Neurotoxic Effects Research Articles

Subchronic Treatment with CBZ Transiently Attenuates Its Anticonvulsant Activity in the Maximal Electroshock-Induced Seizure Test in Mice

The objective of this study is to evaluate the anticonvulsant efficacy of carbamazepine (CBZ) following acute and chronic administration across four treatment protocols in a murine model of maximal electroshock-induced seizures. A single dose of the drug was utilized as a control. The neurotoxic effects were evaluated in the chimney test and the passive avoidance task. Furthermore, plasma and brain concentrations of CBZ were quantified across all treatment protocols. The subchronic administration of CBZ (7 × 2 protocol) resulted in an attenuation of its antielectroshock effect. In the three remaining treatment regimens (7 × 1, 14 × 1, and 14 × 2) the median effective doses of CBZ were comparable to the control. Neither acute nor chronic treatment with CBZ resulted in a discernible impact on motor coordination or long-term memory. The plasma and brain concentrations of CBZ were significantly lower in most chronic protocols when compared to a single-dose application. This may explain the transient attenuation of CBZ effectiveness in the 7 × 2 protocol, but not the return to the previous level. The anticonvulsant and neurotoxic profiles of CBZ did not differ after single and chronic administration. Therefore, experimental chronic studies with CBZ are not prerequisites for concluding and possibly translating results to clinical conditions.

6-Hydroxyflavanone treats anxiety and chemotherapy-induced neuropathy in Sprague–Dawley rats

BackgroundCancer remains a predominant cause of death worldwide. The advent of effective chemotherapy has enormously decreased the mortality rate and increased the life expectancy of cancer patients. However, the adverse effects allied with chemotherapy contribute to the development of neurotoxicity, anxiety, and depression.ObjectiveThe dual effects of a novel flavanone, 6-hydroxyflavanone (6-HF), were investigated in treating chemotherapy-induced neuropathy along with anxiolytic propensity.MethodsThe anti-neuropathy propensity of 6-HF was evaluated utilizing the cisplatin-induced neuropathy (CIN) model, whereas its anxiolytic activity was evaluated utilizing anxiety models, such as the elevated plus maze test (EPM), the staircase test, and the open-field paradigm.ResultCisplatin administration induced static and dynamic allodynia in the rats. Concomitant administration of 6-HF and cisplatin for four successive weeks remarkably reduced the chemotherapy-induced mechanical allodynia, evident from an elevation in the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The anxiolytic-like activity of 6-HF in the EPM apparatus was confirmed by the increased number of entries in the open arm and time spent at the central platform, which was further confirmed by the enhanced head-dipping frequency in the same assay. A decrease in rearing behavior of the mice without suppression of the steps ascended further assured the anxiolytic-like potential of 6-HF. Additionally, the animals under investigation spent more time at the intersection of the open-field apparatus, further confirming the anxiolytic potential of 6-HF.Conclusion6-HF might be considered a potential therapeutic agent for counteracting two common adverse effects of chemotherapy, neurotoxicity and anxiety.

Chemotherapy-Induced Neuropathy Affecting the Gastrointestinal Tract.

Cancer is a major global cause of morbidity and mortality. Survivorship is increasing, bringing new challenges. Cancer treatment, including chemotherapeutic drugs, immunotherapy, and radiotherapy, can have severe and impactful gastrointestinal side effects occurring shortly after treatment (acute toxicity) or persisting for years after treatment ends (late/chronic toxicity). The aim of this article is to review the neurotoxic effects of chemotherapy on the enteric nervous system (ENS) and the gut extrinsic innervation. These effects could contribute to the development of long-term gastrointestinal dysfunctions. Research, primarily conducted in animal models, indicates that antitumoral drugs can lead to chemotherapy-induced enteric neuropathy (CIEN). Studies, mainly performed in the myenteric plexus, show that CIEN is characterized by a reduced density of nerve cells and fibers, as well as an imbalanced representation of neuronal subpopulations or their markers, with enteric glial cells also affected. These alterations underlie changes in neuronal activity and gastrointestinal motor function. Although research on the submucosal plexus remains limited, evidence suggests that CIEN affects the entire ENS. Furthermore, scarce studies show that CIEN also occurs in humans. Moreover, emerging experimental data on chemotherapy-induced alterations in visceral sensitivity suggest that the extrinsic innervation of the gut is also affected, but this has received little attention thus far. Nevertheless, this could contribute to the development of chemotherapy-induced brain-gut axis (BGA) disorders in the long term. Cancer chemotherapy (and probably also immunotherapy and radiotherapy) seems to cause neuropathic effects on the intrinsic and extrinsic innervation of the gastrointestinal tract, with an important impact on gastrointestinal and BGA functions. This is a relatively neglected area deserving further investigation.

Protective effects of naringenin against methamphetamine-induced cell death in dopaminergic SH-SY5Y cells

ABSTRACT Background: Methamphetamine is a psychoactive substance that competes with the dopamine transporter, disrupting its flow and storage. This can trigger oxidative stress, finally resulting in neural cell death. Due to the increasing prevalence of methamphetamine use, extensive research has been devoted to finding treatments that ameliorate its detrimental effects. Naringenin, a dietary flavonoid found in citrus fruits, has shown several neuroprotective and pharmacological properties. Objectives: This study was aimed to assess the protective effects of naringenin against methamphetamine-induced dopaminergic cell death. Methods: Before exposure to methamphetamine, human neuroblastomaSH-SY5Y cells were either pretreated or not treated (controls) with naringenin. Cell viability, level of oxidative stress markers, and expression of some genes involved in apoptosis and autophagy processes were then assessed using MTT, ROS, and MMP assays, and qRT-PCR and Western blotting techniques. Results: Naringenin pretreatment significantly enhanced cell viability following methamphetamine exposure (p < .01). It significantly decreased ROS levels (p < .001), preserved mitochondrial membrane potential, and moderated upregulation of apoptotic (CytC, Casp3, and Bax) and autophagic genes (Beclin-1, and LC-3) and down-regulation of Bcl-2 as an anti-apoptotic gene. Similar naringenin-mediated patterns were observed for cytochrome C and caspase 3 proteins. Conclusion: Naringenin administration can be considered for treating the neurotoxic effects of methamphetamine.

Novel plasma cytokines identified and validated in children during lead exposure according to the new updated BLRV

Lead is a pervasive environmental contaminant with significant health risks, particularly to children. It is known for its neurotoxic and immunotoxic effects, causing developmental, cognitive, and behavioral impairments. Despite extensive research, the mechanisms of lead toxicity remain unclear. Cytokines, which are critical in immune response and inflammation, have emerged as potential biomarkers for lead toxicity. The recent Centers for Disease Control and Prevention (CDC) update to the blood lead reference value (BLRV) to 3.5 µg/dL emphasizes the need to explore novel biomarkers and mechanisms. The study involved 100 healthy children aged 1 to 5 years, divided into two groups based on BLRV: elevated (≥ 3.5 µg/dL) and low (< 3.5 µg/dL). The research consisted of two phases: discovery and validation. Plasma samples were analyzed using RayBio® Human Cytokine Antibody Arrays and Enzyme-linked immunosorbent assay (ELISA) for cytokine levels. Ethical approval was obtained, and statistical analyses included t-tests, chi-squared tests, pearson correlations, and multivariate logistic regression. Protein-protein interaction (PPI), Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to explore the roles of significant differentially expressed proteins (DEPs). No significant differences in age, gender, or BMI between the two groups, but BLRV levels were significantly higher in the elevated BLRV group compared to the low BLRV group. In the discovery phase, significant changes in cytokine expression were identified, including increased levels of IL-6, IL-8, and IL-17, and decreased levels of BDNF, BMP-4, IGF-1, IL-7, IL-10, and Leptin. These findings were validated in the second phase using ELISA. Significant positive correlations were found between BLRV and IL-6, IL-8, and IL-17. Negative correlations were observed with BDNF, BMP-4, IGF-1, IL-7, IL-10, and Leptin. Multivariate regression confirmed that BLRV significantly affects these cytokine levels. PPI networks revealed that DEPs had strong interactions with multiple proteins, indicating their central role in lead toxicity. GO and KEGG analyses highlighted pathways related to neurotoxicity and inflammatory responses, including “negative regulation of myotube differentiation,” “neurotrophin signaling pathway,” and “alcoholism.” This study provides insights into the role of cytokines as biomarkers for lead toxicity and offers a comprehensive analysis of the mechanisms involved. The findings underscore the importance of early detection and intervention based on updated BLRV thresholds.

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Identifying Organic Chemicals with Acetylcholinesterase Inhibition in Nationwide Estuarine Waters by Machine Learning-Assisted Mass Spectrometric Screening.

Neurotoxicity is frequently observed in the global aquatic environment, threatening aquatic ecosystems and human health. However, a very limited proportion of neurotoxic effects (∼1%) has been explained by known chemicals of concern. Here, we integrated machine learning, nontargeted analysis, and in vitro biotesting to identify neurotoxic drivers of acetylcholinesterase (AChE) inhibition in estuarine waters along the coast of China. Machine learning was used to predict AChE inhibitors in a large chemical space. The prediction output was profiled into a suspect screening list to guide high-resolution mass spectrometry (HRMS) screening of AChE inhibitors in estuarine water samples. Ultimately, 60 chemicals with diverse known and presently unknown structures were identified, explaining 82.1% of the observed AChE inhibition. Polyunsaturated fatty acids were unexpectedly found to be neurotoxic drivers, accounting for 80.5% of the overall effect. This proof-of-concept study demonstrates that machine learning-based toxicological prediction can achieve a virtual fractionation role to pinpoint HRMS features with the bioactivity potential. Our approach is expected to enable rapid and comprehensive screening of organic pollutants associated with various in vitro end points for large-scale monitoring of water quality.

Phthalates Induced Neurotoxicity: A Mechanistic Approach.

Phthalates play a significant role as plastic modifying additives in everyday items like plastics, pesticides, paints, and cosmetics. This review explores the relationship between phthalates and neurotoxicity and sheds light on the potential risks these ubiquitous chemicals pose to neurological health. The review elucidates the diverse neurotoxic effects of phthalates exposure, spanning developmental neurotoxicity, neuropathy, neurodegenerative diseases, and neurobehavioral toxicity. Mechanistic insights reveal the pathways through which phthalates induce cellular damage, including oxidative stress, disruption of calcium signalling, alteration in lipid metabolism, and interference with thyroid hormone homeostasis. Moreover, the review discusses regulatory measures aimed at restricting phthalate usage and highlights the imperative for further research and awareness to safeguard public health against the neurotoxic effects of phthalates.

Study on the embryotoxic effects and potential mechanisms of Aconitum diterpenoid alkaloids in rat whole embryo culture through morphological and transcriptomic analysis

Ethnopharmacological relevanceThe lateral root of Aconitum carmichaelii Debeaux, or Fuzi, is recognized in Asia for its anti-inflammatory, analgesic, and cardiotonic effects. Its main active compounds are diester diterpenoid alkaloids (DDAs) such as aconitine (AC), mesoacitine (MA), and hypoaconitine (HA), which are also toxic and have a narrow therapeutic window, limiting their clinical use. Although Aconitum DDAs are known for cardiotoxic and neurotoxic effects, their impact on embryonic development remains unclear. Aim of the studyThe embryotoxicity of three representative Aconitum DDAs (AC, MA, and HA) and their metabolites were systematically assessed, and the mechanisms underlying AC-induced embryotoxicity was explored. Materials and methodsThe embryotoxicity of these DDAs was assessed by indicators such as morphological scores in a whole embryo culture (WEC) system. Immunofluorescence analysis was conducted to detect DNA damage and apoptosis in embryos, and transcriptomic analysis and western blotting were performed to explore the underlying mechanisms. ResultsDDAs, particularly AC, induced dose-dependent developmental retardation and malformation in rat embryos. Notably, the embryotoxicity of AC metabolites such as benzoyltrypine (BAC) and aconine, was significantly reduced. AC treatment caused substantial DNA damage and apoptosis in embryos. Transcriptomic analysis indicate that AC treatment may impair DNA replication and histone synthesis by activating the p53/p21/CDK2/NPAT pathway, ultimately affecting embryonic development. ConclusionAmong these Aconitum DDAs, AC exhibited the strongest embryotoxicity, mainly through DNA damage and regulation of histone genes via the p53/p21/CDK2/NPAT pathway.

Folic acid mitigates the developmental and neurotoxic effects of bisphenol A in zebrafish by inhibiting the oxidative stress/JNK signaling pathway

Bisphenol A (BPA) is a widespread environmental endocrine disruptor (EED) that can cause various environmental and health issues by inducing oxidative stress. The c-Jun N-terminal kinase (JNK) signaling pathway plays a crucial role in oxidative stress-mediated cellular damage. Although folic acid (FA) has demonstrated antioxidant properties, its potential protective effects against BPA-induced developmental and neurotoxicity, as well as the mechanisms involved in the JNK signaling pathway, are still not completely understood. Zebrafish embryos were exposed to different concentrations of BPA ranging from 20 to 40 µM, with or without treatment of 50 µM FA, starting at 6 hours post-fertilization (hpf). Various parameters such as hatchability, survival rate, body length, and heart rate were measured and analyzed. Transcriptome sequencing was conducted to study the changes in gene expression. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), hydrogen peroxide (H2O2), and catalase (CAT) activity, were assessed. The expression of proteins related to the mitogen-activated protein kinase (MAPK)/JNK pathway was analyzed using western blot. Neurodevelopmental and apoptotic outcomes were evaluated through behavioral tests, immunofluorescence and RT-qPCR examinations. The study found that exposure to BPA led to a decrease in hatchability, survival, body length, heart rate, total antioxidant capacity and promoted apoptosis in zebrafish larvae. However, supplementation with FA was able to alleviate these negative effects. BPA exposure increased levels of ROS, LPO, and H2O2, while decreasing CAT activity in zebrafish larvae. Treatment with FA effectively reduced BPA-induced oxidative stress and restored antioxidant defense systems. Moreover, KEGG pathway enrichment analysis revealed that the MAPK signaling pathway was the most enriched signaling pathway. Further studies revealed that BPA activated the JNK signaling pathway, while FA suppressed this activation. Additionally, FA significantly improved BPA-induced neurobehavioral deficits and protected against neurocytological alterations. Our findings demonstrate that FA effectively protects against BPA-induced developmental and neurotoxic effects in zebrafish by suppressing oxidative stress and inhibiting the JNK signaling pathway. This study provides new strategies and insights for preventing BPA-induced developmental and neurotoxicity in aquatic organisms.

Acteoside alleviates salsolinol-induced Parkinson's disease by inhibiting ferroptosis via activating Nrf2/SLC7A11/GPX4 pathway

Salsolinol (SAL), i.e.1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline, is a dopamine metabolite and endogenous neurotoxin that is toxic to dopaminergic neurons, and is involved in the genesis of Parkinson's disease (PD). However, the machinery underlying SAL induces neurotoxicity in PD are still being elucidated. In the present study, we first used RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that ferroptosis-related pathway was enriched by SAL, which was validated by in vitro and in vivo SAL models. SAL inducing ferroptosis through downregulating SLC7A11/GPX4 in SH-SY5Y cells, which neurotoxic effect was reversed by ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1). Acteoside, a phenylethanoid glycoside of plant origin with neuroprotective effect, attenuates SAL-induced neurotoxicity by inhibiting ferroptosis in in vitro and in vivo PD models through upregulating SLC7A11/GPX4. Mechanistically, acteoside activates Nrf2. Nrf2 inhibitor ML385 abolished acteoside-mediated increased SLC7A11/GPX4 and neuroprotection against SAL in SH-SY5Y cells. Meanwhile, the PI3K inhibitor LY294002 suppressed the acteoside-induced Nrf2 expression and ensued decreased expression of SLC7A11/GPX4 in SAL-treated SH-SY5Y cells. Taken together, these results demonstrate that salsolinol-induced PD through inducing ferroptosis via downregulating SLC7A11/GPX4. Acteoside attenuates SAL-induced PD through inhibiting ferroptosis via activating PI3K/Akt-dependant Nrf2. The present study revealed a novel molecular mechanisms underlining SAL-induced neurotoxicity via induction of ferroptosis in PD, and uncovered a new pharmacological effect against PD through inhibiting ferroptosis. This study highlights SAL-induced ferroptosis -dependent neurotoxicity as a potential therapeutic target in PD.

Transgenerational neurotoxic effects of triphenyltin on marine medaka: Impaired dopaminergic system function

Triphenyltin (TPT), a widely used environmental contaminant in antifouling paints, is known for its neurotoxic effects. To investigate the multigenerational impacts of long-term exposure (6 weeks) to environmental concentrations of TPT (100 ng/L) on either parent, we performed mixed mating between control and exposed groups (males or females). Although there was no direct contact with TPT in the subsequent generations, both the first and second generations displayed behavioral abnormalities, including reduced activity and impaired cognitive function, with pronounced gender differences and anxiety-like behaviors. Females were more susceptible than males, displaying a significantly increased time spent in the mirror-proximal zone in both F1 and F2 generations. Additionally, F0 females exhibited a marked reduction in the time spent in the bright area, further supporting the role of sex differences in behavioral responses. Notably, the maternal contribution of marine medaka (Oryzias melastigma) played a more significant role in the inheritance of TPT-induced cognitive deficits. A reduction in DA levels and AChE activity was observed across generations, regardless of gender, underscoring the critical role of DA-AChE balance in maintaining cognitive function. Additionally, gender differences and the hereditary effects of TPT exposure on anxiety-like behaviors were strongly associated with the transcriptional regulation of pparγ and gst. Impaired transcription of key genes in the dopaminergic system resulted in reduced DA levels, with the intergenerational transmission of mao being closely linked to behavioral impairments. In summary, TPT-induced neurotoxicity presents both hereditary effects and gender-specific differences, emphasizing the maternal influence in the inheritance of cognitive abilities and shedding light on the genetic impact of parental exposure.

Early developmental effects of propofol exposure in different stages of zebrafish embryos.

The mechanism of action of propofol, a common intravenous anaesthetic, in early life stages is not well understood with contradictory studies showing neurotoxic and neurogenic effects in the developing brain. Zebrafish early life stages have been established as an alternative model for animal experimentation with propofol toxicological effects reported following chronic exposure. Yet, the acute exposure to other anaesthetics has been shown to induce early life stage-dependent toxicological outcomes. Therefore, the present study aimed to evaluate the teratogenic effects of propofol at the 256-cell, 50% epiboly and 1-4 somite stages following a 20min exposure. Embryos were exposed after primally assessment of propofol acute toxicity (24h-LC50=9.82μgmL-1) and absorption at different developmental stages by chromatography. Embryos (2hours post-fertilization, hpf) were treated with an anaesthetic and toxicological concentration of propofol (2.5 and 10μgmL-1, respectively) for 20-min. Mortality and developmental toxicity were then evaluated until 144 hpf, when the behaviour and oxidative-stress-related biomarkers were assessed. Exposure at the 256-cell stage resulted in a concentration-dependent increased number of abnormalities in head, fins and tail and a decreased body length as well as in changes in ATPase activity for the lowest concentration. On the other hand, exposure at later stages resulted in a decreased survival while no significant malformations were detected. Yet, exposure during the 50% epiboly stage resulted in the increase of ROS levels as well as glutathione (GST and GSSG) levels while exposure at 1-4 somite stage resulted in increased DNA damage and ATPase alterations. The behaviour of zebrafish was similar among treatments. Overall, these findings show highlight the stage-dependent teratogenic potential of short propofol exposures during zebrafish early development. The alterations observed may be linked to the activation of the zygotic transcription in embryos, requiring further studies to delve into the molecular changes underlying the observed effects.

Deferoxamine-induced neurotoxicity: Role of chaperone-mediated autophagy dysfunction in neuronal apoptosis in the hippocampus

Deferoxamine mesylate (DFX) is a microorganism-derived iron chelator used in hematology to treat acute iron intoxication and chronic iron overload. Many studies have reported adverse neurological events from DFX exposure, but it is challenging to distinguish these from the effects of iron intoxication. This study aimed to evaluate whether DFX exposure alone can directly impair neurological functions and to elucidate its toxicological mechanisms. Our findings from in vivo and in vitro experiments indicate that DFX exposure can directly cause emotional and cognitive dysfunction in mice. Neuronal apoptosis, resulting from chaperone-mediated autophagy (CMS) dysfunction, was identified as a key toxicological mechanism underlying DFX-induced neuronal impairment. This study provides evidence for the comprehensive monitoring and timely management of neurotoxic adverse events associated with DFX exposure, as well as a foundation for developing medications to prevent and treat these events to enhance patient quality of life.

Exposure to an environmentally representative mixture of polybrominated diphenyl ethers (PBDEs) alters zebrafish neuromuscular development

Polybrominated diphenyl ethers (PBDEs) are a prevalent group of brominated flame retardants (BFRs) added to several products such as electronics, plastics, and textiles to reduce their flammability. They are reported as endocrine disruptors and neurodevelopmental toxicants that can accumulate in human and wildlife tissues, thus making their ability to leach out of products into the environment a great cause for concern. In this study, zebrafish (Danio rerio) embryos and larvae were exposed to a wide concentration range (1.5, 15, 150 and 300 pM) of a PBDE mixture from one to six days post-fertilization (dpf). Hatching rates, mortality and general morphology were assessed during the exposure period. A delay in hatching was observed at the two highest PBDEs concentrations and mortality rate increased at 6 dpf. By 4 dpf, larvae exposed to 150 pM and 300 pM PBDEs developed an upcurved phenotype. Analysis of motor behavior at 6 dpf revealed that PBDE exposure acutely reduced locomotion. To further analyze these motor deficits, we assessed the neural network density and motor neuron and neuromuscular junctions (NMJ) development by immunostaining and imaging. Acetylated α-tubulin staining revealed a significant loss of neurons in a dose-dependent manner. Synaptic vesicle protein 2 (SV2) and ⍺-bungarotoxin (⍺-BTX) staining revealed a similar pattern, with a significant loss of SV2 and nicotinic acetylcholine receptors, thus preventing the colocalization of presynaptic neurons with postsynaptic neurons. Consistent with these results, the presence of cleaved caspase-3 and acridine orange positive cells showed increased cell death in zebrafish larvae exposed to PBDEs. Our results suggest that exposure to PBDEs leads to deficits in the zebrafish neuromuscular system through neuron death, inducing morphological and motor deficiencies throughout their development. They provide valuable insight into the neurotoxic effects of PBDEs, further highlighting the relevance of the zebrafish model in toxicological studies.

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.

Effects of Laurus extract against cadmium-induced neurotoxicity in rats

Cadmium (Cd) is a hazardous heavy metal with widespread environmental presence, posing significant threats to human and animal health. This study investigates the neurotoxic effects of Cd exposure and explores the therapeutic efficacy of Laurus nobilis L. in counteracting these adverse effects. Cd exposure induces oxidative stress and neurotoxicity, leading to neuronal damage and histopathological alterations. Laurus, known for its antioxidant properties, is assessed for its potential in mitigating Cd-induced neurotoxicity through in vitro antioxidant assays, GC–MS analysis, HPLC profiling, and experimental animal models. Results demonstrate that Laurus ethanolic extract exhibits significant antioxidant activity, attributed to its phenolic and flavonoid constituents. GC–MS analysis reveals various bioactive compounds in the extract, including Hexadecanoic acid methyl ester and (Z)-13-Docosenamide, which posses neuroprotective properties. HPLC analysis identifies phenolic compounds such as ellagic acid and flavonoids like rutin and kaempferol in the extract. In vivo studies in rats exposed to Cd demonstrate that Laurus extract administration mitigates Cd-induced alterations in body and brain weight, hematological parameters, liver and kidney function, oxidative stress markers, and acetylcholinesterase (AchE) activity. Histopathological examination confirms the protective effects of Laurus against Cd-induced neuronal damage. The SOD model, validated with high resolution (2.05 Å) and strong R values (work: 0.192, free: 0.236, observed: 0.194), shows strong structural stability (C-score: 0.30). Docking studies reveal high binding affinities of kaempferol (−8.1 kcal/mol) and rutin (−8.7 kcal/mol) with SOD with kaempferol demonstrating superior solubility, lipophilicity, and drug-likenessSimulation analysis confirms the protein’s flexibility and adaptability, highlighting its therapeutic potential, especially with kaempferol. These findings suggest the therapeutic potential of Laurus. as a natural remedy for Cd-induced neurotoxicity, highlighting its antioxidant and neuroprotective properties.

The role of Sod-2 in different types of neuronal damage and behavioral changes induced by polystyrene nanoplastics in Caenorhabditis elegans

Polystyrene nanoplastics (PS-NPs) have been demonstrated to accumulate in organisms especially from soil and exhibit neurotoxicity. However, the specific mechanisms by which PS-NPs caused neurotoxic effects remain largely unexplored. In this study, we employed PS-NPs with a diameter of 50 nm as the toxicant and used estimated exposure concentrations which are similar to those found in Chinese agricultural soil (i.e., 0, 1, 5 and 10 μg/mL). We found that PS-NPs induced significant neurotoxicity and behavioral damage in nematodes. Taking advantage of neuronal-specific reporter nematodes, we unveiled the order of neuronal damage induced by PS-NPs being DAergic neurons, followed by Achergic neurons and GABAergic neurons. Additionally, PS-NPs significantly reduced the neurotransmitter levels corresponding to these three types of neurons, with the order of reduction being Ach followed by DA and GABA. Moreover, we demonstrated that PS-NPs led to an increase in ROS production, the activation of gst-4 and a decrease in Sod-2 protein content. Furthermore, we unveiled that Sod-2 could suppress the generation of ROS induced by PS-NPs. Then we proved that the pretreatment with mitochondrial ROS scavenger Mitoquinone (Mito Q) was able to alleviate PS-NPs-induced neurotoxic effects and behavioral damage by scavenging ROS and subsequently regulating Sod-2 protein expression. In summary, we have demonstrated for the first time that ROS-mediated reduction of Sod-2 protein plays a crucial role in PS-NPs-induced neurotoxicity and behavioral damage. Furthermore, Mito Q shows potential therapeutic value in alleviating the toxic effects of PS-NPs, providing new insights for the prevention and treatment of PS-NPs-induced neurotoxicity.

Safety and activity of CTX130, a CD70-targeted allogeneic CRISPR-Cas9-engineered CAR T-cell therapy, in patients with relapsed or refractory T-cell malignancies (COBALT-LYM): a single-arm, open-label, phase 1, dose-escalation study

Effective treatment options are scarce for relapsed or refractory T-cell lymphoma. This study assesses the safety and activity of CTX130 (volamcabtagene durzigedleucel), a CD70-directed, allogeneic chimeric antigen receptor (CAR) immunotherapy manufactured from healthy donor T cells, in patients with relapsed or refractory T-cell lymphoma. This single-arm, open-label, phase 1 study was done at ten medical centres across the USA, Australia, and Canada in patients (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma, who had received at least one or at least two previous systemic therapy lines, respectively, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients underwent lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 × 107 CAR+ T cells (dose level 1) to 9 × 108 CAR+ T cells (dose level 4). The primary endpoint was the incidence of adverse events, defined as dose-limiting toxicities occurring within 28 days post-infusion. Secondary endpoints included objective response rate. Safety and activity analyses were performed on data from all patients who received CTX130. The trial is registered with ClinicalTrials.gov (NCT04502446) and EudraCT (2019-004526-25) and is closed to enrolment. Between Aug 28, 2020, and May 30, 2023, 41 patients were enrolled and 39 (95%) received CTX130. The median patient follow-up was 7·4 months (IQR 3·1-12·2). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. The median number of previous lines of anticancer therapy was 2·5 (IQR 1·3-4·0) for patients with peripheral T-cell lymphoma and 5·0 (IQR 5·0-7·0) for patients with cutaneous T-cell lymphoma. Cytokine release syndrome was the most common adverse event, occurring in 26 (67%) of 39 patients (23 were grade 1-2, two were grade 3, and one was a grade 4 dose-limiting toxicity at dose level 4). Grade 1-2 neurotoxic events were observed in four (10%) of 39 patients. The most common grade 3-4 adverse events were neutropenia (14 [36%]), anaemia (11 [28%]), and thrombocytopenia (six [15%]). Serious adverse events occurred in 25 (64%) patients, with CTX130-related serious adverse events in 14 (36%) patients, the most common related serious adverse event being cytokine release syndrome in 11 (28%) patients. 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. 18 of 39 patients (46·2% [95% CI 30·1-62·8) had an objective response. Of those treated at dose level 3 and higher, 16 of 31 patients (51·6% [33·1-69·8]) had objective responses, including six (19·4% [7·5-37·5]) with complete response and ten (32·3% [16·7-51·4]) with a partial response. In patients with heavily pretreated T-cell lymphoma, CTX130 showed manageable safety and a promising objective response rate. This study shows that allogeneic, readily available CAR T cells can be safely given to patients with relapsed or refractory T-cell lymphoma. A next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development. CRISPR Therapeutics.

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood–brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.