The neurotoxicity mechanisms of tetrachloro-1,4-benzoquinone(TCBQ) remain poorly understood. This study integrated computational simulations validation to elucidate TCBQ-induced neurotoxicity. In our investigation of the neurotoxic effects of TCBQ, we employed a diverse range of analytical techniques, including protein-protein interaction (PPI) networks, screening for target genes and protective drugs, as well as performing KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses. Additionally, we utilized advanced methodologies such as molecular docking and molecular dynamics simulations to gain deeper insights into the mechanisms underlying TCBQ's neurotoxicity. These comprehensive approaches enabled us to construct a detailed understanding of how TCBQ may contribute to neurotoxic outcomes. To further assess the potential connections between key target proteins and Alzheimer's disease, we utilized Mendelian randomization as a robust analytical strategy. This statistical method allowed us to explore the causal relationships that may exist between the identified proteins and the incidence of Alzheimer's disease, providing a clearer understanding of the biological pathways involved. For our analysis, we extracted summary-level data regarding the circulating levels of 4,907 proteins from a significant protein quantitative trait loci study conducted by the deCODE Genetics Consortium, which comprised a total of 35,559 individuals. Moreover, the outcome data for Alzheimer's disease were obtained from genome-wide association studies organized by the International Genomics of Alzheimer's Project (IGAP). This extensive research analyzed data from 17,008 participants who were diagnosed with Alzheimer's disease, alongside 37,154 control subjects, all of whom shared a European ancestry. The results of integrated network analysis indicate that TCBQ may promote neurotoxicity through alzheimer 's disease. The main targets involved TNF, NOS2, IL6, and others. TCBQ and protective drug curcumin have a low binding score and compact complex with TNF, NOS2, IL6. 5 TNF subtype TNFSF13B, TNFRSF1B, TNFRSF13C, TNFSF12, NFRSF11B has a causal relationship with Alzheimer's disease. TCBQ can promote neurotoxicity by increasing inflammation and alzheimer 's disease. Our study provides a theoretical basis for the subsequent experimental study of TCBQ in neurotoxicity. TNF plays an important role in alzheimer 's disease.
2,4,6-Tribromophenol (TBP) is a widespread emerging environmental pollutant that tends to accumulate in the brain. Growing evidence implicates disrupted brain lipid homeostasis in contaminant-induced neurotoxicity. To explore this potential link, we investigated the neurotoxic and lipid-disrupting effects of TBP using zebrafish larvae. Multi-level neurotoxicity assessment in whole larvae showed that TBP exposure induced concentration-dependent decreases in locomotor activity and a trend toward anxiety-like behaviors. Moreover, TBP significantly altered neuronal differentiation. At the neurochemical level, neurotransmitter homeostasis was disrupted, specifically marked by decreases in the levels of acetylcholine, serotonin, and epinephrine. Concomitantly, TBP induced a systemic lipid dysregulation, characterized by elevated total cholesterol and reduced triglyceride levels. Region-specific alterations were evident: abnormal neutral lipid accumulation occurred in the yolk sac, while lipid levels in the head region exhibited significant reductions. The transcripts of lipid metabolism genes in whole larvae were widely suppressed. To explore the correlation between lipid dysregulation and neurotoxicity, a rescue experiment was conducted using the liver X receptor (LXR) agonist GW3965. LXR activation restored the gene expression of systemic lipid transport and normalized head lipid levels. Notably, this restoration of lipid homeostasis partially alleviated the TBP-induced neurotransmitter deficits. Collectively, these results suggest that TBP exposure may impair neurodevelopment and function, and support lipid metabolic disruption as a potential mechanistic link underlying the consequent neurotoxicity. Our findings provide a preliminary mechanistic basis for evaluating the neurotoxic potential of other emerging environmental contaminants with metabolism-disrupting properties.
Stroke, primarily due to ischemic injury and neurodegeneration, is a significant global cause of death and permanent neurological impairment in adults. Phytocompounds are promising candidates for stroke care because of their effects on key molecular signaling pathways that promote neuroprotection in stroke. This review highlights the therapeutic potential of phytocompounds, such as curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate, which target signaling pathways, including PI3K/Akt, Nrf2/ARE, MAPK, NF-κB, and JAK/STAT. These substances have neuroprotective properties by managing oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation, excitotoxicity, and blood-brain barrier integrity. Preclinical research has indicated that phytocompound therapy significantly decreases infarct volume, neuronal loss, and behavioral impairments. Despite strong experimental evidence, the clinical application of phytocompounds is limited by their low brain permeability, short half-life, poor bioavailability, and irregular dosages. Furthermore, demonstrating the neurotoxicity and safety profiles of phytocompounds is essential because of the potential risks, such as hepatotoxicity, genotoxicity, and brain transmission interference. Nanotechnology-based delivery methods, such as liposomes and phytocompound-loaded nanoparticles, have demonstrated the ability to overcome pharmacokinetic restrictions while reducing the toxicity. Phytocompounds that target various neuroprotective signaling pathways are potential supplements or alternative treatments for stroke. To ensure clinical efficacy and safety, it is essential to follow the recognized dosage guidelines, perform thorough neurotoxicity evaluations and conduct rigorous clinical studies. Future studies should explore the potential of phytocompounds in conjunction with traditional treatments and precision medicine techniques for personalized stroke care.
Bisphenol A (BPA) is a synthetic chemical widely used in the production of plastics and epoxy resins due to its low cost, durability, and heat resistance.Recognised as an endocrine-disrupting chemical, BPA has raised growing concern regarding its potential effects on brain development, particularly during prenatal and early postnatal life. BPA-induced neurotoxicity involves multiple interconnected mechanisms, including oxidative stress, neuroinflammation, mitochondrial dysfunction, synaptic impairment, and neuroendocrine disruption, which collectively contribute to cognitive and behavioural abnormalities. Kelulut honey, produced by stingless bees (Heterotrigona itama), contains various bioactive compounds such as polyphenols, flavonoids, organic acids, and trehalulose. These compounds possess antioxidant, anti-inflammatory, and neuroprotective properties and may modulate pathways involved in neuronal survival, synaptic plasticity, inflammatory regulation, NMDA receptor signalling, and estrogen-related pathways. This narrative review summarises current findings on the neuroprotective potential of kelulut honey against BPA-induced neurotoxicity, highlights existing research gaps, and discusses future directions for further mechanistic and translational studies.
Drugs contribute to one of the most harmful contributors to neurotoxicity as they stimulate multiple neurotransmitter systems, inculcating oxidative damage, cell death, and glutamate excitotoxicity, which together contribute to brain injury. Common drugs capable of causing neurotoxicity include methylglyoxal, chemotherapy agents, aluminium, glutamate, Lipopolysaccharide (LPS), and aggregated proteins such as Amyloid β1-40, which can lead to neuronal cell damage, cognitive impairment, altered gene expression, and impaired neurogenesis. Metformin, a widely used anti-diabetic medication and first-line treatment, is a biguanide exhibiting several properties, including antioxidant, anti-inflammatory, and anti-apoptotic effects across various tissues. It activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits hepatic gluconeogenesis. Both in vitro and in vivo research has explored its potential neuroprotective mechanisms in cerebral ischaemic injury and other neurodegenerative conditions. However, despite these benefits, long-term use of metformin may cause adverse effects such as the development of dementia and Parkinsonism, as well as accelerated oxidative damage. This highlights the need for further well-designed preclinical and clinical studies to determine the optimal dosing, treatment duration, and patient selection for metformin. This knowledge would help identify key molecular pathways and biomarkers influenced by metformin, enabling exploration of its potential for repurposing in the context of drug-induced neurological damage.
Myclobutanil (MYC) is a systemic synthetic triazole-class fungicide extensively deployed in global agriculture. Residues of MYC are often detected in various ecosystems and biological systems. However, studies investigating its potential neurodevelopmental toxicity are still scarce. In this research, zebrafish embryos were treated with MYC (at 0, 0.5, and 1 mg/L) during 4 to 96 h post fertilization (hpf) to assess its neurotoxic effects and underlying molecular pathways. Our results revealed that MYC adversely affected embryonic development, manifesting as reduced hatching rate, decreased survival rate, lower heart rate, concurrently with elevated malformation and spontaneous movement. Locomotor dysfunction was observed following MYC exposure. MYC also attenuated central nervous system neurogenesis in Tg(HuC:EGFP) zebrafish, as evidenced by diminished cholinesterase activities and decreased transcription of neurodevelopmental genes. In addition, MYC disturbed thyroid hormone balance and modulated the transcriptional profile of hypothalamus-pituitary-thyroid (HPT) axis-related genes. Molecular docking suggests a strong binding interaction between catalytic residues of thyroid hormone receptor β and MYC. Subsequently, MYC triggered apoptosis in brain neurons by upregulating apoptotic genes. These neurotoxic effects were effectively counteracted after T3 administration, suggesting thyroid dysfunction as a vital mechanism of MYC-induced neurotoxicity. Overall, this study reveals that MYC induces neurotoxicity in zebrafish larvae through thyroid hormone disruption and neuronal apoptosis, providing new insights into the developmental neurotoxic risks of triazole fungicides.
Background: Rotenone is a widely used environmental pesticide, and epidemiological studies suggest that exposure is associated with an increased risk of Parkinson's disease (PD); however, the molecular toxicological basis of this association remains incompletely defined. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is relevant to PD and other neurodegenerative disorders. In this study, we provide disease-contextual functional evidence linking ferroptosis to rotenone-induced PD-like neurotoxicity. Methods: We combined network toxicology, human PD substantia nigra transcriptomic analysis using GSE7621, and SH-SY5Y cell-based validation. Rotenone-associated targets were predicted and analyzed for ferroptosis-related enrichment, PD transcriptomic signatures were used for disease-contextual candidate prioritization, and selected findings were validated using qPCR, CCK-8, Western blotting, C11-BODIPY lipid peroxidation staining, and transmission electron microscopy. Results: By further integrating a human PD substantia nigra transcriptomic dataset (GSE7621), we prioritized an 11-gene, PD-contextualized ferroptosis-associated candidate module (LIPF, FAM170A, MCHR1, IL17A, MYB, GFAP, ARMC3, GKN1, GATA3, IL17F, and TEKT1). In SH-SY5Y cells, rotenone exposure consistently upregulated this candidate transcriptional module, and this induction was broadly attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). In parallel, orthogonal functional assays supported an iron- and lipid peroxidation-driven injury state under rotenone exposure that was suppressible by ferroptosis inhibition and iron chelation. Finally, we further performed an exploratory drug-gene association screen to prioritize clinically available candidates, and a limited qPCR check suggested that several selected compounds partially attenuated representative hub-gene induction under rotenone exposure. Conclusions: Collectively, these findings provide disease-contextual and experimentally supported evidence linking rotenone exposure to ferroptosis-associated neurotoxicity, and identify a ferroptosis-responsive transcriptional module for future hypothesis-driven mechanistic investigation.
Per- and polyfluoroalkyl substances (PFAS) have raised increasing concerns due to their potential neurotoxicity; however, their effects on retina, a highly specialized neural tissue, remain unclear. This study aimed to investigate the retinal toxicity of PFAS in adolescents and to elucidate underlying molecular mechanisms and therapeutic targets. A cross-sectional study involving 1,686 Chinese adolescents was conducted to evaluate associations between serum PFAS concentrations and retinal structural characteristics. In parallel, toxicogenomic analyses were performed to identify key genes associated with PFAS exposure and retinal diseases. Correspondingly, in vitro experiments were conducted to reveal the potential molecular mechanisms underlying the cytotoxic effects of PFAS on retinal ganglion cells (RGCs). Higher serum levels of PFOA (β = -0.05, P = 0.01), PFOS (β = -0.06, P = 0.04) and PFHxS (β = -0.11, P = 0.03), were negatively associated with global retinal nerve fiber layer (RNFL) thickness. Applying toxicogenomic screening, nine hub genes related to PFAS (e.g., CCL2, TNF-α, and TLR4) were identified to be enriched in inflammatory pathways. Mechanistically, apoptotic cell death in R28 and RGCs were promoted by PFAS exposure, characterized by elevated cleaved PARP and cleaved Caspase-3. This study provides evidence that PFAS exposures are correlated with retinal neurotoxicity in adolescents through inflammatory activation and apoptosis. The identified gene signatures highlight potential targets for prevention and therapeutic intervention.
Since Ephedra Herba (ephedra) and its major alkaloid ephedrine were prohibited as dietary supplements due to their adverse effects on the cardiovascular and central nervous system (CNS), most studies have focused on their amphetamine-like effects and neurotoxicity. However, ephedra also has a long history of use in the treatment of various CNS diseases (known as "Zhong Feng" syndrome) according to two thousand years of traditional Chinese medicine (TCM) records. Pharmacokinetic reports have also demonstrated that alkaloids of ephedra can quickly penetrate the blood-brain barrier (BBB) once absorbed into the blood and there are multiple alkaloids derived from ephedra which have been identified as natural sympathomimetic drugs. These drugs are capable of interfering with several types of neurotransmitter, and have an especially potent effect on monoamine neurotransmitters. The effects of ephedra on CNS therefore remain both contradictory and confusing. In this review, we summarized the available evidence of pharmacology and toxicology of ephedra and ephedrine on CNS, and aimed to clarify their effects. Given the unmet need for more efficient treatments of neurological disorders, ephedra is potentially valuable herbal medicine which may provide a promising avenue for development of treatments and encourage further drug research and development (R&D).
Adenosine-to-inosine (A-to-I) RNA editing is a major epitranscriptomic mechanism, yet its contribution to non-coding RNA regulation during neurodegeneration is largely unknown. SINE B2 RNAs represent the dominant editing substrates in mice and have been shown to regulate gene expression. Here, we introduce and validate a repeat-aware bioinformatics framework that enables position-specific quantification of A-to-I editing within SINE RNAs, which has been challenging using standard genome-based pipelines. Applying this approach, we identify discrete editing hotspots in mouse SINE B2 RNAs that are selectively increased during early amyloid beta pathology in independent mouse models and in hippocampal neurons exposed to amyloid beta toxicity. Functional perturbation of ADAR activity alters both B2 RNA editing levels and the expression of B2 RNA-regulated genes, directly linking RNA editing to SINE-mediated transcriptional control. Nanopore sequencing confirmed increased RNA modification signals at these regions. Together, our findings establish a previously unrecognized epitranscriptomic response to amyloid beta neurotoxicity mediated by site-specific A-to-I editing of SINE RNAs.
Parkinson's disease (PD) is a progressive neurodegenerative disorder strongly associated with dopaminergic neuronal degeneration and alpha-synuclein pathology. Paraquat (PQ) has been implicated in Parkinsonian neurodegeneration; however, the influence of age on susceptibility to PQ-induced neuropathology remains insufficiently characterized. This study investigated age-dependent effects of paraquat exposure on neurobehaviour, substantia nigra histomorphology, and serum alpha-synuclein levels in male Wistar rats. Sixty-three male Wistar rats were assigned into juvenile, young adult, and adult age categories, each further subdivided into control, PQ-treated, and PQ+recovery groups. Paraquat (10 mg/kg, intraperitoneally) was administered twice weekly for three weeks. Recovery groups were maintained for a two-month post-exposure period. Neurobehavioral assessments were conducted to evaluate locomotor and anxiety-related functions. Serum and nigral alpha-synuclein concentrations were quantified using enzyme-linked immunosorbent assay (ELISA), while histological examination of the substantia nigra was performed to assess neuronal integrity. Adult rats exhibited a significant reduction in locomotor activity following PQ exposure (p = 0.020) and showed more prominent histopathological alterations within the substantia nigra compared with juvenile and young-adult animals. Although improvement in tissue architecture was observed following paraquat withdrawal, residual alterations persisted, particularly in adults. Nigral alpha-synuclein concentrations did not differ significantly among treatment groups in any age cohort. Serum alpha-synuclein levels were similarly unchanged in most groups, except for a reduction observed in recovering young-adult animals (p = 0.039). Age influences vulnerability to PQ-induced neurotoxicity, with adult animals showing greater susceptibility to behavioral and histological damage. However, serum total alpha-synuclein levels did not consistently parallel central neuropathology, suggesting limited reliability as a standalone peripheral biomarker of PQ-induced Parkinsonism.
Background/Objectives: Chimeric antigen receptor T-cell (CAR T) therapy is an effective treatment for relapsed/refractory (r/r) aggressive B-cell lymphomas; however, acute toxicities, such as immune effector cell-associated neurotoxicity syndrome (ICANS), remain common. Interleukin-1 (IL-1) has been implicated in the pathogenesis of ICANS, suggesting that prophylactic anakinra, an IL-1 receptor antagonist, might reduce its incidence or severity. Methods: We retrospectively analyzed 80 patients with B-cell lymphomas who received CD19-directed CAR T-cell therapy (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) at the Bern University Hospital between April 2019 and June 2022. One cohort received prophylactic anakinra (100 mg subcutaneously on days 0 to +6 post-infusion), while the comparison cohort did not. Results: The incidence of ICANS was similar between groups (14 patients, 35%) with anakinra vs. 10 (25%) in the standard cohort (p = 0.464). Rates of grade 3 ICANS were also comparable (eight (20%) vs. seven (18%), p > 0.999). Among patients who developed ICANS, median hospitalization was numerically shorter with anakinra (27 vs. 40 days, p = 0.077). Anakinra did not impair CAR T-cell expansion and was well tolerated, with no treatment-related adverse events. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were similar between cohorts. Conclusions: In summary, prophylactic anakinra did not reduce the incidence or severity of ICANS in our analysis; however, it may be associated with shorter hospitalization in affected patients. Whether this reflects a direct therapeutic effect or improved overall toxicity management remains uncertain. Larger prospective studies are warranted to further clarify the role of anakinra for prophylactic treatment of ICANS following CAR T-cell therapy.
The olfactory bulb (OB) is one of the earliest brain regions affected in neurodegenerative diseases such as Parkinson's disease (PD). Its high metabolic rate, dopaminergic modulation, and connectivity with the cortical and limbic regions make it particularly vulnerable to early neuroinflammatory and oxidative processes. This study aimed to investigate whether the administration of 6-hydroxydopamine (6-OHDA) into the OB induces behavioral, redox, and inflammatory alterations associated with early cortical disturbances. Male Wistar rats were randomly assigned to the sham or 6-OHDA groups and underwent stereotaxic injection of the vehicle or 6-OHDA into the left OB. Behavioral performance was assessed in the open-field test 12 days after surgery, and cortical tissue was collected for biochemical and molecular analyses. Cytokines (IL-1β, IL-6, TNF-α, IL-10, IFN-γ, and MCP-1) were quantified by Luminex, redox parameters (CAT, GPx, MDA, and protein carbonyls) by spectrophotometry, and neuronal signaling proteins (c-FOS, CREB, and BDNF) by qPCR. Animals with 6-OHDA lesions exhibited decreased latency and increased time spent in the central zone of the open field, indicating altered exploratory behavior. IL-6 levels were significantly elevated, whereas IFN-γ was reduced in the cortex, while IL-1β, TNF-α, MCP-1, and IL-10 remained unchanged. The oxidative stress markers MDA and protein carbonyls were increased, while catalase and glutathione peroxidase activities showed no change. The expression of c-FOS, CREB, and BDNF was not significantly modified. These findings indicate that localized 6-OHDA administration in the OB is sufficient to elicit behavioral, inflammatory, and oxidative alterations in connected cortical regions, which may resemble early non-motor features associated with olfactory dysfunction, without representing a neurodegenerative disease-specific process.
Increased evidence from epidemiological research and pre-clinical studies have presented a correlation between exogenous neurotoxicants (such as aluminum, arsenic, lead, cadmium, mercury and ethanol) and various neurobiological disorders which contribute to cognitive impairments. The existing data demonstrate that nutraceutical supplementation affords neuroprotective effects against neurotoxicity. Nutraceuticals improved learning and memory impairments, anxiety and depressive-like behavior, locomotor activity and neuropathic pain. The most common molecular and cellular mechanisms in nutraceutical therapy include attenuation of oxidative stress (by suppressing lipid peroxidation and increasing antioxidant enzymes and contents), suppression of apoptosis (by increasing B-cell lymphoma 2 (Bcl2) expression, and reduction in Bcl-2-associated X protein (Bax), caspase-3 and cytochrome c expression), suppression of neuroinflammation (by inhibiting inflammatory cytokines), inhibition of amyloid β (Aβ) plaque and neurofibrillary tangles, and increased synaptic plasticity (by increasing Brain-derived neurotrophic factor (BDNF), and regulating cholinergic and neurotransmitter systems.
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Zebrafish embryos provide a rapid, low-cost in vivo platform to profile the developmental, neurotoxic, and immunomodulatory effects of engineered nano(bio)materials within a single vertebrate system. This article presents a modular workflow that integrates standardized fish embryo acute toxicity (FET) testing, chemically assisted dichlorination, inflammatory challenge, and regeneration assays to evaluate both bio-based and synthetic nanoparticles. First, embryos are exposed to nanomaterials under FET conditions and subjected to quantitative morphometric analysis to establish sublethal concentration ranges and detect subtle growth defects. Sensitivity to nano(bio)material exposure is enhanced by a pronase-based dechorionation procedure, which removes the chorion to promote direct particle-tissue contact while maintaining acceptable baseline viability. Immunoinflammatory responses are probed using two complementary modules: microinjection of Pseudomonas aeruginosa lipopolysaccharide (LPS) into the yolk sac to induce acute systemic inflammation and caudal fin wounding to elicit a localized inflammatory and regenerative response. Across these models, we combine qPCR panels of cytokine and Wnt/β-catenin pathway genes with Sudan Black B staining of neutrophils and neutral red vital staining of macrophages, providing accessible cellular and molecular readouts in wild-type embryos. Together, these protocols constitute a harmonized, technically accessible pipeline that enables comparative safety and bioactivity profiling of diverse nano(bio)materials and supports their assessment within safe-and-sustainable-by-design frameworks. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Nanoparticle preparation and suspension, and embryo dechorionation procedure (pronase solution) Basic Protocol 2: Sudan Black B staining protocol Basic Protocol 3: Neutral red staining protocol Basic Protocol 4: LPS microinjection protocol Basic Protocol 5: Wound inflammation model generation protocol.
Immunotherapy has emerged as a promising strategy for pediatric high-grade gliomas and diffuse midline gliomas, yet the clinical impact of delivery route remains uncertain. This study evaluated whether intracranial or systemic administration influences survival and toxicity outcomes. A systematic review and meta-analysis were conducted according to PRISMA guidelines. Clinical studies reporting survival or toxicity outcomes of immunotherapy in pediatric brain tumors were identified. Random-effects models were used to pool hazard ratios (HRs) for overall survival (OS) and 12-month survival (OS12), and odds ratios (ORs) for grade ≥ 3 neurotoxicity. Meta-regression assessed the influence of delivery route. Twenty-two studies were included in the quantitative synthesis. Intracranial delivery showed a pooled HR for OS of 1.12 (95% CI 0.88-1.42) with moderate heterogeneity (I2 = 27.3%), whereas systemic delivery showed HR 1.21 (95% CI 0.99-1.47) with minimal heterogeneity (I2 = 1.1%). No significant difference between delivery routes was observed (ratio of HRs 0.93, 95% CI 0.67-1.29). For grade ≥ 3 neurotoxicity, intracranial administration demonstrated markedly higher risk (OR 73.80, 95% CI 41.50-131.20) compared with systemic therapy (OR 6.20, 95% CI 1.80-20.90). Meta-regression confirmed that delivery route was not associated with OS or OS12 but was significantly associated with increased neurotoxicity (β = 3.064, p < 0.001). Immunotherapy delivery route does not appear to influence survival outcomes. Although intracranial administration was associated with higher reported rates of severe neurotoxicity, this finding should be interpreted cautiously given the heterogeneity of immunotherapy platforms and the potential confounding effect of treatment modality. Future studies should prioritize biologically guided therapeutic strategies while carefully balancing locoregional exposure and safety. • Locoregional (intracranial) immunotherapy has been proposed to improve CNS drug delivery in pediatric high-grade and diffuse midline gliomas, but its benefit over systemic administration is unproven. • Early-phase trials show biological activity with heterogeneous survival and toxicity, leaving the clinical impact of delivery route uncertain. • Across 22 studies, immunotherapy delivery route was not associated with overall or 12-month survival (rHR 0.93 and 0.87, both non-significant). • Intracranial delivery carried markedly higher severe neurotoxicity, but meta-regression showed this was largely driven by treatment platform (CAR-T/oncolytic) rather than route itself.
Vincristine is limited by its adverse effect of peripheral neuropathy with only a few inconclusive reports of its genetic occurrence. Therefore, the present research work was intended to identify the distribution of rs1045642 polymorphism in ABCB1 gene and rs924607 polymorphism in CEP72 gene, and their association with clinically documented neurological adverse drug reactions to vincristine. Seventy-five children below 18 years diagnosed with acute lymphoblastic leukemia receiving vincristine were followed for 6 months and analyzed for correlation with vincristine-associated neuropathy. Twenty of 75 patients were homozygous for the risk allele (TT at rs924607) of CEP72 genotype and 25 of 75 patients were homozygous for the risk allele (TT at rs1045642) of ABCB1 genotype. Among patients with the high-risk ABCB1 genotype (TT at rs1045642), 13 of 25 (52%) developed at least one episode of grade 1-3 neuropathy, and had a statistically significant 4.3 times risk of developing neurotoxicity in comparison to patients with the ABCB1 CC or CT genotypes [10 of 50 (20%) patients, odds ratio: 4.3, 95% confidence interval: 1.5-12.3; P = 0.0060]. The patients receiving average dose of vincristine of greater than or equal to 2 mg/m2 (58.3%) when compared to those receiving an average dose of less than 2 mg/m2 (25.4%) had 4.1 times risk of developing neurotoxicity (odds ratio: 4.1, 95% confidence interval: 1.1-14.8; P = 0.0304). This study emphasizes the significant association of ABCB1 genotype (TT at rs1045642) with vincristine-associated neuropathy and highlights the relevance of higher average doses of vincristine in causing neurotoxicity.
Cordycepin, a major bioactive constituent of Cordyceps militaris, exhibits diverse pharmacological properties including anti-inflammatory and antioxidant activities. However, its neuroprotective effects against aluminum-induced neurotoxicity in aquatic organism models remain largely unexplored. In this study, we investigated the neuroprotective effects and underlying mechanisms of cordycepin against aluminium chloride (AlCl3)-induced neurotoxicity in zebrafish (Danio rerio) embryos using behavioral, molecular, and transcriptomic approaches. Exposure to low-dose AlCl3 significantly induced developmental neurotoxicity, as manifested by reduced body length and reduced heart rate. AlCl3-treated larvae displayed locomotor deficits and cognitive dysfunction. Notably, cordycepin treatment markedly attenuated these AlCl3-induced neurodevelopmental abnormalities and aluminum chloride (AlCl3)-induced locomotor and anxiety-related behavioral impairments.RNA-Seq analysis revealed 605 upregulated and 241 downregulated genes following co-exposure to cordycepin and AlCl3. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses identified defense and inflammatory responses as the most significantly enriched pathways, suggesting their critical involvement in cordycepin-mediated neuroprotection. Furthermore, pharmacological inhibition of the Wnt signaling pathway with IWR-1-endo (IWR-1) significantly abolished the protective effects of cordycepin against AlCl3-induced behavioral deficits, indicating that Wnt signaling is essential for its neuroprotective action. Collectively, these findings demonstrate that cordycepin effectively mitigates AlCl3-induced neurotoxicity and AlCl3-induced locomotor and anxiety-related behavioral impairments in zebrafish through the modulation of inflammatory responses and Wnt signaling, supporting its potential as a therapeutic candidate for AD.
Parkinson's Disease (PD) represents the second most prevalent neurodegenerative condition which leads to the progressive destruction of dopaminergic neurons in the substantia nigra through oxidative stress mechanisms. The research evaluated Gallic Acid (GA) as a natural polyphenol with proven antioxidant properties for its ability to protect cells from 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity in SH-SY5Y dopaminergic cell models. The research used SH-SY5Y cells which received 1 mM MPP⁺ treatment alongside different GA concentrations (25, 50 and 100 µM) for 24 and 48 h. The CCK-8 assay measured cell viability while flow cytometry evaluated apoptosis and SOD and MDA levels determined oxidative status through SOD and Catalase and NO measurements. The addition of MPP⁺ resulted in a 32.74% decrease in cell viability at 48 h while simultaneously decreasing SOD and Catalase and NO levels and increasing MDA levels. The addition of 25 µM GA protected cells from damage by increasing their viability to 86.53% at 48 h and decreasing apoptotic cell numbers. Our results revealed that co-treatment with 25-50 µM GA effectively mitigated oxidative damage by preventing the depletion of catalase and NO levels. Furthermore, GA successfully reduced lipid peroxidation; specifically, 25 µM GA decreased MDA levels from 21.18 to 9.64 nM/mg protein at 48 h, thereby restoring the cellular antioxidant defense system against MPP+-induced oxidative stress. In conclusion, the present study demonstrates that GA exerts a significant neuroprotective effect in an in vitro PD model by modulating the endogenous antioxidant network and alleviating lipid peroxidation. By effectively reversing the depletion of crucial enzymes and reducing apoptosis, GA shows potential therapeutic efficacy against oxidative stress-associated neurodegeneration. These findings suggest that GA is a promising phytochemical candidate warranting further in vivo evaluation to clarify its long-term bioavailability and translational value.