Neurotoxicology最新文献

{"title":"Neuroprotective effect of Licochalcone A against aluminum chloride-induced neurotoxicity by reducing Aβ accumulation, oxidative stress and inflammatory reaction","authors":"Zhijuan Tang ,&nbsp;Fang Wang ,&nbsp;Jintao Lv ,&nbsp;Gaohong Yang ,&nbsp;Xinchun Shen ,&nbsp;Fei Zeng ,&nbsp;Lingling Meng ,&nbsp;Wen Zhou ,&nbsp;Libin Zhan ,&nbsp;Zebin Weng","doi":"10.1016/j.neuro.2025.04.011","DOIUrl":"10.1016/j.neuro.2025.04.011","url":null,"abstract":"<div><div>Excessive aluminum exposure is a contributing factor in several neurodegenerative diseases. Natural plant compounds such as Licochalcone A have been shown to have significant neuroprotective effects <em>in vivo</em> and <em>in vitro</em>. In this study, we aim to elucidate the neuroprotective effect of Licochalcone A against aluminum chloride-induced neurotoxicity and its possible mechanism. Adult zebrafish and PC12 cells were used as animal and cell models. Zebrafish and PC12 cells were treated with excessive aluminum trichloride (100 μg/L aluminum chloride hexahydrate solutions for zebrafish or 500 μM Al-malt solution for PC12 cells) to cause neuronal damage. The neuroprotective effect of Licochalcone A was evaluated by measuring ROS production, Aβ_1–42 accumulation, inflammatory cytokines, neuronal apoptosis-associated genes, and MAPK pathway-related proteins to elucidate the mechanism of Licochalcone A against aluminum chloride-induced neurotoxicity. Licochalcone A effectively reduced the level of ROS production and inflammatory cytokines in both zebrafish and PC12 cells treated with excessive aluminum trichloride. In addition, Licochalcone A reduced the expression of BACE1 and generation of Aβ_1–42 as well as the expression of p-JNK and MAPK, the key factor of the MAPK pathway. These results indicated that Licochalcone A has a remarkable neuroprotective effect against neurotoxicity induced by aluminum and has a high potential in the development of therapeutic drugs for neurodegenerative diseases.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 295-305"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892056","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":"Cumulative risk assessment as the pathway to public health protection for behavioral neurotoxicity","authors":"Deborah A. Cory-Slechta ,&nbsp;Cynthia J. Downs ,&nbsp;Marissa Sobolewski","doi":"10.1016/j.neuro.2025.04.015","DOIUrl":"10.1016/j.neuro.2025.04.015","url":null,"abstract":"<div><div>The formulation of adverse outcome pathways (AOPs) based on high-throughput <em>in vitro</em> new approach methods linking biochemical/mechanistic data with an apical endpoint considered an adverse outcome (AO), is increasingly proposed to accelerate the process of risk assessment for environmental chemical exposures. While a laudable goal, this approach ignores the extensive evidence demonstrating context-dependence of neurotoxicological consequences, including behavioral toxicity of chemical exposures. Such contextual modifiers can include environmental conditions (poverty, psychosocial stress, behavioral experience/history), physiological conditions (sex, period of exposure, nutritional status, brain region, exposure parameters), and genetic background. Context dependence represents a serious omission for AOP formulation because an environmental context can alter a chemical’s molecular targets, or potentially enhance toxicity through interactions with other contextual conditions, thus leading to potential underestimation of neurological risks due to such exposures. The integrative physiological basis of AOs requires cumulative risk assessments that model environmental contexts across scales of biology, i.e., integration and testing in whole-animal models. AOPs contribute to the derivation of cumulative risk considerations regarding factors to incorporate into cumulative risk assessments by defining risk factors with shared biological targets. Epidemiological and animal model studies can provide information to prioritize interactive effects of greatest magnitude. Additionally, a focus on how a single risk factor in different physiological contexts may attribute risk across multiple neurologic conditions, rather than to a single unique condition, would provide broader public health protection. Realistic acknowledgement of context-dependence is requisite to understanding both the etiological basis of neurological diseases and disorders and to human health protection.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 400-411"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972370","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":"Developmental neurotoxicity of bisphenol F and bisphenol S in animal model systems: A literature review","authors":"Ricardo Cantua,&nbsp;Kimberly Mulligan","doi":"10.1016/j.neuro.2025.04.008","DOIUrl":"10.1016/j.neuro.2025.04.008","url":null,"abstract":"<div><div>Neurodevelopmental disorders have complex etiologies, stemming both from genetic and environmental risk factors, including gestational exposure to bisphenol A (BPA). BPA is an endocrine-disrupting chemical widely used in the synthesis of plastics and epoxy-resins. In 2012, the Food and Drug Administration issued a ban on the use of BPA in certain baby and childhood products, which contributed to the proliferation of BPA-free products. To make products without BPA, plastic and epoxy manufacturers often use chemical analogs, including bisphenol F (BPF) and bisphenol S (BPS). However, the structural and biochemical similarities BPF and BPS share with BPA suggest they may have similar molecular and cellular impacts on the developing nervous system, despite consumers generally regarding BPA-free products as safer alternatives. In this review, we synthesized all available peer-reviewed primary literature to date reporting on the neurodevelopmental impacts of BPF and/or BPS in animal models. In total, 61 papers were identified as relevant to the topic, including evaluation of BPF- and BPS-associated neurodevelopmental phenotypes such as changes in neurodevelopmental gene expression, the proliferation and differentiation of neural stem cells, synaptogenesis, central nervous system morphology, neuronal cell death, and behavior. Though less extensively studied than BPA, the collective works described here indicate that BPF and BPS can act as developmental neurotoxicants in animal models, urging further mechanistic and epidemiological analyses of these bisphenol analogs, as well as a reconsideration by regulatory agencies of policies surrounding their usage.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 263-280"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892057","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":"Multi-behavioral fingerprints can identify potential modes of action for neuroactive environmental chemicals","authors":"Nadia K. Herold ,&nbsp;Sebastian Gutsfeld ,&nbsp;David Leuthold ,&nbsp;Chloe Wray ,&nbsp;Julia Spath ,&nbsp;Tamara Tal","doi":"10.1016/j.neuro.2025.05.001","DOIUrl":"10.1016/j.neuro.2025.05.001","url":null,"abstract":"<div><div>There is a lack of confidence in the relevance of zebrafish-based behavior data for chemical risk assessment. We extended an automated Visual and Acoustic Motor Response (VAMR) new approach method (NAM) in 5-day post-fertilization (dpf) zebrafish to include 26, behavior-based endpoints that measure visual-motor responses, visual and acoustic startle responses, habituation learning, and memory retention. A correlation analysis from 5159 control larvae revealed that more complex endpoints for learning- and memory-related behavior yielded unique behavior patterns. To build confidence in the VAMR NAM, we established neuroactivity fingerprints using concentration-response profiles derived from 63 reference chemicals targeting neurotransmission, neurodevelopmental signaling, or toxicologically-relevant pathways. Hierarchical clustering revealed diverse toxicity fingerprints. Compounds that targeted the N-Methyl-D-aspartic acid (NMDA) or gamma-aminobutyric acid type A (GABA_A) receptors reduced habituation learning. Pathway modulators targeting peroxisome proliferator-activated receptor delta (PPARδ) or gamma (PPARγ), GABA_A, dopamine, ryanodine, aryl hydrocarbon (AhR), or G-protein-coupled receptors or the tyrosine kinase SRC inappropriately accelerated habituation learning. Reference chemicals targeting GABA_A, NMDA, dopamine, PPARα, PPARδ, epidermal growth factor, bone morphogenetic protein, AhR, retinoid X, or α2-adreno receptors triggered inappropriate hyperactivity. Exposure to GABA_A receptor antagonists elicited paradoxical excitation characterized by dark-phase sedation and increased startle responses while exposure to GABA_A/B receptor agonists altered the same endpoints with opposite directionality. Relative to reference chemicals, environmental chemicals known to be GABA receptor antagonists (Lindane, Dieldrine) or agonists (Tetrabromobisphenol A (TBBPA)) elicited predicted behavior fingerprints. When paired with the phenotypically rich VAMR NAM, behavior fingerprints are a powerful approach to identify neuroactive chemicals.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 377-399"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003025","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 isobenzofuran-1(3H)-one derivative against neuronal injury and enzyme activity dysregulation induced by bipyridyl herbicide in adult male rats","authors":"Iára Mariana Léllis Ribeiro ,&nbsp;Ana Luiza Sciandretti Albuquerque ,&nbsp;Lucas Gabriel Vieira ,&nbsp;Laser Antonio Machado Oliveira ,&nbsp;Frank Silva Bezerra ,&nbsp;Róbson Ricardo Teixeira ,&nbsp;Rodrigo Cunha Alvim de Menezes ,&nbsp;Katiane de Oliveira Pinto Coelho Nogueira","doi":"10.1016/j.neuro.2025.05.002","DOIUrl":"10.1016/j.neuro.2025.05.002","url":null,"abstract":"<div><div>Diquat (DQT) is a bipyridyl herbicide widely used in agriculture. The exposure to DQT may overwhelm the antioxidant system, leading to oxidative damage in organs such as the brain, liver, and kidneys. The brain is particularly susceptible to oxidative damage because of its high oxygen consumption, relatively low antioxidant levels, and limited regenerative capacity. Faced with stressful agents, using compounds capable of repairing and replacing oxidized biomolecules is a promising option to maintain redox homeostasis. Isobenzofuran-1 (3H)-one derivative (named compound 1) emerges as a potential candidate to control the redox imbalance induced by DQT in the brain. The present study aimed to explore the neurotoxicity mechanisms of DQT and the antioxidant potential of compound 1 within the hippocampus and cortex, brain regions impacted by AD, using in vitro and in vivo models. Treatment with compound 1 reduced intracellular levels of ROS and lipid peroxidation in primary cultures of hippocampal neurons caused by DQT. Moreover, compound 1 significantly elevated GSH levels in the brains of rats subjected to DQT treatment. Treatment with compound 1 also decreased lipid peroxidation and carbonylated protein levels in the brain induced by DQT. The exposure to DQT resulted in neuronal injury in the hippocampus. Compound 1, protected against neuronal damage in CA1 and dentate gyrus hippocampal regions. The findings of our study suggest that DQT leads to oxidative damage and neuronal death in both the hippocampus and the cortex. Furthermore, compound 1 exhibits neuroprotective qualities by reducing oxidative damage caused by exposure to DQT.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 368-376"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950542","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":"Pharmacological effects and pharmacokinetics of the novel synthetic cathinone α-pyrrolidinoisohexanophenone (α-PiHP) compared with α-pyrrolidinovalerophenone (α-PVP) in mice","authors":"Anne Marte Baarset ,&nbsp;Synne Steinsland ,&nbsp;Elisabeth Nerem ,&nbsp;Jannike Mørch Andersen ,&nbsp;Michael H. Baumann ,&nbsp;Inger Lise Bogen","doi":"10.1016/j.neuro.2025.05.005","DOIUrl":"10.1016/j.neuro.2025.05.005","url":null,"abstract":"<div><div>α-Pyrrolidinoisohexanophenone (α-PiHP) is a novel pyrovalerone cathinone that was among the top five synthetic cathinones seized by weight across Europe in 2022. Since α-PiHP was first reported to the European Union Drugs Agency in December 2016, its use has been linked to severe poisonings and fatalities. The present study employed in vitro and in vivo methods to evaluate the pharmacological effects and pharmacokinetics of α-PiHP in mice, using α-pyrrolidinovalerophenone (α-PVP) as a comparator drug. Our findings show that α-PiHP is a highly potent inhibitor of dopamine (DA) and norepinephrine (NE) reuptake, with a potency equivalent to that of α-PVP for the DA transporter (DAT) and slightly lower for the NE transporter (NET). The strong and targeted inhibition of DAT and NET indicates that α-PiHP has a high potential for misuse. In vivo studies showed that both drugs induced a significant increase in body temperature compared to the control, however, higher doses of α-PiHP (ED₅₀: 4.0 mg/kg) were required to elicit locomotor activity compared to α-PVP (ED₅₀: 1.1 mg/kg). Pharmacokinetic analyses revealed that α-PiHP reached approximately 40 % lower C_max levels in blood and brain, which could explain the lower potency of α-PiHP in inducing locomotor activity. Overall, these findings highlight the need to evaluate the pharmacological characteristics of evolving synthetic cathinones, such as α-PiHP, to better understand the associated health risks.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 412-421"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094402","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 developmental neurotoxicity of Dechlorane Plus, a recently identified persistent organic pollutant: An in silico study","authors":"Fuat Karakuş ,&nbsp;Zübeyde Tanrıverdi ,&nbsp;Burak Kuzu","doi":"10.1016/j.neuro.2025.04.013","DOIUrl":"10.1016/j.neuro.2025.04.013","url":null,"abstract":"<div><div>Dechlorane Plus (DP), a polychlorinated flame retardant, has recently been recognized as a persistent organic pollutant. In this study, the molecular mechanisms and targets associated with DP-induced developmental neurotoxicity (DNT) in humans were investigated through network toxicology, multi-level bioinformatics approaches, and molecular docking. Through comprehensive database analysis, 32 potential targets associated with DP-induced DNT were identified. Gene Ontology terms enrichment analysis revealed significant enrichment in pathways related to the nervous system processes, GABA-A receptor complex, and various binding and channel activities. KEGG pathway enrichment analysis indicated that DP-induced DNT is mediated through complex interactions involving neuroactive ligand-receptor interaction pathways. Further analysis using GeneMANIA, STRING, Cytoscape tools, and MCODE identified 11 hub targets, including GABRA1, GABRB1, GABRB3, and GABRG2 as key targets. Molecular docking revealed that DP binds to the GABRB3-GABRA1-GABRG2 protein complex to a degree comparable to the control bicuculline, a potent and selective antagonist of the GABA-A receptor. These findings suggest that DP may have antagonistic effects on the GABA-A receptor, potentially increasing neuronal excitability. This study offers valuable insights into the molecular mechanisms underlying DP-induced DNT and provides data for <em>in vitro</em> or <em>in vivo</em> studies.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 318-327"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907782","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":"Infant cognitive home environment as a moderator for the association of prenatal lead on child language","authors":"Amanda C. Wylie ,&nbsp;Michael T. Willoughby ,&nbsp;Rebecca C. Fry ,&nbsp;W. Roger Mills-Koonce ,&nbsp;Sarah J. Short ,&nbsp;Cathi B. Propper","doi":"10.1016/j.neuro.2025.04.010","DOIUrl":"10.1016/j.neuro.2025.04.010","url":null,"abstract":"<div><div>Exposure to lead during early life, including in pregnancy, is toxic to neurodevelopment. Though public health initiatives have resulted in an overall reduction in lead exposure levels, lead remains a significant environmental hazard, requiring innovative efforts to mitigate the burden of early life lead. This study explored whether positive postnatal social experiences in the forms of positive caregiving and a rich cognitive home environment moderate the associations of prenatal lead on child neurodevelopmental outcomes including language skills, effortful control, and executive function skills. We leverage an analytic sample (<em>N</em> = 107) drawn from a prospective cohort of mother-infant dyads. Prenatal lead was measured from maternal urine, positive caregiving from observational methods, and cognitive home environment from a validated questionnaire. Results reveal a negative association of prenatal lead on child language when the cognitive home environment in infancy was poor (<em>β</em>=-0.32, <em>p</em> = 0.04) but not when the cognitive home environment in infancy was rich (<em>β</em>=0.20, <em>p</em> = 0.16). This buffering effect was not observed for the child outcomes of effortful control or executive function skills. Our results encourage future research into the provision of a rich cognitive home environment as a means of mitigating the detrimental effects of prenatal lead exposure on early child language skills.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 306-317"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904539","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 peripheral irritant motor response (PIMR) assay to identify chemical-induced locomotor deficits in larval zebrafish (Danio rerio)","authors":"Demetrius McAtee,&nbsp;Ahmed Abdelmoneim","doi":"10.1016/j.neuro.2025.05.003","DOIUrl":"10.1016/j.neuro.2025.05.003","url":null,"abstract":"<div><div>Zebrafish (<em>Danio rerio</em>) behavioral assays provide valuable insights into the effects of environmental chemicals on the developing nervous system, primarily through motor responses triggered by stimuli-induced CNS activation. However, as these responses rely on the locomotor integrity of larval zebrafish, chemical-induced impairments to their locomotor capacity could obscure behavioral observations and confound findings concerning the developmental neurotoxicity of the tested chemicals. This limitation emphasizes the need for supporting assays designed to specifically evaluate the locomotor capacity of larval zebrafish. In the present study, we evaluated the use of peripheral irritant-elicited motor responses as a method to identify chemical-induced locomotor deficits. The motor activity of 120 hours post-fertilization (hpf) zebrafish larvae exposed to different concentrations of two peripheral stimulants—mustard oil and cinnamon oil—was evaluated. Subsequently, we assessed changes to central (visual and acoustic) and peripheral (irritant) motor responses after tricaine-s (MS-222; neurodepressant) and tubocurarine (neuromuscular blocker) exposures. Additional investigations were also carried out to assess the central and peripheral motor activity of larvae after developmental exposures (114 h) to lead (Pb) and cadmium (Cd)—two suggested developmental neurotoxic environmental contaminants. Our observations revealed that exposure to mustard oil (12.5 µM) elicits the strongest motor response. Larvae exposed to MS-222 showed decreases in motor responses to visual and acoustic stimuli, but the same exposure induced limited effects on motor responses elicited by the peripheral irritant. Exposure to tubocurarine depressed all motor responses examined. Finally, both Pb and Cd exposures induced hypoactivation of central motor responses, but only Cd showed a significant depression in the peripheral irritant motor response (PIMR) in both intact and developmentally deformed larvae. This finding suggests that loss of locomotor capacity might be confounding the behavioral observations associated with Cd exposures. This research underscores the utility of this zebrafish-based PIMR assay in elucidating locomotor impairments induced by chemicals, which may obscure the behavioral findings of motor response assays designed to evaluate developmental neurotoxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 344-353"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946650","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":"Urolithin improves α-synuclein aggregation and DNMT1 expression in rotenone model of Parkinson’s disease","authors":"Ankita Devi ,&nbsp;Sharon Munagalasetty ,&nbsp;Pardeep Kumar ,&nbsp;Rahul Kumar ,&nbsp;Vasundhra Bhandari ,&nbsp;Manoj P. Dandekar","doi":"10.1016/j.neuro.2025.04.009","DOIUrl":"10.1016/j.neuro.2025.04.009","url":null,"abstract":"<div><div>α-synuclein aggregation is a key hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). We examined the multi-targeting effects of urolithin (UA, UB, UC, UD, UE, UM5, and UM6) against α-synuclein aggregation using an <em>in-silico</em> and <em>in-vitro</em> approach. For <em>in-silico</em> analysis, several potential targets were selected like 1XQ8 (α-synuclein monomer), 1H1D (catechol-o-methyltransferase), 2BK3 (monoamine oxidase-B), 3IAM (NADH dehydrogenase), 4I5I (Sirtuin-1), and 5WVO [DNA methyltransferase-1], which play key role in α-synuclein aggregation, levodopa degradation, and mitochondrial dysfunction. In protein-protein docking analysis, 5HF9 (acetylcholinesterase, AChE) was found to interact with 1XQ8 dimer, forming a more stable complex with two additional H-bonds and one salt bridge, which indicates AChE's role as a nucleator in α-synuclein aggregation. In ligand docking and molecular dynamic studies, urolithin-A (UA) formed a more stable complex with 1XQ8, 4I5I, and 5WVO compared to specific inhibitor 1XQ8-ZPD2 and specific activator 4I5I-resveratrol. While other urolithins (UE, UM5, UC, and UD) displayed a more stable complex with 5HF9, 2BK3, 1H1D, and 3IAM compared to specific inhibitor 5HF9-physostigmine, 2BK3-selegiline, 1H1D-BIA, and specific activator 3IAM-resveratrol complexes, respectively. The blood-brain barrier permeability of UA (QPlogBB: −0.97) was predicted to be more than levodopa (QPlogBB: −1.44) and less than rotenone (QPlogBB: 0.08). DNMT1 inhibitor (5-Aza-dC) and rotenone robustly decreased the DNMT1 and α-synuclein expression in Neuro 2 A cells which was significantly reversed by UA treatment at 31.25 µM concentration. These findings indicate the potential of urolithins, specifically UA, UC, UD, UE, and UM5 against α-synuclein aggregation.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"108 ","pages":"Pages 246-262"},"PeriodicalIF":3.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882368","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}