Neurotoxic Potential Research Articles

Long-Term Exposure to Tire-Derived 6-PPD Quinone Causes Neurotoxicity and Neuroinflammation via Inhibition of HTR2A in C57BL/6 Mice.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), a novel contaminant derived from tire wear, has raised concerns due to its potential neurotoxicity, yet its long-term effects on mammalian neurological health remain poorly understood. This study investigates the neurotoxic and neuroinflammatory impacts of prolonged 6-PPDQ exposure using male C57BL/6 mice. Behavioral assessments revealed significant cognitive deficits, while biochemical analyses demonstrated increased levels of reactive oxygen species, apoptosis, and blood-brain barrier (BBB) disruption. Elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activation of microglial cells were observed, indicating a robust neuroinflammatory response. Network pharmacology and molecular docking identified serotonin receptor HTR2A as a key target through which 6-PPDQ mediates its toxic effects. Activation of HTR2A by the agonist DOI (2,5-dimethoxy-4-iodoamphetamine) mitigated these effects, suggesting a potential therapeutic strategy. These findings provide the first evidence of 6-PPDQ-induced neurotoxicity in mammals, underscoring the need for preventive measures to protect neurological health.

Developmental and neurotoxic effects of dimethyl phthalate on zebrafish embryos and larvae.

Dimethyl phthalate (DMP) has been extensively utilized as a plasticizer on a global scale for many years. Its presence in the environment and its harmful effects on living organisms have raised concerns. This study aimed to examine its potential developmental neurotoxicity by utilizing zebrafish as a model. Zebrafish embryos were exposed to different concentrations of DMP (5-100 mg/L) from 4 to 120 h post-fertilization (hpf). The survival, hatching, and malformation rates were recorded for each group. Behavioral analysis was conducted on zebrafish larvae, and transgenic zebrafish Tg(elavl3:EGFP) were used to assess the impact of DMP on neuronal cells. The mRNA levels of key neurological marker genes were evaluated at 96 hpf of DMP exposure. The study revealed that exposure to DMP resulted in decreased survival and hatching rates in zebrafish. Embryos treated with 50 mg/L of DMP exhibited lower average survival rates (72.78-78.33%) between 24-96 hpf, while treatment with 25-50 mg/L of DMP resulted in reduced hatching rates (39.44% and 2.22%, respectively) at 48 hpf compared to the control group. Moreover, exposure to 25-50 mg/L of DMP caused an increase in malformations, such as tail curvature, spinal curvature, yolk sac edema and pericardial edema. Interestingly, at 24 hpf, DMP also resulted in an increase in spontaneous tail coiling in zebrafish embryos, as well as a decrease in their swimming distance at 120 hpf. Furthermore, treatment with 50 mg/L of DMP led to a decrease in the fluorescence intensity of transgenic zebrafish Tg(elavl3: EGFP). RT-qPCR analysis showed a significant down-regulation of marker genes (gap43, mbp, α1-tubulin, syn2a) associated with nervous system function in DMP-treated zebrafish. Overall, these findings offer a thorough understanding of the mechanisms underlying the neurotoxicity caused by DMP, highlighting the risk of DMP on developmental and neurotoxic effects in zebrafish. Therefore, strict supervision of DMP use and release is essential to safeguard ecological and aquatic organisms.

Perfluorohexane sulfonate exposure caused multiple developmental abnormalities in early life of zebrafish

Perfluorohexane sulfonate (PFHxS) has been listed as a new persistent organic pollutant since 2022. Although the production and use of PFHxS are now restricted, it remains highly persistent in aquatic environments for decades. However, so far research about the toxic effects on early-life exposure of PFHxS and underlying mechanisms are still limited. In this study, we employed both wild type and specifically labeled transgenic zebrafish as model to investigate the developmental toxicity of PFHxS during early-stage exposure in zebrafish. A series of phenotypic and molecular indicators were analyzed at various time points between 24 hours post-fertilization (hpf) and 7 days post-fertilization (dpf). Our data showed that the acute toxicity of PFHxS was much lower than PFOS, with a lethal concentration 50% of 508.11 ± 88.54 μM at 120 hpf. Low-dose PFHxS exposure significantly altered heart rates, blood flow, and swimming behavior in zebrafish larvae, suggesting potential cardiotoxicity and neurotoxicity of zebrafish. Data from transgenic zebrafish with specifically labeled hearts (CZ40) confirmed that PFHxS affects cardiovascular system development. PFHxS-induced changes in transgenic zebrafish with labeled liver and pancreas (CZ16) suggest that PFHxS may cause metabolic disorders and contribute to developmental defects. Gene expression analysis showed that PFHxS with potential estrogenic effect might also affect the gonadal development of zebrafish. Our study can offer an insight into the toxicity of PFHxS in aquatic environment and health risks of early-stage PFHxS exposure in humans.

Species- and tissue-specific profiles and potential risks of polychlorinated biphenyls (PCBs) and their metabolites in dogs and cats.

In recent years, there has been growing concern about the long-term health effects of chemical exposure in pets, particularly dogs and cats, from sources such as pet food and house dust. Domestic cats (Felis silvestris catus) and dogs (Canis lupus familiaris) are continuously exposed to polychlorinated biphenyls (PCBs), with particular attention being paid to the toxicity of their metabolites, hydroxylated PCBs (OH-PCBs) and methylsulfonyl PCBs (MeSO2-PCBs). However, the tissue distribution and species-specific differences of these PCB metabolites in domestic animals have not been fully elucidated. This study investigates the tissue-specific profiles of PCBs, OH-PCBs, and MeSO2-PCBs by analyzing blood, brain, liver, and bile samples from dogs and cats. The analysis revealed that hexa- to octa-chlorinated OH-PCBs were the predominant congeners in the brain, liver and bile of dogs. In contrast, tri- to penta-chlorinated OH-PCBs were more prevalent in cats, with lower-chlorinated OH-PCBs tending to accumulate due to limited UDP-glucuronosyltransferase activity. In cats, OH-PCBs are more readily excreted in the bile than in dogs, probably because there are fewer higher-chlorinated thyroxine-like OH-PCBs, which are known to bind to and persist in proteins in the liver and blood. MeSO2-PCBs were detected at lower concentrations than parent PCBs and OH-PCBs and primarily accumulated in the liver due to their lipophilic nature. The consistent concentrations of MeSO2-PCBs across species, despite variations in parent PCB and OH-PCB levels, underscore species-specific differences in metabolic capacity and excretion pathways. In addition, some OH-PCB concentrations in both dog and cat brains exceeded levels known to affect neurons, suggesting the potential for neurotoxicity in these species. Therefore, continued biomonitoring and further investigation of the toxic effects of these compounds in pets is imperative.

A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity: Triggering Neural Stem Cell Senescence by Activating the Integrated Stress Response Pathway.

Atrazine (AT), a widely utilized chemical herbicide, causes widespread contamination of agricultural water bodies. Recently, exposure to AT has been linked to the development of age-related neurodegenerative diseases (NDs), suggesting its neurotoxicity potential. As an endocrine disruptor, AT targets the hypothalamus, a crucial part of the neuroendocrine system. However, the toxicological mechanism of AT exposure to the hypothalamus and its correlation with ND development remain unexplored. Our results indicated that AT exposure caused significant morphological and structural damage to the hypothalamus, leading to the loss of mature and intact neurons and microglial activation. Furthermore, hypothalamic neural stem cells (HtNSCs) were recruited to areas of neuronal damage caused by AT. Through invivo and invitro experiments, we clarified the outcomes of AT-induced HtNSC recruitment alongside the loss of mature/intact neurons. Mechanistically, AT induces senescence in these recruited HtNSCs by activating integrated stress response signaling. This consequently hinders the repair of damaged neurons by inhibiting HtNSC proliferation and differentiation. Overall, our findings underscore the pivotal role of the integrated stress response pathway in AT-induced HtNSC senescence and hypothalamic damage. Additionally, the present study offers novel perspectives to understand the mechanisms of AT-induced neurotoxicity and provides preliminary evidence linking AT contamination to the development of NDs.

Protective effect of astragaloside IV against zinc oxide nanoparticles induced human neuroblastoma SH-SY5Y cell death: a focus on mitochondrial quality control.

Occupational and unintentional exposure of zinc oxide nanoparticles (ZnONPs) raises concerns regarding their neurotoxic potential and there is an urgent need for the development of effective agents to protect against the toxic effects of ZnONPs. Astragalus memeranaceus (AM), a famous Traditional Chinese Medicine, as well as its bioactive components, showing a potential neuroprotective function. This study aims to investigate the neuroprotective effects of bioactive components of AM against ZnONPs-induced toxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. The cell apoptosis, ROS generation, MMP changes, mitochondrial fission/fusion, biogenesis, and mitophagy were assessed. In this study, AM treatment inhibited ZnONPs-induced cell apoptosis and ROS overproduction in SH-SY5Y cells. And astragaloside IV (ASIV) played a dominant role in the attenuation of cytotoxicity after ZnONPs exposure, rather than flavonoids and polysaccharides. ASIV treatment significantly reduced ROS generation and MMP collapse in ZnONPs-exposed cells. Furthermore, the protein expressions of mitochondrial biogenesis (PGC-1α), fusion (Mfn1 and Mfn2), and fission (Drp1) were markedly increased. Meanwhile, the PINK1/Parkin-mediated mitophagy was activated after ASIV administration, which ameliorated ZnONPs-induced SH-SY5Y cell death. Collectively, ASIV administration mitigated ZnONPs-induced cytotoxicity in SH-SY5Y cells through restoring mitochondrial quality control process, which hinted the protective role of ASIV in ZnONPs-induced neurotoxicity.

Human stromal cell-based protocol to generate astrocytes: a straightforward in vitro predictive strategy in neurotoxicology

The inherent adaptability of human mesenchymal stromal cells (hMSCs) to differentiate into neural lineages provides a valuable resource for investigating potential neurotoxicity in humans. By harnessing the ability of hMSCs to transform into astrocytes, we can evaluate the effects of various agents on these vital cells. Our protocol employs hMSCs sourced from umbilical cord tissue, ensuring a readily available supply of high-quality cells. The hMSC-to-neural workflow encompasses six essential steps: hMSC culture, followed by the generation of embryoid bodies (EBs) from these cells on specialized surfaces. Next, EBs and cells are expanded in a growth-promoting medium, directing them toward neural lineages. Subsequent differentiation into immature astrocytes is achieved through the use of specific factors. The process continues with the maturation of EBs/cells into astrocyte-like cells (hALCs) under optimized conditions, culminating in the final development of hALCs in a specialized medium. This methodology yields cells that display astrocyte morphology and express characteristic markers such as GFAP and S100β. The protocol is efficient, requiring roughly 6 weeks to generate hALCs from primary hMSCs without genetic manipulation. The application of hMSCs in evaluating cell damage triggered by neurotoxicants like MeHg and MGO underscores their potential as a valuable component within a more extensive battery of neurotoxicity tests.

Child Outcomes after Prenatal Exposure to Platinum and Taxane-based Chemotherapy: An Unplanned Interim Analysis of the International Network on Cancer, Infertility, and Pregnancy Study

Platina and taxanes are frequently used chemotherapeutic agents to treat cancer, also when diagnosed during pregnancy. This report presents an interim analysis of the largest series of children prenatally exposed to platinum and/or taxane agents and aims to determine their physical health and neurocognitive outcomes. As part of a multicentre, prospective cohort study (ClinicalTrials.gov: NCT00330447), children born between 2000 and 2022 were assessed between 2005 and 2024at ages 1.5-18 years (interim analysis; median length of follow-up, 3.2 years (IQR 3.0-6.4)) by a comprehensive neurocognitive test battery, parent-reported questionnaires, and a physical assessment. Mixed-effects regression and Type III Analysis of Variance models were used to investigate associations between these outcomes and platinum/taxane cumulative dose and agent type, with best-fit models corrected for age and covariates (gestational age at birth, chemotherapy timing, other chemotherapy, sex, parental education level, maternal death). In total, 144 children were included (13% exposed to platinum, 62% to taxanes, 25% to both). Of these, 101 were assessed at age 1.5 years, 96at age 3, 63at age 6, 32at age 9, 18at age 12, 7at age 15, and 2at age 18 years. Neurocognitive outcomes were within normal ranges across all ages, compared with test-specific normative data. Eight children (6%) reported ototoxicity, seven (5%) reported chronic medical conditions, three (2%) had congenital malformations, and two (1%) were diagnosed with Attention-Deficit Hyperactivity Disorder. Thirty-three children (23%) needed extra neurocognitive support, of which 64% were born preterm. Children prenatally exposed to paclitaxel scored lower on visuospatial (β=0.64± 0.21, p=0.0052) and verbal memory (β=0.68± 0.27, p=0.015) than those exposed to docetaxel. In this interim analysis, we found normal neurocognitive outcomes and no increase in congenital malformations nor medical conditions after prenatal exposure to platinum/taxane-based chemotherapy. However, owed to the limited number of older children, further investigation regarding their potential neurotoxicity and its long term effects is necessary in follow-up studies with larger samples. Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Cooperatio program, Research Foundation Flanders.

NeuTox 2.0: A hybrid deep learning architecture for screening potential neurotoxicity of chemicals based on multimodal feature fusion

NeuTox 2.0: A hybrid deep learning architecture for screening potential neurotoxicity of chemicals based on multimodal feature fusion

Nitrogen-rich porous polymer as a solid-phase microextraction coating for the ultrasensitive analysis of nicotine and its metabolites in different rat brain regions

Nicotine, a major component of tobacco smoke, exerts complex effects on the brain, including dependence and potential neurotoxicity. Understanding its distribution and metabolism in different brain regions is crucial for elucidating its neurological impact. This study presents a new solid-phase microextraction (SPME) method using a nitrogen-rich porous polymer coating (BDTB-MBD) that simultaneously quantified nicotine and its six metabolites in different rat brain regions. The coating material exhibited excellent stability with a high surface area (1001.7 m2/g), suitable pore diameter (5.28 nm), and excellent hydrophilic and hydrophobic properties. Under optimal conditions, the SPME tandem ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS) method exhibited a wide linear range (0.01–100 μg L−1), low limits of detection ranging from 0.002–0.020 μg L−1, limits of quantifications ranging from 0.006–0.070 μg L−1, and satisfactory repeatability and reproducibility. The spiked recovery rates ranged from 77.1 % to 99.6 %, indicating that the established method was sensitive, accurate, and reliable. Density functional theory calculations revealed strong non-covalent interactions between BDTB-MBD and analytes, providing insights into the adsorption mechanism. The SPME-UPLC-MS/MS method successfully tracked the pharmacokinetics of nicotine in different rat brain tissues following intraperitoneal injection. The results demonstrated rapid absorption with a regional distribution of nicotine, followed by its gradual metabolism into cotinine, nornicotine, and other metabolites. Notably, the concentration profiles varied across brain regions, highlighting the importance of considering regional specificity in nicotine brain research. Compared with traditional techniques such as solid phase extraction, this approach offers a valuable tool for studying nicotine distribution and metabolism in the brain, with potential applications in neuroscience and drug monitoring.

Neurotoxicity of Realgar: Crosstalk Between UBXD8-DRP1-Regulated Mitochondrial Fission and PINK1-Parkin-Mediated Mitophagy.

Realgar is a toxic mineral medicine containing arsenic that is present in many traditional Chinese medicines. It has been reported that the abuse of drugs containing realgar has potential neurotoxicity, but its mechanism of toxicity has not been fully clarified. In this study, we demonstrated that arsenic in realgar promoted mitochondrial fission via UBXD8-mediated DRP1 translocation to the mitochondria and activated mitophagy via PINK1-Parkin, resulting in mitochondrial dysfunction and nerve cell death in the rat cortex. We used PC12 cells and treated them with inorganic arsenic (iAs). Mdivi-1, a mitochondrial fission inhibitor, and the siRNA UBXD8 or PINK1 were used as interventions to verify the precise mechanism by which arsenic affects realgar-induced mitochondrial instability. The results revealed that the arsenic in realgar accumulated in the brain and led to neurobehavioral abnormalities in the rats. We demonstrated that arsenic in realgar-induced high expression of UBXD8 promoted the translocation of DRP1 to the mitochondria, where it underwent phosphorylation, which led to the over-fission of the mitochondria and mitochondria-mediated apoptosis. Moreover, the over-fission of the mitochondria activates mitophagy, which is self-protective but only partially alleviates apoptosis and mitochondria dysfunction. Our findings revealed the crosstalk between mitochondrial fission and mitophagy in realgar-induced neurotoxicity. These results highlight the role of the transposition of DRP1 by UBXD8 in realgar-induced mitochondrial dysfunction and provide new ideas and data for the study of the mechanism of realgar-induced neurotoxicity.

Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing

The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current in vivo testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days. Using high-throughput RNA sequencing, we compared gene expression profiles of 2D and 3D models at three developmental stages (3, 14, and 21 days of differentiation). Both models exhibit maturation towards post-mitotic neurons, with the 3D model maturing faster and showing a higher prevalence of GABAergic neurons, while the 2D model is enriched with glutamatergic neurons. Both models demonstrate broad applicability domains, including excitatory and inhibitory neurons, astrocytes, and key endocrine and especially the understudied cholinergic receptors. Comparison with human fetal brain samples confirms their physiological relevance. This study provides novel in-depth applicability insights into the temporal and dimensional aspects of hiPSC-derived neural models for DNT testing. The complementary use of these two models is highlighted: the 2D model excels in synaptogenesis assessment, while the 3D model is particularly suited for neural network formation as observed as well in previous functional studies with these models. This research marks a significant advancement in developing human-relevant, high-throughput DNT assays for regulatory purposes.

Euphorbiasteroid induces neurotoxicity through the FOXO/NF-κB/apoptosis signaling pathway

BackgroundEuphorbiasteroid, a bioactive compound from Euphorbia lathyris L., exhibits significant pharmacological effects, including anti-tumor activity and multi-drug resistance reversal. However, its potential neurotoxicity limits its clinical use. This study investigates the neurotoxic effects of euphorbiasteroid and elucidates the underlying mechanisms. MethodsNeurotoxicity was evaluated in differentiated PC12 cells and primary astrocytes through cell viability and lactate dehydrogenase (LDH) assays. Transcriptomic analysis was employed to predict the involvement of the Forkhead box O (FOXO), nuclear factor-kappa B (NF-κB), and apoptosis pathways in euphorbiasteroid-induced cytotoxicity. Apoptosis was detected using TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and western blot analysis of quantified apoptotic markers and key signaling proteins. Molecular docking studies explored the interaction between euphorbiasteroid and FOXO3A, while gene knockdown experiments assessed the role of FOXO3A. ResultsEuphorbiasteroid significantly induced cytotoxicity in differentiated PC12 cells and primary astrocytes, linked to the activation of the FOXO, NF-κB, and apoptosis pathways. Apoptosis was confirmed by TUNEL staining, Bax/Bcl-2 ratio, and cleaved caspase 3 levels. Additionally, euphorbiasteroid reduced phospho-FOXO3A levels, promoted FOXO3A nuclear translocation and enhanced NF-κBp65 phosphorylation. Molecular docking revealed direct binding of euphorbiasteroid to FOXO3A, and FOXO3A knockdown substantially mitigated its neurotoxicity. ConclusionEuphorbiasteroid induces neurotoxicity through the activation of the FOXO/NF-κB/apoptosis signaling pathway. These findings provide new insights into the mechanisms of euphorbiasteroid-induced neurotoxicity and suggest potential strategies to mitigate these effects, which is crucial for its therapeutic application.

Anxiety caused by chronic exposure to methylisothiazolinone in zebrafish: Behavioral analysis, brain histology and gene responses

Methylisothiazolinones (MIT) are a class of preservatives and biocides extensively utilized in everyday products, industrial processes, and medical and healthcare applications. However, reports have indicated that MIT may cause skin irritation and neurotoxicity. Given its pervasive use, the neurotoxic potential of MIT has garnered increasing attention. Recent in vitro cellular experiments have demonstrated that MIT inhibits synaptic growth, although the neurotoxic effects and underlying mechanisms at the organismal level remain largely unexplored. In this study, it was found for the first time that long-term exposure to MIT resulted in anxiety, brain tissue inflammation, and a reduction in the number of Nissl bodies in the brain. Additionally, transcriptomic analysis indicated that exposure to 300 μg/L MIT induced a greater number of differentially expressed genes compared to 30 μg/L MIT, relative to the control group. Enrichment analysis, trend analysis, and GSEA analysis collectively identified the involvement of Steroid hormone metabolism, oxidative metabolism, and the Hedgehog pathway in MIT-induced neurotoxicity. Furthermore, a subsequent reduction in green fluorescence was observed in the MLS-EGFP zebrafish strain larvae of the HD group, suggesting that high dosage of MIT exerts an inhibitory effect on mitochondrial activity. This study confirmed the neurotoxic effects of MIT and investigated the potential genetic networks behind anxiety behavior. These findings contributed to the identification of key brain genes involved in the detection and monitoring of MIT, offering new insights into the neuroendocrine toxicity of other imidazolidinone compounds.

The role of microglia in neurocognitive deficits induced by general anaesthetic agents during neurodevelopment

AbstractBackground and AimsMicroglia are the innate immune cells of central nervous system which play critical roles in brain homeostasis. Recently, the effects of general anesthetic agents (GAAs) on microglia and their potential neurotoxicity in neurodevelopment have attracted the attention of anesthesiologists and neuroscientists.MethodsHere, we review the physiology of microglia in neurodevelopment, the potential mechanisms of GAAs on microglia and the consequent changes in microglial function.OutcomesMicroglia‐mediated neuroinflammation is a key mechanism of neurocognitive deficits during neurodevelopment. In addition, microglia could be primed by active inflammatory processes and have innate immune memory, both of which make them a potential candidate responsible of long‐term neural deficits.ConclusionThis review aims in summarizing the in vivo and in vitro studies associating microglia with general anesthesia and describing how GAAs induce neurocognitive deficits via microglia to further explore the effects of GAAs on neurodevelopment.

Bisphenol F-induced precocious genesis of aggressive neurobehavioral response is associated with heightened monoamine oxidase activity and neurodegeneration in zebrafish brain

The production and use of plastics and plastics products has increased dramatically in recent decades. Moreover, their unprotected disposal into ambient life sustaining environment poses a significant health risk. Bisphenol F (BPF) an alternative to bisphenol A (BPA) has been extensively employed for making of plastics. Recent reports have documented the neurotoxic potential of BPF through induction of altered neurochemical profile, microglia-astrocyte-mediated neuroinflammation, oxidative stress, transformed neurobehavioral response, cognitive dysfunction, etc. In the present study, our approach was to understand the underlying mechanism of BPF-persuaded genesis of aggressive neurobehavioral response in zebrafish. The basic findings advocated a temporal transformation in native explorative behaviour and progressive induction of aggressive behavioural response in zebrafish following exposure to BPF. Our neurobehavioral findings supported the argument of oxidative stress-mediated neuromorphological transformation in the periventricular grey zone (PGZ) of the zebrafish brain. In line with earlier reports, our findings also showed that heightened monoamine oxidase (MAO) activity and downregulation in tyrosine hydroxylase expression in the zebrafish brain is associated with the precocious genesis of aggressive neurobehavioral response in zebrafish brain. Our findings also shed light on BPF-instigated apoptotic neuronal death as revealed by augmented chromatin condensation and cleaved caspase-3 expression. Further observation showed that the downregulation of NeuN (a marker of post-mitotic mature neuron) expression provided substantial neurotoxicity, leading to neurodegeneration in the PGZ region of the zebrafish brain. These basic findings grossly advocate that BPF acts as a potent neurotoxicant in transmuting native neurobehavioral response through the induction of oxidative stress, heightened MAO activity and neuromorphological transformation in the zebrafish brain.

Alhagi maurorum Ethanolic Extract can halt potential topiramate neurotoxicity on sciatic nerve of adult male albino rats

Alhagi maurorum Ethanolic Extract can halt potential topiramate neurotoxicity on sciatic nerve of adult male albino rats

Major depressive disorder, neuroticism, suicidal behaviors, and depression severity are associated with cytokine networks and their intricate interactions with metabolic syndrome

ObjectivesTo identify alterations in the immune profiles in outpatients with major depression (MDD), and its associations with key features, such as suicidal ideation, neuroticism, cognitive symptoms, and the depression phenome while accounting for metabolic syndrome (MetS). MethodsIn this case-control study, we assayed 48 serum cytokines, chemokines, and growth factors in 67 healthy controls and 66 MDD outpatients. Around 50 % of the outpatient MDD and control participants had a diagnosis of MetS. ResultsTen differentially expressed proteins (DEPs) were upregulated in outpatient MDD (i.e., CXCL12, tumor necrosis factor [TNF]β, platelet-derived growth factor [PDGF], CCL11, interleukins [IL]9, IL4, CCL5, CCL2, CCL4, IL1 receptor antagonist [IL1RN]), indicating an immune and defense response. Six DEPs were downregulated (vascular endothelial growth factor A [VEGFA], IL12, CCL3, colony stimulating factor [CSF]1, IL1B, nerve growth factor [NGF]), indicating lowered neurogenesis and neuron death regulation. Significant interactions between outpatient MDD and MetS caused a) substantial increases in IL4, IL17, TNF, TNFB, CCL2, CCL5, PDGF, IL1RN; and b) downregulation of VEGFA and FGF. A large part of the variance in neuroticism (26 %), suicidal behaviors (23 %), and the MDD phenome (31 %) was predicted by immunological data and interactions between MetS and CCL5, TNFB or VEGFA. ConclusionOutpatient MDD is characterized by a cytokine profile with neurotoxic potential which partly explains neuroticism, suicidal behaviors, and the phenome's severity. Lowered IL-10 and activated cytokine profiles with neurotoxic potential are characteristics of outpatient MDD and other depression phenotypes, including severe first-episode inpatient MDD. The presence of MetS in outpatient MDD considerably activates immune profiles with neurotoxic potential. Consequently, immune studies in MDD should always be performed in subjects with and without MetS.

Exposure to PFOA, PFOS, and PFHxS induces Alzheimer's disease-like neuropathology in cerebral organoids

Per- and polyfluoroalkyl substances (PFASs), a class of ubiquitous synthetic organic chemicals, are widely utilized across various industrial applications. However, the long-term neurological health effects of PFAS mixture exposure in humans remain poorly understood. To address this gap, we have designed a comprehensive study to predict and validate cell-type-specific neurotoxicity of PFASs using single-cell RNA sequencing (scRNA-seq) and cerebral organoids. Cerebral organoids were exposed to a PFAS mixture at concentrations of 1 × (10 ng/ml PFOS and PFOA, and 1 ng/ml PFHxS), 30 × , and 900 × over 35 days, with a follow-up analysis at day 70. Pathological alterations and lipidomic profiles were analyzed to identify disrupted molecular pathways and mechanisms. The scRNA-seq data revealed a significant impact of PFASs on neurons, suggesting a potential role in Alzheimer's Disease (AD) pathology, as well as intellectual and cognitive impairments. PFAS-treated cerebral organoids exhibited Aβ accumulation and tau phosphorylation. Lipidomic analyses further revealed lipid disturbances in response to PFAS mixture exposure, linking PFAS-induced AD-like neuropathology to sphingolipid metabolism disruption. Collectively, our findings provide novel insights into the PFAS-induced neurotoxicity, highlighting the significance of sphingolipid metabolism in the development of AD-like neuropathology. The use of cerebral organoids and scRNA-seq offers a powerful methodology for evaluating the health risks associated with environmental contaminants, particularly those with neurotoxic potential.

Plants’ Impact on the Human Brain—Exploring the Neuroprotective and Neurotoxic Potential of Plants

Background: Plants have long been recognized for their potential to influence neurological health, with both neuroprotective and neurotoxic properties. This review explores the dual nature of plant-derived compounds and their impact on the human brain. Discussion: Numerous studies have highlighted the neuroprotective effects of various phytoconstituents, such as those found in Ginkgo biloba, Centella asiatica, Panax ginseng, Withania somnifera, and Curcuma longa. The neuroprotective compounds have demonstrated antioxidant, anti-inflammatory, and cognitive-enhancing properties, making them promising candidates for combating neurodegenerative diseases and improving brain function. Polyphenolic compounds, triterpenic acids, and specific phytocompounds like the ones from EGb 761 extract have shown interactions with key enzymes and receptors in the brain, leading to neuroprotective outcomes. However, this review also acknowledges the neurotoxic potential of certain plants, such as the Veratrum species, which contains steroidal alkaloids that can cause DNA damage and disrupt neurological function, or Atropa belladonna, which interfere with the normal functioning of the cholinergic system in the body, leading to a range of symptoms associated with anticholinergic toxicity. Conslusions: This review also emphasizes the need for further research to elucidate the complex mechanisms underlying the neuroprotective and neurotoxic effects of plant-derived compounds, as well as to identify novel phytoconstituents with therapeutic potential. Understanding the complex relationship between plants and the human brain is crucial for harnessing the benefits of neuroprotective compounds while mitigating the risks associated with neurotoxic substances. This review provides a comprehensive overview of the knowledge on the neurological properties of plants and highlights the importance of continued research in this field for the development of novel therapeutic strategies targeting brain health and neurological disorders.