Neurotoxicology最新文献

{"title":"Dynamic dose-time proteomic profiling of cadmium exposure in rat prefrontal cortex.","authors":"Hu Zhijian, Feng Han, Hao Gao, Sheng Wan, Hui Liu, Li Jie, Yinghui Yin, Maoqin Tian, Yong Yang, Wenjie Chen, Xiao Tan, Xinxin Shi, Qiwen Chen, Shaoxin Huang","doi":"10.1016/j.neuro.2026.103463","DOIUrl":"https://doi.org/10.1016/j.neuro.2026.103463","url":null,"abstract":"<p><strong>Background: </strong>Cadmium (Cd) is a well-recognized neurotoxic metal whose effects on the central nervous system accumulate with both exposure intensity and duration. However, how dose and time jointly sculpt brain proteome trajectories-and which early molecular events emerge under low-dose, short-duration exposure-remain insufficiently resolved. Time-resolved proteomics can map these trajectories, but requires explicit dose-time deconvolution to separate main effects from interaction-driven changes while accounting for biological heterogeneity.</p><p><strong>Methods: </strong>We conducted a 3 × 3 oral-exposure design in Sprague-Dawley rats (vehicle control, CdCl2 30 μg/kg/day and 1 mg/kg/day; 2/4/8 weeks) and profiled the prefrontal cortex using deep DIA (diaPASEF) proteomics. An integrative pipeline combined Mfuzz (soft trend clustering), STEM (short time-series pattern discovery), and linear mixed-effects modeling (LMM) with an explicit Dose×Time interaction to deconvolve main and interaction effects while adjusting for sex, baseline body weight, and batch. Functional context was derived from GO/KEGG enrichment and protein-protein interaction (PPI) analyses with FDR control.</p><p><strong>Results: </strong>After QC, 8209 proteins were quantified. LMM identified 173 proteins significant for the Dose main effect, 476 proteins significant for the Time main effect, and 356 proteins significant for the Dose×Time interaction term (BH-FDR q < 0.05). Across the coefficient matrix, Dose×Time coefficients frequently exceeded the corresponding main-effect coefficients in magnitude, indicating substantial interaction-associated structure in cadmium-responsive proteome variation. Cross-method trend analyses converged on Itpr1 and Pde5a as early-response candidates, each down-regulated at 2 weeks/30 μg/kg and accompanied by coherent shifts in Ca²⁺ handling (e.g., Camk2a/b, Atp2b3, Slc8a1) and glutamatergic receptors (e.g., Grin2d, Gria3/4). Enrichment highlighted network-level perturbations spanning calcium signaling, cGMP-PKG, and glutamatergic synapse (e.g., synaptic membrane, q = 2.1 × 10⁻⁵).</p><p><strong>Conclusions: </strong>By explicitly deconvolving dose, time, and their interaction, we map dynamic proteome responses in the prefrontal cortex and highlight an early Itpr1/Pde5a-centered calcium-cGMP-glutamatergic signature that is detectable under low-dose, short-duration exposure. The accompanying DIA dataset and analytical workflow provide a reusable resource for mechanistic hypothesis generation and candidate readout nomination across neurotoxicants.</p>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"103463"},"PeriodicalIF":3.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840860","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":"Lead (Pb) exposure results in cell type specific changes in the mouse retina and optic nerve","authors":"Labony Khandokar ,&nbsp;Luke L. Liu ,&nbsp;Wei Zheng ,&nbsp;Patrick C. Kerstein","doi":"10.1016/j.neuro.2026.103461","DOIUrl":"10.1016/j.neuro.2026.103461","url":null,"abstract":"<div><div>Chronic exposure to lead (Pb) is known to cause deficits in neuronal function across the nervous system, including the visual nervous system. Visual deficits have been observed in both humans and rodent models following Pb exposure. However, how Pb exposure causes visual deficits is poorly understood. In this study, we evaluated the effects of Pb toxicity on the retina and optic nerve of the mouse visual nervous system. We used C57BL/6 adult mice of both sexes and divided them into one of three different exposure groups. Adult mice received daily oral gavage of 108 mg/kg Na-acetate (control), 54 mg/kg Pb-acetate (low dose), or 108 mg/kg Pb-acetate (high dose) for 4 weeks. At the end of Pb exposure, whole blood, retina, and optic nerve samples were collected for Pb quantification by atomic absorption spectroscopy and tissue immunohistochemical analyses. Cell type specific markers were used to quantify changes in cell density of retinal ganglion cells (RGCs), oligodendrocytes (OLs), oligodendrocyte precursor cells (OPCs), and myelin structure. Following Pb exposure, we observed a significant reduction in the cell density of RGCs in the retina. However, we found no significant changes in branch thickness or coverage of retinal vasculature following Pb exposure. In the optic nerve after Pb exposure, we found a significant reduction in the cell density of OLs and OPCs. Finally, using immunolabeling for Caspr and Nav1.6, we observed significant structural changes in nodes of Ranvier, suggesting a disruption in myelin structure. Our findings suggested that Pb toxicity may impair survival and maturation process of OLs, changes in myelin structures, and potential demyelination of the optic nerve. These results provide the foundation for future investigations into the molecular mechanisms of Pb-dependent changes in myelination and visual nervous system function.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103461"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777270","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":"Adverse effects and mechanisms induced by legacy, emerging per- and polyfluoroalkyl substances on neuron: Human exposure, adverse outcomes","authors":"Rencan Zeng ,&nbsp;Guanghua Mao ,&nbsp;Yao Chen ,&nbsp;Hai Xu ,&nbsp;Yangyang Ding ,&nbsp;Ting Zhao ,&nbsp;Liuqing Yang ,&nbsp;Xiangyang Wu ,&nbsp;Dan Wang ,&nbsp;Weiwei Feng","doi":"10.1016/j.neuro.2026.103459","DOIUrl":"10.1016/j.neuro.2026.103459","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFASs), due to their distinctive physicochemical characteristics, are emerging pollutants that are widely used as raw materials in industrial production, leading to their ubiquitous presence in the environment, plants and animals. Humans may also face health risks from exposure to PFASs. This paper reviews that the different populations are exposed to PFASs in their daily lives through diet, drinking water, indoor air, and assess the health risks to susceptible populations from various exposure pathways. Research has shown that PFASs can persist in organisms for a long time and can cross the blood-brain barrier, accumulating in the brain. Additionally, experimental studies on animals have demonstrated the occurrence of neurodevelopmental toxicity induced by PFASs, including behavioral problems, alterations to neurotransmitters, and brain tissue lesions. Epidemiological studies have demonstrated that PFASs are associated with adverse outcomes in susceptible populations, including cognitive function, learning, memory, and motor function. Finally, this paper elucidates the potential mechanisms from the perspectives of disrupted signaling pathways, synaptic plasticity, and endocrine disruption. It demonstrates that PFASs may alter neuronal synaptic structures, leading to abnormal neurotransmitter secretion and affecting intracellular calcium homeostasis and calcium signaling. It is hoped that this review will provide a reference for further research on the neurodevelopmental toxicity and health risks of PFASs.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"114 ","pages":"Article 103459"},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777312","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":"Lysosomal dysfunction contributes to lead (Pb) and high-fat diet (HFD)-induced neuronal apoptosis: A link with cathepsin B.","authors":"Yongke Yuan, Mengchen Liu, Mengdi Zhai, Meijia Wu, Wenhui Zhang, Yongjuan Xin, Yue Ba, Yu Zhang, Lin Han, Lihua Gao, Hui Huang","doi":"10.1016/j.neuro.2026.103462","DOIUrl":"10.1016/j.neuro.2026.103462","url":null,"abstract":"<p><p>Environmental lead (Pb) exposure and high-fat diet (HFD) intake are known to trigger massive neuronal apoptosis that contributes to neurologic dysfunction. Previous studies mainly focused on isolated mitochondrial dysfunction, autophagy-lysosomal pathway damage, and neuronal apoptosis from Pb or HFD. Nevertheless, the precise role of the lysosomal and proteasomal clearance processes in promoting neuronal cell death induced by Pb and HFD remains unclear. In this study, male Sprague-Dawley (SD) rats were employed to elucidate the mechanisms underlying Pb-induced neurotoxic mitochondrial apoptosis and to investigate the effects of co-exposure to HFD. In vitro, PC12 cells were treated with Pb and palmitic acid (PA) to mimic the in vivo conditions. Specifically, such exposures prompted the translocation of cathepsin B (CTSB) from lysosomes to the cytosol and downregulation of lysosomal-associated membrane protein 1 (LAMP1), ATPase H⁺ Transporting V1 Subunit A (ATP6V1A), and Bcl-2 within rat cortex. In contrast, the levels of pro-apoptotic factors including BID, Bax, mitochondrial cytochrome C (Cyt C), and caspase 3 were significantly elevated. We also observed a significant decrease in the fluorescence intensity of lysosomes while lysosomal pH was ascertained to have ascended appreciably. Concurrently, CTSB inhibition by CA-074 me prevented neural apoptosis processing triggered by Pb and/or PA via mitigating lysosomal damage and mitochondrial Cyt C translocation, indicating that CTSB is a key mediator in the apoptotic process induced by Pb and HFD.</p>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":" ","pages":"103462"},"PeriodicalIF":3.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818243","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":"Gut microbiota: A critical regulator of oxaliplatin-induced peripheral neurotoxicity development.","authors":"Zhen Liu, TingRong Zhang, SiMin Wang, HuaFang Yin, XiaXia Shao, LingJuan Gao, XiangDong Lu","doi":"10.1016/j.neuro.2026.103460","DOIUrl":"10.1016/j.neuro.2026.103460","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Oxaliplatin-induced peripheral neuropathy (OIPN) is a common dose-limiting toxicity that significantly affects patients' quality of life. Although neuroinflammation has been implicated, the precise contribution of the gut-nerve axis remains incompletely understood. This study aimed to investigate the role of gut microbiota and associated inflammatory signaling in OIPN.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;An OIPN model was established in Sprague Dawley rats. Gut microbiota depletion was achieved via antibiotic (ABX) treatment, and fecal microbiota transplantation (FMT) from healthy donors was performed to restore microbial communities. Mechanical allodynia and cold hypersensitivity were assessed using the von Frey filament test and the acetone test, respectively. Systemic inflammation was evaluated by measuring serum cytokine levels via enzyme-linked immunosorbent assay (ELISA). The composition of the gut microbiota was analyzed by 16S rRNA gene sequencing. Intestinal barrier integrity and local inflammation were assessed through histopathology, immunofluorescence, and quantification of tight junction proteins (ZO-1, occludin) and inflammatory markers (NF-κB, TNF-α) via quantitative polymerase chain reaction (qPCR) and Western blotting. Network pharmacology was employed to screen for potential common targets of oxaliplatin and neurotoxicity. Molecular alterations in the dorsal root ganglia (DRG) were examined using histology, qPCR, Western blotting, and immunofluorescence, with a focus on the TLR4/MyD88/NF-κB signaling pathway and pro-inflammatory cytokines.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Antibiotic-mediated depletion of gut microbiota significantly attenuated OXA-induced neuropathic pain and systemic inflammation, as evidenced by reduced levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β), whereas FMT reversed these protective effects. Analysis of 16S rRNA gene sequencing revealed that OXA altered gut microbiota composition, including reduced alpha diversity, altered beta diversity, a decreased Firmicutes/Bacteroidetes ratio, and taxonomic changes. These alterations were partially restored following FMT under the present experimental conditions. Functional prediction analysis indicated enrichment of the lipopolysaccharide (LPS) biosynthesis pathway. Consistently, OXA treatment was associated with elevated LPS levels in plasma and feces, which were reduced by ABX treatment and increased following FMT. OXA was also associated with impaired intestinal barrier integrity, as evidenced by decreased expression of ZO-1 and Occludin and increased inflammatory markers (NF-κB, TNF-α) in the colon, changes that were modulated by microbiota status. Network pharmacology analysis identified inflammation-related pathways and potential targets. In the DRG, OXA treatment was associated with neuronal injury, increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), ","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":" ","pages":"103460"},"PeriodicalIF":3.9,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777286","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":"Targeting glutamate receptors with IEM-1925: A strategy against soman-induced status epilepticus and neurodegeneration","authors":"Yuxin Lin,&nbsp;Qian Jin,&nbsp;Yuanqing Chen,&nbsp;Jingyan Wang,&nbsp;Yi Zhang,&nbsp;Manzhu Cao,&nbsp;Jingjing Shi,&nbsp;Liqin Li","doi":"10.1016/j.neuro.2026.103389","DOIUrl":"10.1016/j.neuro.2026.103389","url":null,"abstract":"<div><div>Exposure to organophosphorus nerve agents (OPNAs) like soman frequently develops status epilepticus (SE), leading to brain damage. Existing antiseizure medications (e.g., diazepam, DZP) often demonstrate insufficient efficacy. To develop more effective treatments for OPNA-induced seizures, this study evaluated the efficacy of glutamate receptor antagonists with distinct mechanisms of action in a soman-induced rat seizure model. After 5 min of subcutaneous exposure to 110 μg/kg soman, which induced SE, rats received intraperitoneal injections (10 mg/kg) of perampanel (PER), fanapanel (FNP), IEM-1925 (IEM), or DZP. The results showed that IEM significantly suppressed seizure activity and improved survival. The survival rate of the vehicle-treated control group was 31.25 %, whereas DZP, FNP, and IEM increased survival rates to 50 %, 43.75 %, and 56.25 % respectively. Electroencephalographic (EEG) recordings for 24 h indicated that both DZP and IEM controlled soman-induced SE. However, while DZP initially blocked the onset of seizures, they recurred after its transient anticonvulsant effect wore off. In contrast, IEM reduced behavioral convulsion intensity and total duration of SE. Histopathological examinations (HE, Nissl, immunohistochemistry, and immunofluorescence) showed that IEM attenuated hippocampal CA1, CA2, and DG neuronal damage. Behavioral tests (open field, novel object recognition, and Y maze) confirmed IEM outperformed DZP and the solvent-treated group in ameliorating soman-induced anxiety, cognitive dysfunction, and memory impairment. In conclusion, IEM demonstrates potent triple effects-antiseizure, neuroprotective, and cognitive improving in soman exposure model, providing a novel therapeutic strategy and candidate drug for the medical treatment of OPNAs poisoning.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103389"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952523","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":"Larval zebrafish as a translational model for neurotoxicity screening of emerging psychoactive substances","authors":"Courtney Hillman ,&nbsp;James Kearn ,&nbsp;Maciej Trznadel ,&nbsp;Matthew J. Winter ,&nbsp;Matthew O. Parker","doi":"10.1016/j.neuro.2026.103386","DOIUrl":"10.1016/j.neuro.2026.103386","url":null,"abstract":"<div><div>The rapid emergence of novel psychoactive substances poses a growing neurotoxicological concern, characterised by poorly defined mechanisms, high potency, and escalating overdose fatalities. Effective treatments remain limited, highlighting the need for scalable <em>in vivo</em> systems capable of identifying hazardous pharmacological profiles before widespread harm occurs. Here, we evaluated larval zebrafish (<em>Danio rerio</em>) as a medium/high-throughput model for early hazard assessment of γ-aminobutyric acid (GABA)_A positive allosteric modulators (PAMs) and N-methyl-<span>D</span>-aspartate (NMDA) receptor antagonists. Behavioural analysis of 4 days post-fertilisation (dpf) larvae revealed concentration-dependent locomotor effects consistent with mammalian pharmacodynamics, while whole-body bioanalysis confirmed compound uptake, revealing substance-specific differences in internal exposure. Notably, diazepam and tiletamine deviated from expected class profiles, highlighting the model’s sensitivity to compounds with distinctive neuropharmacological signatures. These findings demonstrate the translational value of larval zebrafish for rapid neurotoxicity screening and pharmacodynamic profiling, offering an ethically advantageous, 3Rs-aligned platform to inform overdose treatment development and prioritisation of emerging psychoactive threats.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103386"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903965","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":"Triggers of highly lethal seizures induced by novel stimulants: A systematic review focused on synthetic cathinones and phenethylamines","authors":"Martin Macháček ,&nbsp;Markéta Bébarová","doi":"10.1016/j.neuro.2026.103391","DOIUrl":"10.1016/j.neuro.2026.103391","url":null,"abstract":"<div><div>Synthetic cathinones and phenethylamines are increasingly prevalent novel psychoactive substances with stimulant and hallucinogenic properties. They are associated with acute symptomatic seizures, often with lethal outcomes. Current management is usually limited to symptomatic therapy, as serotonin and sympathomimetic toxidromes are widely regarded as the main seizure-inducing mechanisms. However, intoxications frequently involve severe organ toxicities or metabolic disturbances with high epileptogenic potential, which may be preventable or treatable. This review aimed to assess seizure mechanisms beyond central monoaminergic toxicity to identify additional factors and improve seizure management. A systematic search of PubMed and Web of Science (2003–2024) identified reports describing individual human cases of acute intoxication with synthetic cathinones or phenethylamines, published in English and providing detailed clinical data. Inclusion criteria were met by 42 cases from 34 reports. A descriptive synthesis was performed to summarize observed patterns across substance groups. Most seizures occurred in previously healthy young adults and resulted in death in nearly 50 % of cases, with higher fatality among cathinone users. Serotonin and sympathomimetic toxidromes were present in most cases, supporting a primary role in seizure generation. However, intracranial hemorrhage and cerebral edema (often precipitated by hypertensive crisis), hypoglycemia, and hyponatremia likely contributed to seizures in several cases. Based on these findings, we recommend that young adults presenting with seizures and signs of monoaminergic toxicity, in whom synthetic cathinone or phenethylamine intoxication is confirmed or suspected, should be promptly assessed for focal brain injury and metabolic disturbances to identify treatable causes and potentially improve outcomes.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103391"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980113","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":"Beta-caryophyllene restores liver–brain axis integrity in thioacetamide-induced hepatic encephalopathy: Behavioral and molecular insights","authors":"Samet Tekin ,&nbsp;Merve Bolat ,&nbsp;İsmail Bolat ,&nbsp;Ömercan Alat ,&nbsp;Burak Batuhan Laçin ,&nbsp;Burak Çınar ,&nbsp;Aslıhan Atasever ,&nbsp;Mehmet Emin Kanat ,&nbsp;Emin Şengül ,&nbsp;Mohamad Warda ,&nbsp;Ahmet Hacımüftüoğlu","doi":"10.1016/j.neuro.2026.103400","DOIUrl":"10.1016/j.neuro.2026.103400","url":null,"abstract":"<div><div>Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver dysfunction, driven by hyperammonemia, oxidative stress, neuroinflammation, apoptosis, and endoplasmic reticulum (ER) stress, which disrupt the hepato-encephalic axis and impair cognition and motor functions. Despite its clinical burden, effective therapies that target this multi-organ pathology remain limited. β-Caryophyllene (BCP), an antioxidant and anti-inflammatory dietary sesquiterpene, has not been evaluated for its ability to modulate liver–brain crosstalk in HE. This study investigated the hepatoprotective and neuroprotective effects of BCP in a rat model of thioacetamide (TAA)-induced HE. Rats received TAA (200 mg/kg, i.p.) for three days, followed by BCP (100–400 mg/kg) for 14 days. A comprehensive evaluation included serum biochemistry, oxidative stress indices, inflammatory cytokines, apoptosis-related proteins, neurotrophic factors (BDNF), astroglial activation marker (GFAP), ER stress regulators (GRP78, IRE1, XBP1, PERK, CHOP, ATF6), histopathology, and behavioral outcomes. TAA caused severe hepatic and cerebral injury with elevated liver enzymes, oxidative and inflammatory mediators, ER stress dysregulation, pro-apoptotic signaling, reduced BDNF and GFAP, and impaired motor and exploratory behaviors. BCP treatment dose-dependently restored biochemical and molecular parameters, suppressed oxidative stress and neuroinflammation, normalized ER stress signaling, promoted anti-apoptotic pathways, preserved BDNF and maintained astroglial status as reflected by GFAP, and improved histoarchitecture. Importantly, moderate to high doses fully restored locomotor and exploratory activity, indicating coordinated protection across the hepato-encephalic axis. Here, for the first time, the BCP concurrently mitigates hepatic and cerebral pathology via oxidative, inflammatory, apoptotic, and ER stress pathways, supporting its translational potential as a dual hepatoprotective and neuroprotective candidate for xenobiotic-induced HE and related liver–brain disorders.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103400"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137790","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":"Neuroprotection via IGF-1 neuronal signaling activation by melatonin and edaravone synergy in methylmercury-induced ALS-like neurotoxicity: Comprehensive analysis of brain regions, spinal cord, CSF, and blood plasma","authors":"Gurudev Singh Raina ,&nbsp;Sidharth Mehan ,&nbsp;Ghanshyam Das Gupta","doi":"10.1016/j.neuro.2026.103398","DOIUrl":"10.1016/j.neuro.2026.103398","url":null,"abstract":"<div><div>Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5 mg/kg (MLT5) and 10 mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103398"},"PeriodicalIF":3.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132350","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}