Neurotox Res [JOURNAL]
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200 papers
Silymarin Reverses Seizure-Precipitating Effects of Alcohol and Associated Psychiatric Comorbidities, and Neurotoxicity in Pentylenetetrazol Pre-Kindled Mice.
Ben-Azu B, Omogbiya IA, Emudainohwo JOT … +9 more , Fokoua AR, Annafi OS, Chijioke BS, Esuku DT, Chidebe EO, Oritsemuelebi B, Oboh M, Onoriadjeren WO, Nwangwa EK
Neurotox Res · 2026 Jul · PMID 42399577 · Publisher ↗
Heavy alcohol consumption has multiple negative cognitive, psychological, and neurobiological consequences for people with epilepsy. However, the psychopharmacological interactions remain unclear with limited therapeutic...
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.
EGF and GHRP6 Co-Administration Attenuates Cognitive Decline in Preclinical Models: Behavioral and Molecular Evidences.
Risco-Acevedo D, Subirós-Martínez N, Camacho-Rodríguez H … +14 more , Ramírez-Sánchez J, Rodríguez-Virulich Y, Etchegoyen-Amoros AY, Hernández-Estrada W, Wong-Guerra M, Montano-Peguero Y, Estrada-Olivares T, Fuentes-Morales D, Palenzuela-Gardón D, Pérez-Saad H, Núñez-Figueredo Y, Wen L, Guillén-Nieto GE, García-Del-Barco-Herrera D
Neurotox Res · 2026 Jul · PMID 42399524 · Publisher ↗
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 growt...
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.
In vivo Administration of Atorvastatin Does Not Impair Mitochondrial Function or Cellular Viability in the Prefrontal Cortex of Mice.
Gessler KB, Rescaroli J, Pires SM … +6 more , Lippert FGW, Spanamberg ES, Bernardes G, Zavorne IM, Tasca CI, Mancini G
Neurotox Res · 2026 Jun · PMID 42360657 · Full text
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 mi...
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.
Prolonged In Vitro Exposure to Methylmalonic Acid Induces Inflammation, Glutamate Metabolism Disruption, and Alters Functional Gene Expression in C6 Astroglial Cells.
de Souza Almeida RR, Bobermin LD, Schmitz I … +11 more , Dias FRP, Bezerra CCR, Rocke-Peters M, Rezena E, Wartchow KM, Fontella FU, Souza DO, Wajner M, Gonçalves CA, Leipnitz G, Quincozes-Santos A
Neurotox Res · 2026 Jun · PMID 42334510 · Full text
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 progressi...
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.
Carbamazepine-Induced Paroxysmal Dysarthria and Ataxia in an Elderly Patient: A Case Report and Clinical Considerations.
Ji F, Wu D, He C … +2 more , Si Y, Sun H
Neurotox Res · 2026 Jun · PMID 42319725 · Publisher ↗
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 (T...
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.
Impact of Chronic Mild Stress on Neurotrophic and Hypothalamic-Pituitary-Adrenal Factors in the Brain of Rats Submitted to Sepsis.
Peper-Nascimento J, Possamai-Della T, Gois-Carvalho T … +5 more , Aguiar-Geraldo JM, Pescador B, Quevedo J, Dal-Pizzol F, Valvassori SS
Neurotox Res · 2026 May · PMID 42176200 · Full text
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 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.
Regional Crosstalk Between the Amygdala, Hippocampus, and Prefrontal Cortex Following Na,K-ATPase Inhibition by Ouabain.
Schmidt BE, Leite AKO, Farias CP … +4 more , Rieder AS, Prauchner GRK, Netto CA, Wyse ATS
Neurotox Res · 2026 May · PMID 42096113 · Full text
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...
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.
TDP-43 Dysfunction Causes Hyper-Lactate State, Increased AARS1 Expression and Enhanced Protein Lactylation.
Zhang T, Yan K, Liao Q … +5 more , Liu R, Liu R, Zhou J, Liu Y, Bi F
Neurotox Res · 2026 Apr · PMID 42029805 · Publisher ↗
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 mitochon...
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.
From In Vitro Genotoxicity Assays to Human Biomarkers: Interpreting DNA Damage Signals in Long-Term SSRI Therapy through a Translational Neurotoxicology Lens.
Kamel EM, Khadrawy SM, Yassin NYS … +1 more , Ahmed NA
Neurotox Res · 2026 Apr · PMID 42024228 · Publisher ↗
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. Int...
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.
Trifloxystrobin-Induced Neurotoxicity in Wistar Rats: Biomarkers of Oxidative Stress, Cholinergic Dysfunction, and DNA Damage.
Chaabani H, Mnassri A, Rich S … +6 more , Rjiba K, Massoudi I, Guedri Y, Mokni M, Abid S, Ayed-Boussema I
Neurotox Res · 2026 Apr · PMID 42012572 · Publisher ↗
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 ne...
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.
Protective Effects of Ozone against Quinolinic Acid-Induced Redox Imbalance in Murine BV-2 Microglial Cells.
Zatti PH, da Silva NP, Rigotti M … +4 more , Scariot FJ, Davidson CB, Machado AK, Branco CS
Neurotox Res · 2026 Apr · PMID 41989645 · Full text
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...
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.
MicroRNA-132 Alleviates Ischemia-Reperfusion-Induced Neuronal Apoptosis by Targeting Mecp2 in Stroke Models.
Wang X, Ma R, Liu Z … +5 more , Sun W, Xia L, Wang Y, Shao D, Sun C
Neurotox Res · 2026 Apr · PMID 41989510 · Full text
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....
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.
Associations between air pollution and markers of neuroinflammation, synaptic dysfunction and core Alzheimer's disease pathology vary by APOE genotype.
Kimura K, Driscoll I, Cook N … +12 more , Shahzad S, Betthauser TJ, Johnson SC, Asthana S, Gallagher CL, Hermann BP, Sager MA, Blennow K, Zetterberg H, Carlsson CM, Kollmorgen G, Okonkwo OC
Neurotox Res · 2026 Apr · PMID 41944915 · Full text
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...
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.
Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.
Nekabari MK, Ben-Azu B, Chijioke BS … +8 more , Esuku DT, Chidebe EO, Friday FB, Usin SG, Iwhiwhu P, Moses AS, Diakparomre O, Onyeukwu OB
Neurotox Res · 2026 Mar · PMID 41910845 · Publisher ↗
Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerate...
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.
Flavonoid Rutin Reduces Intestinal Inflammation in an Experimental Model of Parkinson's Disease.
De Jesus LB, Frota AF, De Araújo FM … +7 more , Passos FC, Gutierrez NAG, de Lima LBA, Silva VDA, Baccan GC, Gois MB, Costa SL
Neurotox Res · 2026 Mar · PMID 41903068 · Full text
The enteric nervous system (ENS), a complex network of neurons and glial cells, is essential for maintaining intestinal homeostasis and is implicated in neurodegenerative diseases such as Parkinson's disease (PD). The gu...
The enteric nervous system (ENS), a complex network of neurons and glial cells, is essential for maintaining intestinal homeostasis and is implicated in neurodegenerative diseases such as Parkinson's disease (PD). The gut-brain axis, modulated by gut microbiota (GM), is influenced by dietary compounds that can alter its composition. Despite advances in the understanding of PD pathophysiology, effective treatments remain limited, underscoring the need for novel therapeutic approaches. Among plant-derived compounds, the flavonoid rutin has shown significant antioxidant, anti-inflammatory, and neuroprotective properties in vivo. This study evaluated the effects of rutin on leukocyte infiltration, intestinal morphology, and GM composition in an experimental model of PD. Adult male Wistar rats received a stereotaxic injection of 6-hydroxydopamine (6-OHDA) and were treated orally with rutin (10 mg/kg) for 14 days. Intestinal segments were analyzed histomorphometrically, and fecal samples were assessed for the abundance of Firmicutes, Bacteroidetes, Prevotellacea, Entererobactereacea, Bifidobacterium sp and Lactobacillus sp. by PCR. Rutin administration significantly reduced intraepithelial lymphocyte infiltration and goblet cell numbers in the ileum and colon and prevented hyperplasia of Paneth cells in the ileum. Importantly, GM composition remained unchanged following rutin treatment. These findings demonstrated that rutin reduces intestinal inflammation in PD models without altering gut microbiota composition, highlighting its potential as a therapeutic strategy.
Decoding the RNA Shield: HNRNPC and YTHDF2 Act as Guardians of Neurons in Parkinson's Disease.
Shreya, Aran KR
Neurotox Res · 2026 Mar · PMID 41888434 · Publisher ↗
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in hallmark motor symptoms such as tremor, bradykinesia,...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in hallmark motor symptoms such as tremor, bradykinesia, rigidity, and postural instability. Beyond these classical features, emerging evidence highlights the critical role of RNA modifications, particularly N6-methyladenosine (m6A), in regulating neuronal health and disease. The m6A modification is dynamically controlled by writers (METTL3, METTL14, WTAP), erasers (FTO, ALKBH5), and readers (e.g., YTHDF2, HNRNPC), which together influence RNA splicing, stability, and translation. Dysregulation of the readers HNRNPC and YTHDF2 has been implicated in oxidative stress, neuroinflammation, and dopaminergic neurodegeneration, positioning the HNRNPC/YTHDF2 axis as a central regulator of RNA metabolism and as a potential therapeutic target. In the healthy brain, HNRNPC ensures proper splicing and stabilizes transcripts essential for neuronal function, while YTHDF2 promotes the degeneration of deleterious m6A-modified RNAs to maintain neuronal homeostasis. In PD, their downregulation disrupts these processes, leading to transcript accumulation, impaired splicing, heightened neuroinflammation, oxidative stress, and apoptosis, contributing to dopaminergic neuron susceptibility and degeneration. We further highlight their role in α-synuclein regulation, dopaminergic signaling, and neuroimmune interactions, underscoring their promise as biomarkers and therapeutic targets. Finally, we discuss emerging therapeutic strategies targeting the m6A landscape, including antisense oligonucleotides (ASOs), RNA interference (RNAi), CRISPR-Cas13-based epitranscriptomic editing, and small-molecule modulators of m6A regulators. This review integrates molecular insights with therapeutic perspectives to elucidate how HNRNPC and YTHDF2 contribute to PD pathophysiology and explore novel avenues for interventions.
Camphor-Induced Seizures in Rats Increase the Potency of Gamma Oscillations During the Ictal Period, A Component that may Lead to Refractoriness in Seizure Control.
Hartcopff PFP, da Paz CA, Quirino LE … +10 more , de Sousa Reis T, de Araujo DB, de Souza RDR, da Silva Motta CG, Araújo MFF, Dos Santos Brito MV, Dos Santos MF, Lima ABL, Lins A, Hamoy M
Neurotox Res · 2026 Mar · PMID 41874845 · Full text
Particularly in the evaluation of substances that can cause neuronal hyperexcitability, triggering refractoriness to antiepileptic drugs, this has always been of interest to science. This study investigated the neurobeha...
Particularly in the evaluation of substances that can cause neuronal hyperexcitability, triggering refractoriness to antiepileptic drugs, this has always been of interest to science. This study investigated the neurobehavioral and electrocorticographic (ECoG) characteristics of seizures induced by camphorated oil in Wistar rats and compared them to those triggered by pentylenetetrazol (PTZ), a classical chemoconvulsant model. Male rats received intraperitoneal administration of camphor (470 mg/kg), and behavioral evolution was monitored to characterize seizure onset and progression. ECoG recordings from the motor cortex were acquired for 30 min to assess cortical oscillatory activity during ictal and interictal periods. Camphor administration elicited six distinct and rapidly evolving behavioral patterns culminating in generalized clonic seizures with loss of postural reflexes. ECoG analyses revealed cyclic high-power ictal discharges interspersed with low-power interictal activity, resembling PTZ-induced seizures but with lower potency. Evaluation of anticonvulsant efficacy demonstrated that camphor-induced seizures were refractory to phenobarbital and phenytoin, whereas diazepam and propofol significantly reduced β- and γ-band power and effectively controlled convulsive activity. These findings suggest that camphor produces a reproducible chemoconvulsant model characterized by prominent cortical excitability and partial pharmacoresistance, supporting its potential utility in neurotoxicological and neuropharmacological studies aimed at understanding seizure mechanisms and testing antiepileptic drug responsiveness.
Decreased Length of Locus Coeruleus Norepinephrine Axons and Increased Amyloid Beta Pathology in Male APP/PS1 Mice During Protracted Abstinence From Alcohol.
Garland IJZ, Engel S, Scalf M … +3 more , Payne NR, Lee AM, Graves SM
Neurotox Res · 2026 Mar · PMID 41870711 · Full text
Alzheimer’s disease (AD) is the leading cause of dementia and evidence suggests that alcohol, the most commonly used addictive substance, may increase AD risk. Locus coeruleus (LC) neurons are the primary source of norep...
Alzheimer’s disease (AD) is the leading cause of dementia and evidence suggests that alcohol, the most commonly used addictive substance, may increase AD risk. Locus coeruleus (LC) neurons are the primary source of norepinephrine in the brain and these neurons degenerate early in AD. In rodent models, lesioning the LC increases amyloid beta (Aβ) pathology suggesting that LC integrity and norepinephrine signaling obstruct Aβ pathogenesis. We recently reported a decrease in the number of LC norepinephrine neurons and increased Aβ pathology when measured after protracted abstinence from chronic intermittent alcohol consumption in female APP/PS1 mice. Clinically, female subjects are at a higher risk for AD; additionally, female mice consume more alcohol than male mice making it unclear as to whether alcohol consumption would produce similar adverse outcomes in male subjects. To address this gap, male APP/PS1 and non-transgenic mice underwent chronic intermittent access (IA) to alcohol followed by protracted abstinence with water drinking controls run in parallel, consistent with our prior study. In contrast to our previous results with female mice, the number of LC norepinephrine neurons was unchanged in male APP/PS1 mice that had IA to alcohol; however, the length of LC axons was decreased and Aβ pathology was increased in male APP/PS1 mice that consumed alcohol. These data demonstrate that alcohol consumption during early adulthood results in negative consequences in male APP/PS1 mice, although the effect may not be as severe as previously observed in female mice.
Role of LncRNA NEAT1 in Alzheimer's Disease: Pathophysiological Insights and Therapeutic Approaches.
Shreya, Singh G, Hunjan G … +1 more , Aran KR
Neurotox Res · 2026 Mar · PMID 41863580 · Publisher ↗
AD is a progressive neurodegenerative disease characterized by oxidative stress (OS), mitochondrial dysfunction, and synaptic dysfunction. Long non-coding RNAs (lncRNAs) play a crucial role in gene expression at transcri...
AD is a progressive neurodegenerative disease characterized by oxidative stress (OS), mitochondrial dysfunction, and synaptic dysfunction. Long non-coding RNAs (lncRNAs) play a crucial role in gene expression at transcriptional and post-transcriptional levels. Among them, NEAT1 is a structural component of nuclear paraspeckles that maintains transcriptional stability and coordinates stress responses. NEAT1 serves as a molecular scaffold that interacts with RNA-binding proteins to regulate pre-mRNA splicing, transcriptional repression, and cellular homeostasis. NEAT1 expression is elevated in AD and is associated with neuroinflammation, synaptic plasticity alterations, and neuronal apoptosis. It epigenetically regulates targets including CAV2, TGFB2, TGFBR1, and FZD3, suggesting context-dependent protective and pathogenic roles in AD progression. This multifaceted nature highlights NEAT1 as a potential noninvasive biomarker and therapeutic target. This review summarizes the structure and function of NEAT1, its regulatory role in the pathophysiology of AD, and new therapeutic approaches to regulate its expression.
Tubuloside B Alleviates Aβ Induced PC12 Cell Injury by Attenuating Pyroptosis, Apoptosis and Excessive Autophagy.
Yang H, Fu R, Duan Y … +13 more , Hua Y, Wei T, Li G, Gu X, Li M, Yu X, Li L, Cao L, Wang ZZ, Zhang C, Lv Y, He M, Xiao W
Neurotox Res · 2026 Mar · PMID 41854817 · Publisher ↗
Cistanche, a traditional Chinese medicine with reported neuroprotective effects, contains multiple bioactive constituents whose specific mechanisms of action remain incompletely defined. Here, we aimed to identify a key...
Cistanche, a traditional Chinese medicine with reported neuroprotective effects, contains multiple bioactive constituents whose specific mechanisms of action remain incompletely defined. Here, we aimed to identify a key neuroprotective component and explore its potential mechanism against Aβ-induced neurotoxicity. Fourteen commercially available Cistanche-derived compounds were screened for neuroprotection in an Aβ25-35 (Aβ fragment 25–35)-injured PC12 cell model. The most active compound, Tubuloside B (TB), was further investigated using polymerase chain reaction (PCR) array, immunoblotting, flow cytometry, immunofluorescence, and mitochondrial function assays. TB exerted concentration-dependent protective effects in the Aβ25-35-injured PC12 model. Aβ25-35 exposure was associated with marked activation of pyroptotic signaling, characterized by caspase-1 activation, GSDMD cleavage, and increased interleukin (IL)-1β/IL-18 levels. These alterations were substantially blunted in the presence of TB. Modulation of the absent in melanoma 2 (AIM2) inflammasome pathway was further supported by reduced AIM2 expression and diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation. Mitochondrial perturbations induced by Aβ25-35, including excessive mitochondrial reactive oxygen species (ROS) generation, membrane depolarization, and cytosolic mtDNA accumulation, were concurrently ameliorated by TB. In addition, markers of apoptosis and dysregulated autophagy were partially normalized following TB treatment. These findings suggest that TB may contribute to neuroprotection in an Aβ25-35-induced PC12 cell model, potentially involving modulation of mitochondrial dysfunction–associated inflammasome activation and downstream cell death pathways. Given the in vitro design and limited sample size, these results should be considered preliminary and warrant further validation in vivo.
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