Neurotoxicology最新文献

{"title":"The combined effects of HSV-1 glycoprotein D and aluminum hydroxide on human neuroblastoma cells: Insights into oxidative DNA damage, apoptosis, and epigenetic modifications","authors":"Deniz Arca Çakır ,&nbsp;Anıl Yirün ,&nbsp;Selinay Başak Erdemli-Köse ,&nbsp;Göksun Demirel ,&nbsp;Jülide Secerli ,&nbsp;Merve Güdül-Bacanlı ,&nbsp;Pınar Erkekoğlu","doi":"10.1016/j.neuro.2025.03.007","DOIUrl":"10.1016/j.neuro.2025.03.007","url":null,"abstract":"<div><div>Herpes simplex virus type 1 (HSV-1) infections are a significant global health concern due to the virus's ability to evade apoptosis and establish lifelong latency in the peripheral nervous system. The specific viral components responsible for these effects remain unclear, necessitating individual examination of their molecular impacts. This study focused on investigating the effects of recombinant HSV-1 glycoprotein D (HSV-1 gD), a viral protein essential for host cell entry, and/or aluminum hydroxide, a known neurotoxic agent, on reactive oxygen species (ROS) production, apoptotic markers, and epigenetic modifications in SH-SY5Y neuroblastoma cells. Using inhibitory concentration 20 (IC₂₀) values for HSV-1 gD and aluminum hydroxide, experimental groups were established. Intracellular ROS levels, oxidative DNA damage, and the expression and activity of key apoptotic proteins were measured. Additionally, global DNA methylation, histone H3 and H4 acetylation, and the activities of histone deacetylases (HDAC3 and HDAC8) were evaluated. Results of the study showed that both HSV-1 gD and aluminum hydroxide independently increased ROS production and induced apoptosis in SH-SY5Y cells. Notably, significant alterations in epigenetic markers were observed, including decreased global DNA methylation and histone acetylation levels. These epigenetic modifications suggest potential underlying mechanisms for the neurotoxic effects of aluminum hydroxide and HSV-1 gD. In addition to the traditional suggestions for HSV-1 gD as an anti-apoptotic factor, our findings indicate that it may also contribute to neurotoxicity. This study provides new insights into the molecular interactions between viral components and neurotoxic agents and emphasizes the importance of epigenetic regulation in neuronal cell death.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 123-133"},"PeriodicalIF":3.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670322","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":"Effects of daily exposure to pyrethroid pesticides during infancy on children neurodevelopment at age four: A prospective study in rural Yunnan, China","authors":"Jirong Li ,&nbsp;Xiaoxiao Song ,&nbsp;Tong Luo ,&nbsp;Kek Khee Loo ,&nbsp;Shuqi Chen ,&nbsp;Tengwei Gui ,&nbsp;Xia Xiao ,&nbsp;Yan Li","doi":"10.1016/j.neuro.2025.03.006","DOIUrl":"10.1016/j.neuro.2025.03.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Exposure to pyrethroid pesticides (PYRs) of children in infancy at ages 1 and 2 may affect their neurodevelopmental outcomes at age 4.</div></div><div><h3>Objectives</h3><div>The study aimed to explore the longitudinal association of infancy PYRs exposure with neurodevelopment at age 4.</div></div><div><h3>Methods</h3><div>This study based on Xuanwei birth cohort study that started from January 2016 in rural Yunnan, China. Urine samples (n = 263) at ages 1 and 2 were tested for PYRs metabolites 3-phenoxybenzoic acid (3-PBA), 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA). PYRs metabolites were classified as low and high exposure using the 75th percentile values. Neurodevelopment of children aged 4 was assessed by Griffiths Development Scales-Chinese Edition (GDS-C). The development quotient below 85 was defined as low development level. Multiple linear regression and logistic regression were used to analyze the association of children’s PYRs exposure with their neurodevelopmental outcomes.</div></div><div><h3>Results</h3><div>Children’s PYRs metabolites detection rates were 98.48 % in infants at both age 1 and 2. The average levels of 3-PBA, 4-F-3-PBA and DBCA were 0.51 µg/L, 0.30 µg/L and &lt; 0.09 µg/L, respectively at age 1; and 0.88 µg/L, 0.82 µg/L, and 0.52 µg/L at age 2. The levels of three metabolites in 2-year-olds were higher than those in 1-year-olds. The children aged 4 had a general developmental quotient of 90.87 ± 11.37, with 28.14 % classified in low development level. Multiple linear regression analysis showed that higher 3-PBA level at 2-year-old was negatively associated with the quotient in locomotor (<em>β</em>=-14.61, <em>95 % CI:</em> −24.93, −4.30) and language (<em>β</em>=-10.89, <em>95 % CI:</em> −19.38, −2.41). Logistic regression displayed that higher 3-PBA level aged 2 was positively correlated with low development level in the language domain (<em>OR</em>=3.23, <em>95 % CI:</em> 1.33, 7.83), but negatively correlated with personal social domain (<em>OR</em>=0.23, 95 % <em>CI:</em> 0.07, 0.79).</div></div><div><h3>Conclusion</h3><div>Children were widely exposed to PYRs in infancy, which may impact on their neurodevelopment at age 4. Age 2 may be a sensitive window when PYRs exposure may negatively impact locomotor and language development. This study suggests that PYRs exposure should be minimized or avoided in child care, especially in children aged 2 years.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 105-112"},"PeriodicalIF":3.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625480","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 protective effect of Fingolimod upon visual behavior in a demyelination animal model is associated with synaptopathy prevention","authors":"Ana Carolina de Pádua ,&nbsp;Saulo Augusto Alves da Cruz ,&nbsp;Luiza dos Santos Heringer ,&nbsp;Greice Nascimento Pires ,&nbsp;Daniel Areias da Silva Raquita ,&nbsp;Jéssica dos Santos Tavares ,&nbsp;Pedro Souto Rodrigues ,&nbsp;Ana Beatriz Miranda de Sá ,&nbsp;Cintia Monteiro de Barros ,&nbsp;Sérgio Henrique Seabra ,&nbsp;Henrique Rocha Mendonça ,&nbsp;Renato Augusto DaMatta ,&nbsp;Sheila Espírito-Santo","doi":"10.1016/j.neuro.2025.03.004","DOIUrl":"10.1016/j.neuro.2025.03.004","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that causes motor, cognitive, and sensory dysfunctions, with visual disorder being one of the most prevalent. Synaptopathy has been recognized as one of the predominant pathogenic components of MS. We previous characterized inhibition of synaptopathy in the visual thalamus using the cuprizone-induced demyelination MS animal model. However, investigations about potential treatments to prevent synaptopathy have received little attention. Fingolimod is one of the most widely used and effective immunomodulators for controlling inflammatory relapses in MS, but few studies in MS animal models have tested its effect on synaptopathy. Given that none of these investigations used the cuprizone-induced demyelination model, our study investigated the preventive effect of Fingolimod on cuprizone-induced synaptopathy. Using Western blotting for synaptophysin, PSD-95, and gephyrin, as well as ultrastructural analysis, we demonstrated that daily intraperitoneal injections of Fingolimod (1 mg/Kg) protect against the increase of inhibitory synapses in cuprizone-treated mice. Fingolimod also prevented reduction of ARC immunolabeling, a sensor of neuronal activity, in cuprizone animals. Finally, through the visual Cliff test, Fingolimod was able to protect cuprizone animals against visual dysfunction. On the other hand, through immunostaining for CNPase, GFAP and IBA-1 we observed that Fingolimod failed to prevent demyelination and glial reactivity in the cuprizone animals. Taken together, the data indicate the potential of preventive treatment with Fingolimod against synaptopathy and visual dysfunction associated with inflammatory demyelination.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 113-122"},"PeriodicalIF":3.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630688","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":"Neuronal degeneration, mitochondrial dysfunction, and disturbance of movements induced by rotenone in the ascidian Styela plicata","authors":"Nathany da Silva Nogueira ,&nbsp;Taynan Motta Portal ,&nbsp;Thuany da Silva Nogueira ,&nbsp;Aurenita Emile Sá Miranda ,&nbsp;Eldo Campos ,&nbsp;Cintia Monteiro de Barros","doi":"10.1016/j.neuro.2025.03.003","DOIUrl":"10.1016/j.neuro.2025.03.003","url":null,"abstract":"<div><div>Parkinson's disease (PD), a movement disorder caused by dopaminergic degeneration in the midbrain, has been induced in various organisms after injection of different neurotoxins, such as rotenone (ROT), which affect mitochondrial complex I. Due to the conserved characteristics of ascidians, these animals constitute an interesting model for comparative and genetic studies of neurodegenerative diseases. In this study, we investigated the effects of ROT on the ascidian nervous system, evaluating apoptosis, catecholaminergic enzymes, behavioral deficits, and mitochondrial dysfunction. The study revealed morphological disorganization, inducing vacuolation in the ascidian brain. Neuronal death was confirmed by elevated transcriptional levels of caspase-3 and intense caspase-3 staining by immunofluorescence. In addition, there was reduced staining for dopa-decarboxylase (DDC), which is involved in dopamine biosynthesis. Furthermore, the mitochondria exhibited dysfunction in their membrane potential, followed by a decrease in the hydrolytic activity of ATP synthase and high transcriptional levels of ubiquitin. Finally, after administration of the drug l-3,4-dihydroxyphenylalanine (L-DOPA), recovery of motor movements was observed, as revealed by behavioral tests. Overall, the current research provides new data on the effects of rotenone on the ascidian brain, inducing neuronal death, mitochondrial dysfunction, and siphon movement disorders in the ascidian <em>Styela plicata</em>.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 69-80"},"PeriodicalIF":3.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610617","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":"1-Octen-3-ol exacerbates depression-induced neurotoxicity via the TLR4/NF-κB and Nrf2/HO-1 pathways","authors":"Hao Song ,&nbsp;Yongjiao Wang ,&nbsp;Liyuan Ren ,&nbsp;Anxiang Su ,&nbsp;Minhao Xie ,&nbsp;Hui Xu ,&nbsp;Jianhui Liu ,&nbsp;Yizhou Liu ,&nbsp;Wenjian Yang","doi":"10.1016/j.neuro.2025.03.002","DOIUrl":"10.1016/j.neuro.2025.03.002","url":null,"abstract":"<div><div>1-Octen-3-ol is a volatile compound widely found in various fungi and plants, and studies have suggested its potential role in the development of neurodegenerative diseases. However, the mechanism by which 1-octen-3-ol induces neural injury in rats remains unclear. In this study, we used aerosolized 1-octen-3-ol to treat depressive model rats to investigate its effects on neural injury behaviors and neurophysiology in SD rats. The results showed that 1-octen-3-ol significantly increased the lung index to 0.47, reduced the sucrose preference rate to 42.9 %, decreased spontaneous exploration in the open field test, and increased immobility time in the forced swim test. Furthermore, 1-octen-3-ol disrupted blood-brain barrier permeability by reducing the expression of tight junction proteins Occludin and Claudin-1. It also promoted corticosterone secretion, reduced the release of monoamines (serotonin and norepinephrine) and amino acid neurotransmitters (5-hydroxytryptophan), and increased pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), leading to neuroendocrine damage. Additionally, it reduced the expression of synaptic proteins (PSD-95, Synapsin, and NMDA1) and neurotrophic factors (NT3 and NT4), resulting in impaired neuroplasticity. Simultaneously, 1-octen-3-ol activated the TLR4/NF-κB inflammatory pathway and suppressed the expression of the Nrf2/HO-1 antioxidant pathway, exacerbating neural injury in rats. These findings provide a mechanistic basis for the exacerbation of depression-induced neural injury by 1-octen-3-ol.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 81-93"},"PeriodicalIF":3.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610618","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":"Role of dopaminergic RE1-silencing transcription factor (REST) in manganese-induced behavioral deficits and dysregulating dopaminergic and serotonergic neurotransmission in mice","authors":"Sanghoon Kim ,&nbsp;Edward Pajarillo ,&nbsp;Alexis Digman ,&nbsp;Itunu Ajayi ,&nbsp;Deok-Soo Son ,&nbsp;Michael Aschner ,&nbsp;Eunsook Lee","doi":"10.1016/j.neuro.2025.03.001","DOIUrl":"10.1016/j.neuro.2025.03.001","url":null,"abstract":"<div><div>Chronic exposure to elevated levels of manganese (Mn) induces manganism, a neurological disorder, exhibiting symptoms resembling Parkinson’s disease (PD). Mn is well known to dysregulate dopaminergic (DAergic) function, while the repressor element-1 silencing transcription factor (REST) induces protection against Mn-induced toxicity and several neurodegenerative diseases, including PD and Alzheimer’s disease. In the present study, we investigated if DAergic REST plays a role in Mn-induced neurotoxicity by assessing behavioral deficits and alteration of neurotransmitter levels using high-performance liquid chromatography with electrochemical detector (HPLC-ECD), and microdialysis between DAergic-specific REST-deleted (REST cKO) mice and REST loxP mice as wild-type (WT) controls. Mice were exposed to Mn (330 μg, daily intranasal instillation for 3 weeks), followed by assessment of locomotor activity and novel object recognition, and subsequent brain dissection. Neurotransmitters, including DA, serotonin (5-HT), norepinephrine (NE), and glutamate, were analyzed in different brain regions, such as the striatum, midbrain, cortex, hippocampus, and cerebellum. After Mn exposure, extracellular DA levels in the striatum were measured by HPLC-microdialysis. The results showed that DAergic REST deletion exacerbated Mn-induced behavioral deficits and decreased DA levels in the nigrostriatal regions of WT mice. REST cKO increased DA turnover rates (DOPAC/DA and HVA/DA) by 10-fold in the nigrostriatal regions, showing lesser effects in other brain regions. Mn decreased extracellular DA levels, as measured by microdialysis, in the striatum in both genotypes. Mn decreased cortical NE levels in both genotypes and further exacerbated in REST cKO, while Mn decreased nigrostriatal NE levels only in REST cKO mice. REST cKO reduced 5-HT levels in all brain regions tested compared to WT mice. Mn increased glutamate and GABA levels in the striatum and midbrain, while these Mn effects were not altered by REST cKO. Taken together, our findings demonstrate that DAergic REST deficiency exacerbates Mn-induced motor and cognitive deficits along with dysregulation of neurotransmitters, mainly DA, 5-HT, and NE, suggesting that DAergic REST is important in Mn-induced dysregulation of monoaminergic neurotransmission.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 57-68"},"PeriodicalIF":3.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586425","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 see-saw effect of neuroactive steroids and endocrine disrupting compounds on maternal mental health status","authors":"S. Aishwarya ,&nbsp;V.M. Vinodhini ,&nbsp;P. Renuka ,&nbsp;M. Anuradha ,&nbsp;R. Arul Saravanan","doi":"10.1016/j.neuro.2025.02.007","DOIUrl":"10.1016/j.neuro.2025.02.007","url":null,"abstract":"<div><h3>Background</h3><div>Antepartum depression, a non-psychotic mood disturbance occurring during pregnancy, is influenced by hormonal fluctuations and environmental endocrine disruptors. Despite its association with adverse postpartum outcomes, it has been studied to a limited extent. Hence, this study aims to investigate the association of neuroactive steroids, endocrine-disrupting compounds, and nutritional status of pregnant women with the manifestations of antepartum depressive symptoms.</div></div><div><h3>Materials and methods</h3><div>This cross-sectional study assessed 400 pregnant women in their third trimester for depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) and evaluated for severity using the Beck Depression Inventory-II. The concentrations of allopregnanolone, DHEA-S, bisphenol A, methyl paraben, estradiol, progesterone, oxytocin, vitamin B₁₂, folic acid, vitamin D, iron, magnesium and zinc were analysed. Statistical analysis included Mann Whitney U test, Chi-square test, Spearman Correlation, and Logistic regression.</div></div><div><h3>Results</h3><div>The prevalence of antepartum depressive symptoms was 23 %. Allopregnanolone, DHEA-S, bisphenol A, methyl paraben, estradiol, oxytocin, and TSH levels were associated with depressive symptoms. Reduced levels of allopregnanolone, DHEA-S, and estradiol, along with elevated bisphenol A levels, were identified as significant independent risk factors for antepartum depressive symptoms. Selective micronutrient deficiency was also noted. Risk cutoff for antepartum depressive symptoms was established for allopregnanolone (≤17.9 ng/ml), DHEA-S (≤0.20 µg/ml), bisphenol A (≥2027.1 pg/ml), and methyl paraben (≥1.15 µg/ml).</div></div><div><h3>Conclusion</h3><div>Our study on 400 antepartum women showed a 23 % prevalence of depressive symptoms, with significant association reported with reduced neuroactive steroids, elevated endocrine disruptors, lower reproductive hormones, and micronutrient deficiency. These findings emphasize the need for comprehensive screening, monitored nutritional supplementation, and hormonal assessments in effectively managing pregnancy-related depressive symptoms.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 48-56"},"PeriodicalIF":3.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551859","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":"A prospective study of a whole blood metal mixture and depressive symptoms among Black women from Detroit, Michigan","authors":"Samantha Schildroth ,&nbsp;Birgit Claus Henn ,&nbsp;Ruth J. Geller ,&nbsp;Amelia K. Wesselink ,&nbsp;Kristen Upson ,&nbsp;Anissa I. Vines ,&nbsp;Marco Vinceti ,&nbsp;Quaker E. Harmon ,&nbsp;Donna D. Baird ,&nbsp;Ganesa Wegienka ,&nbsp;Lauren A. Wise","doi":"10.1016/j.neuro.2025.02.005","DOIUrl":"10.1016/j.neuro.2025.02.005","url":null,"abstract":"<div><div>Exposure to metals has been previously associated with depressive symptoms, but few studies have considered potential effects of metal mixtures. In addition, few previous studies have been conducted among Black women, who are disproportionately at risk for exposure to some metals and greater depression incidence and severity. We analyzed data from the Study of Environment, Lifestyle, and Fibroids (SELF), a prospective cohort study of reproductive-aged Black women from Detroit, to examine associations between a mixture of metals, metalloids, and trace elements (“metals”) and depressive symptoms (n = 1450). SELF participants self-identified as Black or African American and were 23–34 years of age at enrollment. We collected covariate information on structured questionnaires and whole blood samples at baseline. We quantified 17 metals in whole blood using inductively coupled plasma mass spectrometer triple quadruple or Direct Mercury Analyzer-80. Participants reported depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D) at the 20-month follow-up visit, where higher CES-D scores reflected greater depressive symptoms. We used quantile-based g-computation to estimate the cumulative association of the metal mixture with CES-D scores, adjusting for age, household income, educational attainment, body mass index, smoking status, alcohol intake, and parity. We estimated beta coefficients (with 95 % confidence intervals [CI]) as the percent difference in CES-D scores per quartile increase in all metals. A one-quartile increase in the metal mixture was associated with 14.8 % lower (95 % CI=-26.7 %, −1.1 %) CES-D scores, reflecting lower depressive symptoms. The mixture association was driven by nickel, copper, cesium, molybdenum, and lead. Other neurotoxic metals (cadmium, arsenic, mercury, chromium) were associated with greater depressive symptoms. Findings from this study suggest that exposure to a mixture of metals may affect depressive symptoms in Black women, with individual metals acting in opposing directions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 94-104"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541539","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":"Hippocampal apoptosis: Molecular mechanisms triggered by toxic cannabinoid exposure: A narrative review","authors":"Habibeh Mashayekhi-sardoo ,&nbsp;Mahdiyeh Hedayati-Moghadam ,&nbsp;Yousef Baghcheghi","doi":"10.1016/j.neuro.2025.02.006","DOIUrl":"10.1016/j.neuro.2025.02.006","url":null,"abstract":"<div><div>Hippocampal apoptosis is increasingly recognized as a significant consequence of toxic cannabinoid exposure, with profound implications for cognitive function and mental health. This narrative review comprehensively examines the molecular mechanisms underlying cannabinoid-induced apoptosis, focusing on the interplay of various bioactive compounds and their effects on neuronal integrity. We begin by discussing the key players in cannabinoid biology, followed by a synthesis of findings from animal and clinical studies that highlight the neurotoxic potential of cannabinoids. Central to our analysis are the roles of neuroinflammation and oxidative stress, which exacerbate neuronal damage and contribute to cell death. The activation of cannabinoid receptors, particularly CB1 and CB2, is scrutinized for its dual role in mediating neuroprotective and neurotoxic effects. We explore calcium dysregulation as a critical mechanism that leads to excitotoxicity, mitochondrial dysfunction, and the activation of pro-apoptotic pathways. Additionally, we address the inhibition of anti-apoptotic proteins, induction of endoplasmic reticulum (ER) stress, and disruption of neurotransmitter systems, all of which further facilitate apoptosis in hippocampal neurons. Alterations in neurotrophic factor levels are also examined, as they play a vital role in neuronal survival and plasticity. Ultimately, this review underscores the multifaceted nature of cannabinoid-induced hippocampal apoptosis and calls for further research to elucidate these complex interactions, aiming to inform clinical practices and public health policies regarding cannabinoid use. The findings presented herein highlight the urgent need for a nuanced understanding of the risks associated with cannabinoid exposure, particularly in vulnerable populations.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 28-47"},"PeriodicalIF":3.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534865","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":"Tanshinone IIA mitigates postoperative cognitive dysfunction in aged rats by inhibiting hippocampal inflammation and ferroptosis: Role of Nrf2/SLC7A11/GPX4 axis activation","authors":"Yan Yang ,&nbsp;Bo Wang ,&nbsp;Yichen Jiang ,&nbsp;Wan Fu","doi":"10.1016/j.neuro.2025.02.003","DOIUrl":"10.1016/j.neuro.2025.02.003","url":null,"abstract":"<div><h3>Objective</h3><div>Postoperative cognitive dysfunction (POCD) is a common and debilitating complication in elderly patients following surgery, leading to increased morbidity and reduced quality of life. This study aims to investigate the neuroprotective effects of Tanshinone IIA, a lipophilic compound derived from <em>Salvia miltiorrhiza</em>, in an aged rat model of POCD, and explore its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>POCD model was established by a modified abdominal exploratory laparotomy. Rats were then intraperitoneally administered with Tanshinone IIA (10 mg/kg, 20 mg/kg, or 40 mg/kg) for 30 days. Cognitive functions were assessed using the morris water maze, novel object recognition test, and Y-maze test. Synaptic structures in the hippocampal CA1 region were examined by electron microscopy. Inflammatory and ferroptosis pathways were evaluated by measuring inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-4), nitric oxide synthase (iNOS) activity, lipid peroxidation products (malondialdehyde [MDA]; 4-hydroxy-2-nonenal [4-HNE]), Fe^2 + levels, and antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH]) using ELISA and commercial kits. mRNA and proteins levels were quantified by real-time quantitative polymerase chain reaction and western blot analysis.</div></div><div><h3>Results</h3><div>Tanshinone IIA significantly ameliorated cognitive deficits in aged POCD rats according to behavioral tests. It also restored synaptic ultrastructure in the hippocampal CA1 region and upregulated the expressions of synaptic proteins, including synapsin-1 and PSD-95. In addition, Tanshinone IIA effectively suppressed the hippocampal inflammatory pathway, as evidenced by the decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), an increased level of the anti-inflammatory cytokine IL-4, and the upregulation of the iNOS/NO pathway in the hippocampus. Furthermore, Tanshinone IIA mitigated ferroptosis by reducing MDA and 4-HNE contents, lowering Fe²⁺ level, and enhancing SOD activity and GSH level. Notably, Tanshinone IIA activated the Nrf2/SLC7A11/GPX4 axis in the hippocampus of aged POCD rats.</div></div><div><h3>Conclusion</h3><div>These findings suggest that Tanshinone IIA exerts neuroprotective effects in an aged rat model of POCD by attenuating hippocampal inflammation and ferroptosis, primarily through the activation of the Nrf2/SLC7A11/GPX4 axis.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"107 ","pages":"Pages 62-73"},"PeriodicalIF":3.4,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437409","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}