Neurotoxicity Research最新文献

{"title":"Caffeic Acid Mitigates Behavioral and Biochemical Alterations in Lead-induced Neurotoxicity in Rats With Possible Involvement of TFEB.","authors":"Pratham Gautam, Varinder Singh, Navjot Kanwar, Tanveer Singh, Manjinder Singh, Thakur Gurjeet Singh, Amarjot Kaur Grewal, Ravinder Singh, Sheikh F Ahmad, Haneen A Al-Mazroua","doi":"10.1007/s12640-026-00813-2","DOIUrl":"10.1007/s12640-026-00813-2","url":null,"abstract":"<p><p>Lead (Pb) neurotoxicity is characterized by persistent cognitive and motor impairments that arise from converging disturbances in mitochondrial function, oxidative balance, and neuroinflammatory signaling. Increasing evidence suggests that these pathological outcomes are closely linked to disruption of Transcription Factor EB (TFEB), a key regulator of autophagy-lysosomal pathways and mitochondrial quality control. Impaired TFEB function can promote the accumulation of dysfunctional mitochondria and perpetuate oxidative and inflammatory cascades, thereby exacerbating Pb-induced neurodegeneration. The present study evaluated whether caffeic acid (CFA) protects against Pb-induced neurotoxicity and investigated the involvement of TFEB signaling in its neuroprotective effects. Wistar rats were exposed to lead acetate (100 mg/kg, p.o.) for 30 days, followed by treatment with caffeic acid (CFA; 20 and 40 mg/kg). To validate the mechanistic role of TFEB, eltrombopag, a TFEB inhibitor, was co-administered in dedicated groups. Behavioral outcomes were assessed using the Morris Water Maze and rota rod tests, and hippocampal and cerebellar tissues were examined for mitochondrial complex I-III activities, oxidative stress indices (TBARS, GSH), and inflammatory mediators (TNF-α, IL-1β, NF-κB). Pb exposure produced marked spatial memory deficits, motor impairment, suppression of mitochondrial complex activities, oxidative imbalance, and enhanced inflammatory signaling. CFA treatment attenuated these alterations; however, these benefits were lost upon TFEB inhibition. Collectively, these findings demonstrate that CFA attenuates Pb-induced behavioral and biochemical alterations and suggest that its neuroprotective effects are mediated, at least in part, through TFEB-associated pathways.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520728","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":"C-terminal Domain of the Heavy Chain of Tetanus Toxin Ameliorate Lipopolysaccharide Induced Hemiparkinsonism in Rats.","authors":"Irving Parra, José Aguilera, Yousef Tizabi, Liliana Mendieta","doi":"10.1007/s12640-026-00811-4","DOIUrl":"10.1007/s12640-026-00811-4","url":null,"abstract":"<p><p>Neuroinflammation is recognized as a central mechanism in Parkinson's disease (PD) pathogenesis. The C-terminal domain of the heavy-chain of tetanus toxin (Hc-TeTx) has shown neuroprotective effects in toxin-based PD models, but its efficacy in inflammatory-induced PD conditions remain unexplored. To test this possibility, we used the hemiparkinsonism model induced by central injection of lipopolysaccharide (LPS) to evaluate potential antiinflammatory effects of Hc-TeTx in adult male Wistar rats. Seven days post LPS-injection motor coordination and gait maintenance were assessed using elevated beam test. The day after, that is 8 days post LPS-injection, the cylinder test was used to assess forelimb motor asymmetry during spontaneous vertical exploration. Immediately after this test the animals were sacrificed for tissue collection. Dopaminergic degeneration was assessed by immunohistochemical quantification of tyrosine hydroxylase in substantia nigra pars compacta. Astroglial activation, reflective of neuroinflammation was evaluated by glial fibrillary acidic protein in the striatum. LPS administration caused forelimb motor asymmetry, which was significantly attenuated by Hc-TeTx treatment. Hc-TeTx also tended to attenuate LPS-induced dopaminergic neurodegeneration reflected by a reduced TH ipsilateral/contralateral ratio, as well as astroglial activation that was markedly increased after LPS administration. Beam test parameters showed no significant differences among groups. Although further verification and mechanistic studies are needed, current results support potential utility of Hc-TeTx in an inflammatory model of PD.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497766","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":"Human Stem Cell-Derived Neurospheroids and a Multi-Assay Strategy Provide Brain Cytotoxicity New Insights from ADB-FUBIATA Exposure.","authors":"Uliana De Simone, Carlo Alessandro Locatelli, Francesca Caloni, Davide Lonati, Luciana Alessandra Russo, Teresa Coccini","doi":"10.1007/s12640-026-00808-z","DOIUrl":"10.1007/s12640-026-00808-z","url":null,"abstract":"<p><p>Synthetic cannabinoids (SCs) are chemical and inhomogeneous broad group of new psychoactive substances associated with severe toxicity and death. This study aims to characterize neurotoxicological profile of ADB-FUBIATA, third-generation indole-3-acetamide-type SCRA, applying 3D human stem-cell-derived neuronal (3D-hNLCs) spheroids testing at different concentrations (25-2000 nM) and exposure times. i)Single exposure to ADB-FUBIATA induced decrease of: cell viability (2000 nM after 24-h and ≥ 800 nM after 48-h), spheroid compactness (≥ 1600 nM after 24-h and ≥ 200 nM after 48-h), collagen I fibre content (25-35%; 400-800 nM; after 24-48-h), E-cadherin expression (40% from 400 nM after 48-h), enolase (800 nM after 24-h and 400 nM after 48-h) and MAP-2 expression (400-800 nM after 48-h) and increase of interstitial space between cells (400-800 nM). NF-κB p50 and CB1 receptor were not modified. ii)Repeated administration at fixed doses caused at the end of treatment (day 10) several concentration-dependent effects: cell mortality (≥ 200 nM), spheroid compactness loss (≥ 50 nM) and disaggregation, cells detachment from the main body (400-800 nM) and spheroid diameter/size reduction (400-800 nM). 3D-hNLC spheroids reproduce and simulate microenvironment conditions more closely the native human brain and provide relevant information about mechanism-based and biological responses induced by ADB-FUBIATA after both short and long-term repeated exposure, contributing to the development of a more accurate toxicological evaluation method for different SCs. Findings show a translational relevance since data may be transferable to human context expanding the mechanistic understanding of the cellular responses to understand the clinical effects associated with persistence SC use.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472119","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":"Oral Microbial Extracellular Vesicles as Novel Mediators of Alzheimer's Pathogenesis: A Critical Review of the Periodontal-Brain Axis.","authors":"Seyed Ebrahim Alavi, Hasan Ebrahimi Shahmabadi, Robert M Love, Arun V Kurumathur, Lavanya A Sharma, Ajay Sharma","doi":"10.1007/s12640-026-00802-5","DOIUrl":"10.1007/s12640-026-00802-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose origins extend beyond the brain. Chronic periodontitis has emerged as a modifiable risk factor, and extracellular vesicles (EVs) have recently been proposed as important mediators of the periodontal-brain axis. Periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) release bacterial EVs enriched with virulence factors including gingipains, lipopolysaccharide, and regulatory RNAs. These vesicles can enter systemic circulation, interact with the blood-brain barrier, activate microglia, and trigger inflammatory signaling pathways such as NF-κB and NLRP3. These processes contribute to neuroinflammation, amyloid-β accumulation, and tau hyperphosphorylation, hallmarks of AD pathology. Host-derived EVs further contribute to this complex signaling network by facilitating intercellular communication and potentially propagating pathogenic proteins while also carrying protective molecules. Preclinical studies suggest that periodontal-derived vesicles can reach the hippocampus and impair cognition, while clinical studies have detected P. gingivalis DNA and gingipains in AD brain tissues. EV-associated biomarkers in blood or cerebrospinal fluid and engineered therapeutic vesicles represent promising tools for early diagnosis and intervention. Targeting oral microbial EVs may therefore offer novel avenues for AD prevention and therapy.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472068","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":"Bisphenol S-Induced Neurobehavioral Impairment Is Characterized by c-Jun Activation and Distinct Dysregulation of Nrf2 and BDNF in the Zebrafish Brain.","authors":"Bhabani Sankar Sahoo, Prerana Sarangi, Pradyumna Kumar Sahoo, Suvam Bhoi, Lilesh Kumar Pradhan, Saroj Kumar Das","doi":"10.1007/s12640-026-00809-y","DOIUrl":"10.1007/s12640-026-00809-y","url":null,"abstract":"<p><p>Bisphenol S (BPS), a widely used substitute for bisphenol A (BPA), is increasingly detected in consumer products and aquatic environments, yet its neurotoxic potential remains insufficiently understood. Building on our previous findings that BPS induces anxiety-like behaviour and oxidative damage in zebrafish, the present study investigates the mechanistic basis of BPS-mediated neurotoxicity with a focus on stress-activated kinase signalling, antioxidant defences, and neurotrophic regulation. Adult zebrafish were exposed to a sub-lethal concentration of BPS (63.93 µM) for 7, 14, and 21 days, followed by neurobehavioral, biochemical, molecular, and histological analyses. Chronic BPS exposure resulted in pronounced anxiety-like behaviour and deficits in recognition memory, as evidenced by performance impairments in the novel tank diving test and novel object recognition test. These behavioural alterations coincided with elevated oxidative stress, including increased lipid peroxidation and protein carbonylation, alongside a progressive decline in superoxide dismutase activity. BPS also caused a significant, time-dependent rise in intracellular calcium levels, suggesting disrupted cellular homeostasis. Neuromorphological assessment revealed marked neuronal loss and pyknosis in the periventricular grey zone of the optic tectum, consistent with oxidative and excitotoxic damage. At the molecular level, western blot analysis showed robust activation of the c-Jun N-terminal kinase (JNK) pathway, evidenced by elevated phosphorylated c-Jun, accompanied by a substantial reduction in Nrf2 expression, indicating suppressed antioxidant defence capacity. In parallel, expression of brain-derived neurotrophic factor (BDNF) was significantly decreased following prolonged exposure, pointing to impaired neurotrophic support and synaptic plasticity. Together, these findings demonstrate that BPS induces neurobehavioral disturbances through a multifaceted mechanism involving oxidative stress, calcium dysregulation, activation of pro-apoptotic JNK signalling, suppression of Nrf2-mediated antioxidant activity, and inhibition of BDNF expression.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422858","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":"Biological Effects of High-Frequency Electromagnetic Fields on CNS Function and Neuroimmune Responses: A Systematic Review of In Vitro and In Vivo Experimental Studies.","authors":"Shihshuan Fang, Shenghan Chen","doi":"10.1007/s12640-026-00810-5","DOIUrl":"10.1007/s12640-026-00810-5","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Background the deployment of fifth-generation (5G) wireless telecommunications infrastructure, incorporating millimeter-wave (mmWave, 24-100 GHz) and sub-6 GHz frequencies, has renewed scientific and public health interest in the potential neurobiological effects of radiofrequency electromagnetic fields (RF-EMF). While extensive research has examined lower-frequency RF-EMF from 2G/3G/4G technologies, the specific effects of mmWave frequencies on CNS cellular biology-including microglial polarization and intracellular calcium signaling-remain less characterized. This systematic review evaluates experimental evidence from in vitro and in vivo studies on the effects of high-frequency EMF (300 MHz-300 GHz) on neuroimmune responses, microglial function, CNS calcium homeostasis, and related outcomes. Methods PubMed, EMBASE, Web of Science, and the EMF-Portal were searched from inception to January 2026 following PRISMA 2020 guidelines. Experimental (in vitro and animal) studies reporting CNS-relevant outcomes after high-frequency RF-EMF exposure were eligible. Exposure must have been within the 300 MHz to 300 GHz range. Quality assessment used adapted OHAT risk-of-bias criteria. A narrative synthesis was conducted; quantitative pooling was performed where three or more studies reported the same outcome. Results forty-one studies met inclusion criteria (see PRISMA Flow Diagram, Fig. 1): 7 in vitro (cell culture), 29 in vivo (rodent model), and 5 reviews/meta-analyses. The detailed characteristics of all included studies are summarized in Table 1. At specific absorption rate (SAR) levels at or below the International Commission on Non-Ionizing Radiation Protection (ICNIRP) general public exposure guidelines (2 W/kg averaged over 10 g), the majority of studies (27/41, 66%) found no statistically significant effects on neuroinflammatory markers, microglial morphology, or calcium signaling. Eleven studies (27%) reported transient, low-magnitude increases in intracellular Ca²⁺ or pro-inflammatory cytokine expression at exposures near or exceeding guideline limits; these effects were not consistently reproducible across independent laboratories. Three studies (7%) reported effects below guideline thresholds that may warrant further investigation. No study identified neuropathological changes (neuronal death, axonal injury) attributable to RF-EMF at guideline-compliant exposures. Conclusions current experimental evidence does not establish that high-frequency RF-EMF at guideline-compliant exposure levels produces significant adverse effects on microglial polarization, CNS calcium homeostasis, or neuroinflammatory responses. Methodological heterogeneity, inadequate dosimetry, and limited independent replication constrain confidence in both positive and negative findings. Standardized, rigorously controlled experimental studies are needed, particularly for mmWave frequencies (&gt; 6 GHz) where data are sparse. Our findings support the current scientific conse","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405403","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":"EGF and GHRP6 Co-Administration Attenuates Cognitive Decline in Preclinical Models: Behavioral and Molecular Evidences.","authors":"Daniela Risco-Acevedo, Nelvys Subirós-Martínez, Hanlet Camacho-Rodríguez, Jeney Ramírez-Sánchez, Yaima Rodríguez-Virulich, Ana Yansi Etchegoyen-Amoros, Wendy Hernández-Estrada, Maylin Wong-Guerra, Yanay Montano-Peguero, Thalia Estrada-Olivares, Dasha Fuentes-Morales, Daniel Palenzuela-Gardón, Héctor Pérez-Saad, Yanier Núñez-Figueredo, Li Wen, Gerardo E Guillén-Nieto, Diana García-Del-Barco-Herrera","doi":"10.1007/s12640-026-00807-0","DOIUrl":"10.1007/s12640-026-00807-0","url":null,"abstract":"<p><p>Cognitive decline is a hallmark of neurodegenerative diseases. The complex pathophysiology of these diseases has limited the efficacy of current therapies. The co-administration of epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP6) emerges as a promising neuroprotective candidate. The present study evaluated the therapeutic potential of this combination in two preclinical models of cognitive impairment: (i) age-related decline and (ii) impairment induced by intracerebroventricular administration of streptozotocin (STZ). In both experiments, C57BL/6 mice were used and distributed into three experimental groups, each comprising 14-15 animals per group. Cognitive and motor function was assessed through gait pattern, Y-maze and novel object recognition tests. Differential gene expression was analyzed using qPCR. Both models reproduced hallmark features of cognitive decline, including deficits in working and spatial memory and changes in the expression of genes associated with oxidative stress, neuroinflammation and synaptic plasticity. In aged animals, EGF + GHRP6 treatment increased step length (p = 0.04). In the forced alternation Y-maze test, aged-EGF + GHRP6 animals made more visits to the novel arm than to the familiar arm 1 (p = 0.001) or to the familiar arm 2 (p = 0.04). Cognitive benefits were also observed in the STZ-induced model. STZ-EGF + GHRP6 group exhibited an alternation percentage higher than the STZ-vehicle group (p = 0.03). Moreover, EGF + GHRP6 treatment significantly increased the expression of genes associated with antioxidant defense (Hmox1), synaptic plasticity (Creb1), and oligodendrocyte differentiation (Olig1) while concurrently reducing the expression of Nfkb1. These findings highlight the therapeutic potential of EGF + GHRP6 co-administration as a neuroprotective strategy to mitigate neurodegeneration and preserve cognitive function.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382565","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":"Silymarin Reverses Seizure-Precipitating Effects of Alcohol and Associated Psychiatric Comorbidities, and Neurotoxicity in Pentylenetetrazol Pre-Kindled Mice.","authors":"Benneth Ben-Azu, Itivere A Omogbiya, Joseph O T Emudainohwo, Aliance R Fokoua, Olajide S Annafi, Bienose S Chijioke, Daniel T Esuku, Emmanuel O Chidebe, Benjamin Oritsemuelebi, Maxwell Oboh, Whiliki Oscar Onoriadjeren, Eze K Nwangwa","doi":"10.1007/s12640-026-00804-3","DOIUrl":"10.1007/s12640-026-00804-3","url":null,"abstract":"<p><p>Heavy alcohol consumption has multiple negative cognitive, psychological, and neurobiological consequences for people with epilepsy. However, the psychopharmacological interactions remain unclear with limited therapeutic interventions. In this study, we investigated the diverse impact of alcohol on experimental simulated pentylenetetrazol-induced seizures and alcohol-use disorder, and the effects of silymarin, a polyphenolic compound with neuroprotective properties. Following seven days of ethanol binge exposure (2 g/kg, oral gavage) in mice, maximal and sub-convulsive pentylenetetrazol-induced seizures were administered from days 8 to 14, alongside silymarin (50 and 100 mg/kg) or diazepam (3 mg/kg) oral administration. This study evaluated the interplay between ethanol and pentylenetetrazol-induced seizures, assessing behavioural comorbidities, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis, neurochemical and neurotrophic alterations, oxidative stress, and neuroinflammation in the hippocampus, prefrontal-cortex, and striatum, which are involved in the disease. Ethanol increased seizure severity and frequency caused by pentylenetetrazol, and worsened anxiety-like and depressive behaviours, along with spatial working memory deficits linked to higher alcohol preference. These effects were reduced by silymarin. Ethanol also increased corticosterone release and reduced GABA-dependent glutamic acid decarboxylase activity, raising glutamate levels, while decreasing serotonin and brain-derived neurotrophic factor across the studied brain regions. Silymarin significantly reduced neuroinflammatory markers such as myeloperoxidase, TNF-α, IL-6, nitrite, and malondialdehyde, while enhancing IL-10 levels and antioxidant defenses, including catalase, superoxide dismutase and glutathione in the brain regions. These findings suggest alcoholism with alcohol-use disorders worsens epilepsy, notably involving neurochemical imbalance, neurotropic, HPA-axis upregulation, oxidative stress, and neuroinflammation, which were reversed by silymarin.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382546","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":"In vivo Administration of Atorvastatin Does Not Impair Mitochondrial Function or Cellular Viability in the Prefrontal Cortex of Mice.","authors":"Karen B Gessler, Júlia Rescaroli, Silvana M Pires, Francisco G W Lippert, Eduarda S Spanamberg, Gabriel Bernardes, Isabel M Zavorne, Carla I Tasca, Gianni Mancini","doi":"10.1007/s12640-026-00805-2","DOIUrl":"10.1007/s12640-026-00805-2","url":null,"abstract":"<p><p>Atorvastatin is a widely prescribed statin used for its cholesterol-lowering effects; however, it also exerts known pleiotropic effects, including antioxidant and anti-inflammatory properties. Atorvastatin´s impact on mitochondrial function remains controversial, with reports of toxicity in skeletal muscle and liver, while exhibiting beneficial effects on the brain. Atorvastatin has a neuroprotective effect, modulating glutamatergic transmission and reducing oxidative stress. Additionally, we previously showed that atorvastatin treatment in vivo increases mitochondrial capacity in the mouse hippocampus. Nonetheless, the bioenergetic impact of atorvastatin on the prefrontal cortex, a critical region for cognitive function, remains underexplored. This study investigated whether short-term administration of atorvastatin alters mitochondrial respiration and redox status in the prefrontal cortex of adult mice. Male Swiss mice received atorvastatin (10 mg/kg/day) or vehicle orally (p.o., in a voluntary consumption protocol) for 7 days. A behavioral analysis showed that atorvastatin slightly increased spontaneous locomotor activity and does not compromise short- (90 min) and long-term (24 h) memory in the object recognition task. The evaluation of cellular viability, cell membrane integrity, reactive oxygen species (ROS) production, and mitochondrial membrane potential in slices from the prefrontal cortex showed that atorvastatin did not induce oxidative stress, cell damage, or mitochondrial depolarization. High-resolution respirometry (HRR) was used to assess oxygen consumption rates (OCR) in prefrontal cortex homogenates, and we observed no significant alterations in any of the mitochondrial respiratory states: basal, LEAK, phosphorylating, maximal electron transfer system (ETS) capacity, or coupling efficiency. Furthermore, direct analysis of the enzymatic activity of respiratory chain complexes I and II also showed no alterations. These findings indicate that short-term atorvastatin administration is bioenergetically neutral in the murine prefrontal cortex under basal conditions, and does not compromise cognition, mitochondrial function, or cellular viability.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339439","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":"Prolonged In Vitro Exposure to Methylmalonic Acid Induces Inflammation, Glutamate Metabolism Disruption, and Alters Functional Gene Expression in C6 Astroglial Cells.","authors":"Rômulo Rodrigo de Souza Almeida, Larissa Daniele Bobermin, Izaviany Schmitz, Filipe Renato Pereira Dias, Caio César Ramalho Bezerra, Mariana Rocke-Peters, Ester Rezena, Krista Minéia Wartchow, Fernanda Urruth Fontella, Diogo Onofre Souza, Moacir Wajner, Carlos-Alberto Gonçalves, Guilhian Leipnitz, André Quincozes-Santos","doi":"10.1007/s12640-026-00806-1","DOIUrl":"10.1007/s12640-026-00806-1","url":null,"abstract":"<p><p>Methylmalonic acidemia is an inherited neurometabolic disorder characterized by accumulation of methylmalonic acid (MMA) in different tissues, particularly in the brain. As a result, patients frequently exhibit progressive neurological deterioration, accompanied by episodes of acute encephalopathy following metabolic decompensation. Astrocytes are glial cells that maintain the central nervous system homeostasis and may be important cellular targets of MMA-induced dysfunction. However, most in vitro experimental models for the study of methylmalonic acidemia are based on short-term exposure to the toxic metabolites that accumulate in patients. In this study, we used a prolonged experimental model, which has not been yet explored in the context of glial cells, focusing on the inflammatory response, glutamate metabolism, and putative signaling pathways that can contribute to understanding cellular damage observed in methylmalonic acidemia. It is emphasized that MMA is persistently elevated in the brain of the affected patients. Prolonged MMA exposure induced inflammation with significant increase in gene expression of cyclooxygenase 2, interleukin (IL)-1β and its receptor (IL1R1), and IL-6, accompanied by a decrease in IL-10 expression. MMA also increased glutamate uptake and the activity and gene expression of the enzyme glutamine synthetase, while it downregulated glial cell-derived neurotrophic factor (GDNF). The expression of NFκB, p38 MAPK, Nrf2, heme oxygenase 1, PGC-1α, and sirtuin 1 were also modulated by MMA treatment, indicating the critical role of these signaling pathways in the MMA-induced persistent gliotoxicity. Finally, it is conceivable that these changes may significantly contribute to clarify the pathogenesis of methylmalonic acidemia.</p>","PeriodicalId":19193,"journal":{"name":"Neurotoxicity Research","volume":"44 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148302422","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}