones. Regarding neurotrophic factors, CMS reduced the levels of BDNF, NT-3, NT-4, and NGF in both the hippocampus and frontal cortex, regardless of prior sepsis exposure. Sepsis alone was also associated with reduced levels of these neurotrophins, although the magnitude of the effect varied depending on the specific neurotrophin and brain region, with greater reductions observed for BDNF and NGF. No interaction between sepsis and CMS was detected for these neurotrophins, suggesting independent effects. Our findings suggest that sepsis and CMS independently affect most neurotrophin levels, with no clear evidence that prior sepsis potentiates the effects of subsequent CMS. GDNF represents an exception, pointing to potential region-specific mechanisms that warrant further investigation.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005867","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":"Regional Crosstalk Between the Amygdala, Hippocampus, and Prefrontal Cortex Following Na⁺,K⁺-ATPase Inhibition by Ouabain.","authors":"Bianca Estefani Schmidt, Ana Karla Oliveira Leite, Clarissa Penha Farias, Alessandra Schmitt Rieder, Gustavo Ricardo Krupp Prauchner, Carlos Alexandre Netto, Angela T S Wyse","doi":"10.1007/s12640-026-00800-7","DOIUrl":"10.1007/s12640-026-00800-7","url":null,"abstract":"<p><p>The Na⁺,K⁺-ATPase plays a fundamental role in memory formation by regulating neuronal excitability and NMDA receptor-dependent synaptic plasticity. While this enzyme's dysfunction is broadly linked to cognitive disorders, its specific contribution to fear memory consolidation, particularly within the key brain structure of the basolateral amygdala (BLA), remains undefined. We investigate whether Na⁺,K⁺-ATPase inhibition disrupts contextual fear conditioning (CFC) memory consolidation and examine downstream molecular, oxidative, and inflammatory responses in interconnected brain regions. Fifty-day-old male Wistar rats received bilateral cerebral infusions of the Na⁺,K⁺-ATPase inhibitor ouabain (1 μm) or vehicle immediately after CFC training. Memory retention was assessed 24 h later. Additional cohorts were euthanized 6-24 h after infusion for biochemical analysis of Na⁺,K⁺-ATPase activity, expression of Na⁺,K⁺-ATPase isoforms (α1, α2, α3, β1), oxidative stress markers, and pro-inflammatory cytokines in the amygdala, hippocampus, and prefrontal cortex. Post-training Na⁺,K⁺-ATPase inhibition in the BLA selectively impaired fear memory consolidation. Ouabain induced changes in Na⁺,K⁺-ATPase activity in the hippocampus and prefrontal cortex, and induces time-dependent upregulation of α1 and β1 isoforms. Six hours after infusion, ouabain triggered oxidative imbalance - characterized by reduced CAT activity. Pro-inflammatory cytokine expression was markedly elevated in the hippocampus and prefrontal cortex, while D-serine co-administration failed to rescue memory deficits. These findings establish a previously unrecognized role for Na⁺,K⁺-ATPase signaling in the BLA in coordinating the neurobiological processes essential for fear memory consolidation, indicating that its precise regulation is required for adaptive fear memory formation.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13152888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841024","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":"TDP-43 Dysfunction Causes Hyper-Lactate State, Increased AARS1 Expression and Enhanced Protein Lactylation.","authors":"Tianshuo Zhang, Kaixin Yan, Qiao Liao, Ruiyang Liu, Ruyuan Liu, Jinxia Zhou, Yongmin Liu, Fangfang Bi","doi":"10.1007/s12640-026-00797-z","DOIUrl":"10.1007/s12640-026-00797-z","url":null,"abstract":"<p><p>Objective abnormal function of TAR DNA-binding protein of 43 (TDP-43) is closely associated with the development of various neurodegenerative diseases. Previous studies have shown that TDP-43 dysfunction induces mitochondrial damage. However, whether TDP-43 dysfunction further promotes lactate accumulation and enhances protein lactylation remains unclear. This study aimed to investigate the effects of TDP-43 loss-of-function on lactate metabolism and protein lactylation. Methods a neuron-specific TDP-43 conditional knockout mouse model (TDP-43 cKO mice) and a TDP-43 knockdown NSC34 cell model were established. Survival was recorded and motor function was monitored in TDP-43 cKO mice. Mitochondrial morphology and mitochondrial DNA (mtDNA) leakage were examined by high-speed structured illumination microscopy (HIS-SIM). L-lactate levels were quantified using an L-lactate detection kit. TDP-43 and AARS1 mRNA levels were measured by RT-qPCR. The degree of protein pan-lactylation and the expression of TDP-43 and AARS1 were analyzed by Western blot. Results TDP-43 cKO mice exhibited motor deficits and shortened lifespan. In the TDP-43 knockdown cell model, TDP-43 deficiency caused marked mitochondrial structural and functional abnormalities, including reduced mitochondrial number and perimeter, mtDNA leakage, decreased mitochondrial membrane potential, reduced ATP production and impaired cell viability. In both the motor cortex of TDP-43 cKO mice and cell model, L-lactate levels, pan-lactylation, and AARS1 expression were significantly increased. In addition, sodium lactate treatment further enhanced pan-lactylation and AARS1 protein expression in NSC34 cells. Conclusion TDP-43 deficiency induces mitochondrial injury and is associated with lactate accumulation, increased protein lactylation, and AARS1 upregulation. These findings provide new insights into the mechanisms underlying TDP-43 loss-of-function-mediated neurodegeneration and suggest potential therapeutic targets for TDP-43-related neurodegenerative diseases.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777232","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":"From In Vitro Genotoxicity Assays to Human Biomarkers: Interpreting DNA Damage Signals in Long-Term SSRI Therapy through a Translational Neurotoxicology Lens.","authors":"Emadeldin M Kamel, Sally Mostafa Khadrawy, Nour Y S Yassin, Noha A Ahmed","doi":"10.1007/s12640-026-00795-1","DOIUrl":"10.1007/s12640-026-00795-1","url":null,"abstract":"<p><p>Selective serotonin reuptake inhibitors (SSRIs) are among the most frequently prescribed long-term neuropsychiatric medications, making any potential impact on genomic stability a clinically relevant safety question. Interpreting an SSRI “genotoxicity signal,” however, is challenging because evidence spans heterogeneous endpoints (DNA strand breaks, oxidative base lesions, micronuclei/chromosomal damage, and DNA-damage response markers) and experimental systems with widely different exposure conditions. In this translational review, we synthesize in vitro, in vivo, and human biomarker evidence to clarify what reported DNA-damage findings do—and do not—imply for chronic SSRI therapy. Across cell-based models, several SSRIs can induce oxidative stress–linked DNA-damage endpoints and DNA-damage response activation, but these effects commonly emerge at micromolar concentrations that are supratherapeutic and/or near cytotoxicity thresholds, and their magnitude can vary with metabolic competence and exposure design. Animal studies show mixed outcomes, including endpoint discordance between comet and micronucleus assays and occasional evidence of clastogenic or aneugenic effects under specific dosing regimens, limiting generalization from any single positive finding. Human biomarker studies are the most direct evidence for clinical relevance but remain limited and sensitive to confounding by indication. Available data are more consistent with an absence of a robust, clinically meaningful peripheral-blood genotoxic signal during SSRI therapy, while acknowledging scarce longitudinal follow-up, heterogeneous endpoints, and incomplete control for disease state, lifestyle, and co-medications. We propose an “interpretation ladder” to reconcile discrepancies across evidence streams and outline priorities for future research, including therapeutically relevant exposure modeling (with attention to unbound exposure), standardized reporting and quality practices, and well-controlled multi-endpoint longitudinal cohorts with transparent data sharing.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777178","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":"Trifloxystrobin-Induced Neurotoxicity in Wistar Rats: Biomarkers of Oxidative Stress, Cholinergic Dysfunction, and DNA Damage.","authors":"Hanen Chaabani, Asma Mnassri, Siwar Rich, Karima Rjiba, Imed Massoudi, Yosra Guedri, Moncef Mokni, Salwa Abid, Imen Ayed-Boussema","doi":"10.1007/s12640-026-00799-x","DOIUrl":"10.1007/s12640-026-00799-x","url":null,"abstract":"<p><p>Trifloxystrobin (TFX), a broad-spectrum fungicide, inhibits mitochondrial Complex III. While widely used, its neurotoxic mechanisms in mammalian systems remain poorly characterized. This study investigated TFX-induced neurotoxicity in male Wistar rats following 28-day oral exposure to 3, 6, 12, and 24 mg/kg/bw (corresponding to NOAEL/2, NOAEL, NOAEL × 2, and NOAEL × 4). We evaluated dose-dependent effects on brain histopathology, cholinergic function, lipid metabolism, oxidative stress, and DNA integrity. TFX exposure induced significant histopathological alterations, including neurodegeneration, cellular infiltraion, and blood congestion. It also produced a dose-dependent impairment of cholinergic neurotransmission, indicated by suppressed acetylcholinesterase activity, which correlated with observed reduced motor activity and hindlimb strength. Furthermore, TFX disrupted lipid homeostasis by elevating total cholesterol, LDL-C, and HDL-C, while reducing triglycerides. Oxidative stress was evident through increased lipid peroxidation and protein carbonylation, accompanied by altered activities of key antioxidant enzymes (SOD, CAT, GPx, GST). The Comet assay confirmed dose-dependent DNA fragmentation, demonstrating TFX's genotoxic potential. These findings elucidate multiple pathways of TFX-induced neurotoxicity and highlight the need for further investigation into the long-term neurological risks of this fungicide.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777153","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":"MicroRNA-132 Alleviates Ischemia-Reperfusion-Induced Neuronal Apoptosis by Targeting Mecp2 in Stroke Models.","authors":"Xiang Wang, Rui Ma, Zilu Liu, Wenjin Sun, Lin Xia, Yurou Wang, Donghua Shao, Caixia Sun","doi":"10.1007/s12640-026-00796-0","DOIUrl":"10.1007/s12640-026-00796-0","url":null,"abstract":"<p><p>Cerebral ischemia-reperfusion injury (CI/RI) remains a significant challenge in ischemic stroke treatment, often leading to exacerbated neuronal apoptosis and poor neurological recovery despite successful recanalization. MicroRNAs (miRNAs) are known to influence neurodegeneration and repair through post-transcriptional modulation of apoptosis-related genes. In this study, we investigated the neuroprotective role of miR-132 and its interaction with the epigenetic regulator Mecp2 under CI/RI conditions. Utilizing a rat MCAO model and SH-SY5Y neuronal cells exposed to OGD/R, we found that miR-132 levels were significantly decreased while Mecp2 expression was elevated following ischemic injury. Functional assays revealed that overexpression of miR-132 restored neuronal viability, increased anti-apoptotic Bcl-2, and reduced pro-apoptotic Bax expression. In contrast, inhibition of miR-132 exacerbated apoptosis. Bioinformatic analysis and dual-luciferase reporter assays confirmed that miR-132 directly targets the 3′UTR of Mecp2. Importantly, Mecp2 overexpression abolished the protective effects of miR-132, indicating that this axis is essential for apoptosis modulation. These findings establish the miR-132/Mecp2 axis as a key determinant of neuronal fate in CI/RI and identify it as a promising target for neuroprotective therapies.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699236","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":"Protective Effects of Ozone against Quinolinic Acid-Induced Redox Imbalance in Murine BV-2 Microglial Cells.","authors":"Pedro Henrique Zatti, Nicole Peyrot da Silva, Marina Rigotti, Fernando Joel Scariot, Carolina Bordin Davidson, Alencar Kolinski Machado, Catia Santos Branco","doi":"10.1007/s12640-026-00798-y","DOIUrl":"10.1007/s12640-026-00798-y","url":null,"abstract":"<p><p>Ozone gas (O₃) has emerged as a promising therapeutic agent for various pathological conditions, including neurodegenerative diseases (NDs). These illnesses are associated with the accumulation of neurotoxic metabolites by microglia, including tryptophan catabolites. This study aimed to investigate the effects of O₃ exposure on BV-2 microglial cells in the presence or absence of quinolinic acid (QA). O₃ at increasing concentrations (5, 12, 20, 40, and 70 µg/mL) was added in cell culture medium, both under baseline conditions and following exposure to QA (1.5 mM) for 24 h. Spectrophotometry and flow cytometry were performed to assess cell viability, apoptosis, reactive oxygen species (ROS), nitric oxide (NO), mitochondrial membrane potential (ΔΨm), lipid peroxidation (TBARS), and the activities of superoxide dismutase (SOD) and cytochrome c oxidase (COX). qRT-PCR assessed TNF-α gene expression levels. O₃ exposure enhanced cell viability without inducing oxidative/nitrosative stress or DNA damage in BV-2 cells. In addition, 12 µg/mL of O₃ significantly improved cell viability and alleviated oxidative stress and inflammation induced by QA by normalizing SOD activity, reducing lipid peroxidation, and TNF-α gene expression. Nevertheless, O₃ did not restore COX activity nor prevent the hyperpolarization observed under co-treatment conditions. The results suggest that O₃ exerts a biphasic effect, depending on the cellular redox state. This study provides critical insights into the complex mechanisms underlying ozone action in glial cells, highlighting its potential for developing new therapeutic strategies for NDs.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 3","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147699240","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":"Associations between air pollution and markers of neuroinflammation, synaptic dysfunction and core Alzheimer's disease pathology vary by APOE genotype.","authors":"Kana Kimura, Ira Driscoll, Noah Cook, Sonia Shahzad, Tobey J Betthauser, Sterling C Johnson, Sanjay Asthana, Catherine L Gallagher, Bruce P Hermann, Mark A Sager, Kaj Blennow, Henrik Zetterberg, Cynthia M Carlsson, Gwendlyn Kollmorgen, Ozioma C Okonkwo","doi":"10.1007/s12640-026-00786-2","DOIUrl":"10.1007/s12640-026-00786-2","url":null,"abstract":"<p><p>To determine whether long-term residential air pollution [AP; ozone (O₃) and fine particulate matter (PM₂.₅)] is associated with (1) incident mild cognitive impairment (MCI) or Alzheimer’s disease (AD), (2) biomarkers of core and AD-relevant pathology, and (3) whether these relationships are moderated by APOE4+/- (carrier/non-carrier of one or both ε4 alleles) status or mediated by neuroinflammation. Sample included 795 participants (Mage 68.7 ± 7.9; 68% female) from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention parent studies, both enriched for AD risk at enrollment based on parental AD history. Residential zip code and 2009–2021 EPA-based annual AP reports were used to estimate individual exposure. Cox proportional hazards models assessed MCI/AD risk. Linear regressions examined the relationships between AP exposure and biomarkers of core and AD-relevant pathology, with and without APOE4 + stratification. Causal mediation analysis examined whether markers of inflammation mediated the AP-AD pathology relationships. Neither O₃ nor PM₂.₅ exposure predicted MCI/AD incidence nor core AD pathology (Ps > 0.05). Higher PM₂.₅ was associated with higher CSF GFAP levels (P = 0.003). APOE4 + with higher levels of PM₂.₅ exposure had higher CSF levels of tTau (P = 0.01), pTau₁₈₁ (P = 0.01) and neurogranin (P = 0.02). These relationships were not mediated by neuroinflammation (Ps > 0.05). In this AD-risk enriched cohort, AP was not associated with MCI/AD incidence. However, higher PM₂.₅ exposure was associated with astrocytic activation, and in APOE4+, AD pathology, neurodegeneration, and synaptic dysfunction. Our findings suggest AP as an environmental risk factor contributing to AD-relevant pathology, particularly among genetically at-risk individuals.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 2","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628248","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":"Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.","authors":"Miracle K Nekabari, Benneth Ben-Azu, Bienose S Chijioke, Daniel T Esuku, Emmanuel O Chidebe, Faith B Friday, Saviour G Usin, Prosper Iwhiwhu, Ayereoghene S Moses, Ovovwe Diakparomre, Onyeka B Onyeukwu","doi":"10.1007/s12640-026-00785-3","DOIUrl":"10.1007/s12640-026-00785-3","url":null,"abstract":"<p><p>Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 2","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574934","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}