Neurotoxicology最新文献

{"title":"Cannabidiol potentiates phenobarbital-induced cell death in the developing brain","authors":"Rubia Aparecida Fernandes ,&nbsp;João Vitor Melo Ribeiro ,&nbsp;Rodrigo Espindula Torres ,&nbsp;Giovanna Bruno Borges ,&nbsp;Larissa Gabrielly Ribeiro de Freitas ,&nbsp;Olagide Wagner de Castro ,&nbsp;Marcio Flávio Dutra Moraes ,&nbsp;Norberto Garcia-Cairasco ,&nbsp;Fabrício A. Moreira ,&nbsp;Victor Rodrigues Santos","doi":"10.1016/j.neuro.2025.06.005","DOIUrl":"10.1016/j.neuro.2025.06.005","url":null,"abstract":"<div><div>Epilepsy, affecting about 1 % of the global population, is more prevalent in children. The primary treatment is antiseizure medications (ASMs), with phenobarbital (PB) being the most common for pediatric cases. However, PB is effective in only two-thirds of patients and can cause side effects like cell death in developing brains. Early-life epilepsy treatment is particularly challenging, as many patients continue to experience poorly controlled seizures. Due to the limitations of current ASMs, cannabidiol (CBD) has emerged as a promising alternative, offering fewer side effects, neuroprotective properties, and efficacy in treatment-resistant cases. However, its impact on the developing brain remains unclear. In this study, we evaluated the safety profile of CBD in immature rodent brains, with particular attention to possible neurodegenerative effects as detected by Fluoro-Jade C histochemical staining (a sensitive marker of neuronal degeneration. CBD was administered at doses of 2, 20, and 200 mg/kg to postnatal day 7 wistar rats (male and female), with neuronal cell death assessed 24 h later. Results showed no overall increase in cell death compared to controls, suggesting comparable cell viability across doses. Notably, combining CBD 30 mg/kg with PB 75 mg/kg significantly increased neuronal death, with the PB+CBD group showing over twice the neurodegeneration of PB alone. These findings indicate that CBD may exacerbate PB-induced neurotoxicity, countering its expected neuroprotective benefits at certain doses. This highlights the need for caution when combining CBD with PB in pediatric epilepsy treatment.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 10-22"},"PeriodicalIF":3.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron species in cerebrospinal fluid and dementia risk in subjects with mild cognitive impairment: A cohort study","authors":"Teresa Urbano ,&nbsp;Bernhard Michalke ,&nbsp;Annalisa Chiari ,&nbsp;Carlotta Malagoli ,&nbsp;Roberta Bedin ,&nbsp;Manuela Tondelli ,&nbsp;Marco Vinceti ,&nbsp;Tommaso Filippini","doi":"10.1016/j.neuro.2025.06.006","DOIUrl":"10.1016/j.neuro.2025.06.006","url":null,"abstract":"<div><h3>Background</h3><div>Iron dysregulation has been implicated in the pathogenesis of dementia, since it is an essential nutrient for neuronal function, but also contributes to oxidative stress and neurotoxicity at elevated levels.</div></div><div><h3>Methods</h3><div>We enrolled 56 individuals with newly-diagnosed mild cognitive impairment (MCI) and followed over a 47-month period to monitor conversion to dementia according to baseline percentage concentrations of cerebrospinal fluid iron species.</div></div><div><h3>Results</h3><div>In this cohort, 28 participants developed Alzheimer’s dementia, 5 frontotemporal dementia, 2 Lewy body dementia, and 2 vascular dementia during the follow-up. Higher Fe-Ferritin was associated with a higher though statistically unstable dementia risk (hazard ratio-HR 1.36 for 10-unit % increase, 95 % confidence interval-CI 0.88–2.11), while Fe-Transferrin was linked to a lower risk (HR 0.65, 95 % CI 0.21–2.08) and inorganic Fe showed little association (HR 1.06, 95 % CI 0.80–1.40). Patterns of association were non-linear: inorganic Fe had a U-shaped association, with reduced risk at 25–40 % and increased risk above 45 %; Fe-Ferritin showed an inverted U-shaped relation with higher risk between 10 % and 20 %; Fe-Transferrin showed almost no relation with dementia risk. When considering conversion to Alzheimer’s dementia only, the relation was similarly U-shaped for inorganic Fe and almost null for Fe-Transferrin, while Fe-Ferritin showed a positive relation with risk above 15 %.</div></div><div><h3>Conclusions</h3><div>Despite the statistical imprecision of the estimates, our study provides novel evidence linking iron species in cerebrospinal fluid to dementia risk in individuals with MCI. These findings also underscore the importance of elemental speciation in dementia research.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"110 ","pages":"Pages 1-9"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of micro- and nanoplastics on blood-brain barrier crossing and neurotoxicity: Current evidence and future perspectives","authors":"Yu Ma,&nbsp;Haitao Yang,&nbsp;Shuyan Niu,&nbsp;Menghao Guo,&nbsp;Yuying Xue","doi":"10.1016/j.neuro.2025.06.003","DOIUrl":"10.1016/j.neuro.2025.06.003","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs), as emerging global pollutants, pose increasing threats to ecological environments and human health due to their widespread distribution and potential toxicity. Recent studies have demonstrated that MNPs not only enter the human body through multiple pathways but may also cross the blood-brain barrier (BBB), causing irreversible toxic damage to the central nervous system (CNS). This review summarizes the possible mechanisms of MNPs crossing the BBB, including the disruption of tight junctions and adherens juctions, paracellular transport, and endocytosis pathways. We focused on investigating the key roles of oxidative stress, inflammatory responses, mitochondrial dysfunction, and iron metabolism disorders in MNP-induced neurotoxicity, and discovered significant interconnections among these mechanisms. Furthermore, as carriers of pollutants, MNPs can facilitate co-exposure with other environmental contaminants such as heavy metals and persistent organic pollutants, producing synergistic toxic effects that further aggravate neurological damage. This review synthesizes the main research progress in this field, evaluates the potential toxicological impacts of MNPs on the CNS, and identifies key scientific questions that need to be addressed in future research, thereby providing theoretical foundations for in-depth studies of MNP neurotoxicity mechanisms and risk assessment.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 92-107"},"PeriodicalIF":3.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous study of cochleotoxicity and vestibulotoxicity of 3,3’- iminodipropionitrile in rats through several experimental approaches","authors":"M. Chalansonnet ,&nbsp;A. Thomas ,&nbsp;S. Boucard ,&nbsp;L. Merlen ,&nbsp;L. Guenot ,&nbsp;T. Venet ,&nbsp;E. Bernal ,&nbsp;B. Pouyatos","doi":"10.1016/j.neuro.2025.06.004","DOIUrl":"10.1016/j.neuro.2025.06.004","url":null,"abstract":"<div><div>Many industrial chemicals and clinical compounds are toxic to the inner ear. Some preferentially target the cochlea or vestibular structures, whereas others are harmful to both. The reasons behind these distinct ototoxic profiles remain poorly understood. The lack of a clear structure-toxicity relationship means that the prediction of the ototoxic potential of new drugs or chemical compounds is challenging and that <em>in vivo</em> testing is necessary. Vestibular or cochlear toxicity can be readily assessed independently, but we lack a method to simultaneously evaluate both functional and histological impairments in the same animals. Here, we describe and test such a method using 3,3’-iminodipropionitrile (IDPN), a compound known to induce hair cell loss in both cochlear and vestibular epithelia in the inner ear of rodents. Female Long-Evans rats were treated with IDPN (0, 150, 200, or 300 mg/kg/day for three days, i.p.). Auditory function was assessed using distortion product otoacoustic emissions (DPOAEs), while vestibular function was evaluated by measuring post-rotatory nystagmus (PRN) and anti-gravity reflexes: the tail-lift and air-righting tests. These tests were conducted before, and four weeks after treatment. Inner ears were collected to count hair cells and to examine the cochlea, utricle, saccule, and cristae by scanning electron microscopy (SEM). Auditory and balance deficits, as well as histological damage in all epithelia, were observed from 200 mg/kg/day, with a strong correlation between functional impairments and histological findings. The method described provides a comprehensive and unbiased means to compare vestibular and cochlear toxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 108-118"},"PeriodicalIF":3.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective role of root-derived betulinic acid from Artocarpus heterophyllus against arsenic-induced neurotoxicity in Drosophila melanogaster","authors":"B. Srihari ,&nbsp;K.V. Harish Prashanth","doi":"10.1016/j.neuro.2025.06.002","DOIUrl":"10.1016/j.neuro.2025.06.002","url":null,"abstract":"<div><div>Exposure to arsenic (<strong>As</strong>) has several adverse health effects, including cognitive deficits in humans and animals. In the present study, neuroprotective effect of <em>Artocarpus heterophyllus</em> root derived purified (98 %) betulinic acid powder (BAP) was examined against <strong>As</strong> induced neurotoxicity in <em>Drosophila melanogaster</em> (Oregon K, wild type). BAP was well characterized using HPTLC and LC-MS. Adult flies treated with <strong>As</strong> alone showed significant behaviour deficits, enhanced oxidative stress, neurotoxicity, and mortality. Further, flies were co-fed with BAP along with <strong>As</strong> (0.5 mM) for 7 days. As a result, BAP decreased the mortality rate in a concentration dependent manner against <strong>As</strong> toxicity (36–77 %). Behavioural studies indicated that flies treated with BAP had an improved locomotor phenotype and increased survival potential (18 days) for <strong>As</strong> induced flies. The biochemical analysis revealed that BAP restored <strong>As</strong> induced elevation of oxidative markers in both head and body regions of flies. BAP enhanced the activity of membrane-bound enzymes such as succinate dehydrogenase and NADH-cytochrome c reductase. Additionally, it was found that BAP alleviated cholinergic disturbances and dopamine depletion, which are associated with <strong>As</strong> and bring down abnormal brain architecture to normal. Overall, data suggests that BAP may provide neuromodulatory effects against <strong>As</strong>-induced neurotoxicity by suppressing oxidative stress and attenuating mitochondrial dysfunction.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 80-91"},"PeriodicalIF":3.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of insufficient sleep on subjective cognitive dysfunction: Exploring the moderating role of environmental factors at the census tract level","authors":"Emily Feldman,&nbsp;Amanda Bates,&nbsp;Danica C. Slavish","doi":"10.1016/j.neuro.2025.06.001","DOIUrl":"10.1016/j.neuro.2025.06.001","url":null,"abstract":"<div><div>Subjective cognitive decline (SCD) affects approximately 50 % of adults in the United States. Insufficient sleep (&lt; 7 h per night) and environmental hazards (e.g., exposure to traffic, hazardous chemicals, and air pollution) have each been identified as independent risk factors for cognitive dysfunction. Furthermore, sleep duration and environmental hazards may interact to exacerbate cognitive dysfunction. However, this has yet to be tested empirically using nationally representative data. Using the CDC PLACES and EPA EJScreen datasets, we examined the associations between insufficient sleep, environmental hazards (particulate matter &lt; 2.5 micrometers [PM_2.5], Superfund site proximity, traffic volume/proximity), and cognitive dysfunction across 58,014 U.S. Census tracts. Multiple regression analyses revealed that insufficient sleep and more environmental hazard exposure (i.e., higher levels of PM_2.5, and higher volume/closer proximity to traffic) were each significantly associated with an increased prevalence of cognitive dysfunction. Significant interactions also were observed between insufficient sleep and environmental hazards: In Census tracts with higher exposure to PM_2.5, closer proximity/higher volume of traffic, and farther proximity from a Superfund site there was a stronger association between insufficient sleep and cognitive dysfunction. These findings underscore the importance of addressing multiple environmental and behavioral risk factors in efforts to mitigate cognitive dysfunction. The synergistic effects observed highlight the need for integrated interventions that target both sleep health and environmental exposures to improve cognitive health outcomes and promote health equity, especially in underserved populations.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 66-79"},"PeriodicalIF":3.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Occupational aluminum exposure in northern China’s large-scale plants: Unveiling dual-pathway mediation of fasting blood glucose and systolic blood pressure in cognitive impairment among workers","authors":"Xin Guo ,&nbsp;Qiang Yang ,&nbsp;Fangyu Gao ,&nbsp;Baolong Pan ,&nbsp;Feng Gao ,&nbsp;Jingsi Zhang ,&nbsp;Shanshan Wang ,&nbsp;Xiaoting Lu ,&nbsp;Jing Song ,&nbsp;Linping Wang ,&nbsp;Huifang Zhang ,&nbsp;Qiao Niu","doi":"10.1016/j.neuro.2025.05.011","DOIUrl":"10.1016/j.neuro.2025.05.011","url":null,"abstract":"<div><h3>Introduction</h3><div>The relationship between aluminium exposure and cognitive impairment remains to be fully elucidated. Furthermore, studies examining potential mediating mechanisms are limited. Objectives: The study investigated the relationship between plasma aluminium (P-Al) levels and cognitive impairment (was defined as a Montreal Cognitive Assessment (MoCA) score &lt; 26 (i.e., mild cognitive impairment, MCI). The parallel mediating effects of systolic blood pressure (SBP) and fasting blood glucose (FBG) in the association between plasma aluminum (P-Al) and cognitive function were analyzed.</div></div><div><h3>Methods</h3><div>In this cross-sectional study of 229 aluminum workers (2024 survey), we conducted a three-step analysis:Descriptive statistics: Demographic and clinical variables were summarized as mean ± SD or median (IQR) for continuous data, and frequencies (%) for categorical data.Group comparisons: ANOVA with Bonferroni correction (normal-distributed variables) and Kruskal-Wallis H test were used to compare differences across P-Al quartiles (Q_{1 -} Q₄). Categorical variables were analyzed by χ² or Fisher’s exact tests.Mediation analysis: A dual-pathway mediation model (SBP and FBG as parallel mediators) was tested using bootstrap method. Effects were reported as standardized β coefficients with 95 % CIs.</div></div><div><h3>Results</h3><div>Workers in the high P-Al group had significantly lower MoCA scores (<em>P</em> &lt; 0.05) and higher incidence of cognitive dysfunction (<em>P</em> &lt; 0.05). <em>P</em>-Al levels were negatively correlated with MoCA scores (r = -0.716, <em>P</em> &lt; 0.05) and indirectly affected cognitive function through the parallel mediating pathways of SBP (7.41 % of indirect effect) and FBG (18.52 % of indirect effect), with the direct effect accounting for 74.07 % of the total effect.</div></div><div><h3>Conclusion</h3><div>Aluminum exposure is significantly associated with cognitive impairment, which may have dual effects on metabolic disorders (elevated FBG) and vascular damage (elevated blood pressure) pathways.In order to reduce the risk of occupational cognitive dysfunction, it is necessary to implement enhanced P-Al monitoring and metabolic index interventions for aluminium workers.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 59-65"},"PeriodicalIF":3.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental adversity, endoplasmic reticulum stress, and neurogenesis","authors":"Zuohui Zhang,&nbsp;Wen Wen,&nbsp;Di Hu,&nbsp;Hui Li,&nbsp;Hong Lin,&nbsp;Jia Luo","doi":"10.1016/j.neuro.2025.05.010","DOIUrl":"10.1016/j.neuro.2025.05.010","url":null,"abstract":"<div><div>Environmental adversity experienced during the prenatal period can include maternal nutritional deficiency, infectious agents, heavy metals, industrial chemicals, air pollution, medication, alcohol exposure, and substance use, as well as maternal factors such as diabetes. If these adversities occur during certain developmental time windows, they can significantly impact fetal development and have long-lasting neurobehavioral deficits. However, molecular mechanisms underlying the impact of environmental adversity remains unclear. The process by which new neurons form in the brain is neurogenesis. In certain brain regions neurogenesis continues throughout the lifespan and is essential for continued neurodevelopment and good mental health. Appropriate cellular responses to both extrinsic and intrinsic stressors require maintenance of the proteome, which relies on homeostasis of the endoplasmic reticulum (ER). Perturbations of ER homeostasis, such as the depletion of nutrients and disturbances in calcium or redox status, lead to abnormal accumulation of misfolded proteins and induce ER stress, which is monitored by the unfolded protein response (UPR). UPR is an adaptive reaction that restores protein homeostasis or triggers apoptotic cell death. Recent research indicates that ER stress during development can impair neurogenesis. We hypothesize that ER stress-mediated disruption of neurogenesis underlies the neurobehavioral deficits caused by environmental adversity. In this review, we discuss evidence of the impact that environmental adversities have on neurogenesis and the involvement of ER stress. We also discuss crosstalk across ER stress, oxidative stress, autophagy, and neuroinflammation, as well as potential therapeutic strategies that target ER stress/UPR for the treatment of neurobehavioral deficits associated with environmental adversities.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 32-45"},"PeriodicalIF":3.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144195813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective and gastroprotective effects of rutin and fluoxetine Co-supplementation: A biochemical analysis in Nauphoeta cinerea","authors":"Carlos Alonso Leite dos Santos ,&nbsp;Antonia Adeublena de Araújo Monteiro ,&nbsp;Mateus Santana de Deus ,&nbsp;Jean Paul Kamdem ,&nbsp;Antonia Eliene Duarte ,&nbsp;Mashal M. Almutairi ,&nbsp;Abid Ali ,&nbsp;Mohammad Ibrahim","doi":"10.1016/j.neuro.2025.05.009","DOIUrl":"10.1016/j.neuro.2025.05.009","url":null,"abstract":"<div><div>A significant portion of the global population is affected by depression, leading to considerable social and economic burdens. Although antidepressants such as fluoxetine are effective, their prolonged use is often associated with adverse side effects. This study investigated the biochemical effects of fluoxetine and rutin, individually and in combination, using the <em>Nauphoeta cinerea</em> model. Cockroaches were supplemented with the compounds for seven days, during which toxicity, body weight, and food intake were monitored. At the end of the treatment, neural and intestinal tissues were subjected to biochemical analyses, and <em>in silico</em> evaluations of the compounds were also performed. Co-supplementation with rutin (5 mg/mL) and fluoxetine (20 mg/mL) significantly reduced TBARS levels compared to fluoxetine alone and prevented the weight loss typically observed with fluoxetine treatment, despite similar food intake across groups. Rutin also mitigated the toxicity associated with fluoxetine administration. These findings suggest that rutin co-supplementation may attenuate fluoxetine-induced oxidative stress and toxicity, supporting its potential as a protective agent during antidepressant therapy.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 46-58"},"PeriodicalIF":3.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of P2X7R by hypericin improves diabetic cardiac autonomic neuropathy through the proteasome- Nrf2 - GPX4 signaling axis","authors":"Yusen Sun ,&nbsp;Xiaoqian Ma ,&nbsp;Yanning Gong ,&nbsp;Hongmin Guo ,&nbsp;Congfa Zhou ,&nbsp;Qixing Hu ,&nbsp;Zhiying Zhou ,&nbsp;Yuanyuan Zhang ,&nbsp;Shangdong Liang ,&nbsp;Guilin Li","doi":"10.1016/j.neuro.2025.05.008","DOIUrl":"10.1016/j.neuro.2025.05.008","url":null,"abstract":"<div><div>Hypericin (HYP), a primary active compound derived from Hypericum perforatum has been studied in the context of diabetes. The purpose of this study is to observe whether HYP can improve diabetic cardiac autonomic neuropathy (DCAN) and its possible mechanism. The current findings suggest that multiple drivers of ferroptosis in DCAN converge on the antioxidant protein nuclear factor erythroid 2-related factor 2(Nrf2). Overactivated P2X7 receptor (P2X7R) increases Nrf2 degradation by increasing proteasome activity through calcium ion accumulation. This work showed that HYP inhibited P2X7R expression, leading to elevated Nrf2 levels, thereby counteracting ferroptosis. This inhibition improves abnormal changes in cardiac function during the pathological process of DCAN in diabetic rats, including heart rate (HR), blood pressure (BP), heart rate variability (HRV), and sympathetic nerve discharge (SND). In summary, HYP enhances Nrf2 protein levels by suppressing P2X7R expression, reducing calcium-induced proteasome activity, and inhibits ferroptosis and inflammation. Thus, HYP alleviated DCAN progression.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"109 ","pages":"Pages 1-10"},"PeriodicalIF":3.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}