European journal of pharmacology最新文献

{"title":"Cannabinoids in peripheral neuropathic pain: Resolving mechanistic mismatch through CB2-oriented phenotype stratification","authors":"Amina M. Bagher","doi":"10.1016/j.ejphar.2026.179130","DOIUrl":"10.1016/j.ejphar.2026.179130","url":null,"abstract":"<div><div>Peripheral neuropathic pain (PNP) affects approximately 7–10% of the population, yet 40–60% of patients derive inadequate relief from first-line pharmacotherapies. Cannabinoid-based medicines engage the endocannabinoid system and offer a strong biological rationale for analgesia, but randomised trials show only modest, heterogeneous benefits and non-trivial adverse-effect liability. The 2025 Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain meta-analysis (313 trials; 48,789 participants) issued a weak recommendation against routine cannabinoid use, and the 2025 Agency for Healthcare Research and Quality review reported small analgesic effects with increased adverse events.</div><div>This review argues that limited efficacy reflects translational mismatch rather than biological implausibility. Cannabinoid receptor type 1 (CB₁)-biased, centrally penetrant formulations are misaligned with inflammation-dominant PNP phenotypes, whereas peripheral cannabinoid receptor type 2 (CB₂)-mediated neuroimmune modulation, attenuating cytokine release, macrophage infiltration, and glial activation, represents an aetiology-aligned target. CB₂ is framed as a hypothesis-driven precision target with strong preclinical support but limited clinical validation, the most informative signals emerging from prespecified subgroup analyses (olorinab CAPTIVATE; lenabasum RESOLVE-1 and DETERMINE) rather than primary endpoints. Cannabidiol is repositioned as a tolerability- and symptom-modifying adjunct rather than a primary analgesic.</div><div>Translation has been further constrained by species-specific CB₂ pharmacology, heterogeneous cohorts, and trial durations misaligned with immunomodulatory time courses. We therefore propose a tiered precision framework integrating sensory phenotyping, inflammatory biomarker profiling, endocannabinoid tone, and pharmacogenomic profiling, coupled with an operational trial template. Its predictive validity remains hypothesis-generating and requires prospective clinical testing.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179130"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419824","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":"Retraction notice to \"Applying spectral analysis to the arterial pulse to discriminate cardiovascular side effects following administration of Moderna's mRNA-1273 vaccine\" [Eur. J. Pharmacol. 1007 (2025) 178269].","authors":"Chun-Chao Chen, Wen-Ting Chang, Chun-Chih Chiu, Tsung-Yeh Yang, Wen-Rui Hao, Tzu-Wei Huang, Kuan-Jie Lin, Yu-Ann Fang, Min-Huei Hsu, Tsung-Lin Yang, Yu-Hsin Lai, Hung-Chang Jong, Ju-Chi Liu, Hsin Hsiu","doi":"10.1016/j.ejphar.2026.179067","DOIUrl":"10.1016/j.ejphar.2026.179067","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"179067"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197881","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":"Corrigendum to “ROS-mediated senescence and autophagy inhibition drive 5-FU/Aumoler tinib synergy in colorectal cancer” [Eur. J. Pharmacol. 1011 (2026) 178448]","authors":"Peipei Liu,&nbsp;Xiao Wu,&nbsp;Zuojie Jiang,&nbsp;Pei Zhang,&nbsp;Zixuan Meng,&nbsp;Chenming Xu,&nbsp;Di Ao,&nbsp;Jing Jiang,&nbsp;Hao Liu","doi":"10.1016/j.ejphar.2026.179079","DOIUrl":"10.1016/j.ejphar.2026.179079","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179079"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential advantages of the combinatorial use of naringenin/naringin with clinically approved drugs","authors":"Anran Cao,&nbsp;Xiao Wu,&nbsp;Hao Wu,&nbsp;Weiwei Su,&nbsp;Peibo Li","doi":"10.1016/j.ejphar.2026.179116","DOIUrl":"10.1016/j.ejphar.2026.179116","url":null,"abstract":"<div><div>Single-target therapies face growing constraints from complex disease etiologies, dose-limiting toxicities, and drug resistance. Integrating multi-target natural products into conventional regimens offers a promising synergistic strategy. Naringenin and naringin, well-defined flavanones with broad bioactive properties, exhibit multi-target profiles that make them attractive candidates for drug combination. This review consolidates evidence on the synergistic efficacy and organ-protective effects of these flavonoids combined with clinically approved drugs. Through pleiotropic mechanisms, these combinations enhance therapeutic efficacy while mitigating adverse effects. We systematically discuss the underlying pharmacological mechanisms, synthesizing a framework that decodes the interplay between pharmacokinetic modulation and pharmacodynamic engagement. Overall, these findings highlight the potential of naringenin and naringin as versatile adjuvants, providing insights for developing improved, multi-target clinical regimens.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179116"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419800","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":"Spinosin attenuates DSS-induced ulcerative colitis in rats in association with increased Nrf2/HO-1 and reduced TLR4/NFKB1-related inflammatory markers","authors":"Esam Qnais,&nbsp;Yousra Bseiso,&nbsp;Abdelrahim Alqudah,&nbsp;Mohammad E. Rabeh,&nbsp;Ahmad M. Rabi,&nbsp;Alaa A.A. Aljabali,&nbsp;Tuleen Badran,&nbsp;Muna Oqal,&nbsp;Omar Gammoh,&nbsp;Sireen Abdul Rahim Shilbayeh","doi":"10.1016/j.ejphar.2026.179117","DOIUrl":"10.1016/j.ejphar.2026.179117","url":null,"abstract":"<div><h3>Background</h3><div>Ulcerative colitis involves epithelial injury, oxidative stress, and exaggerated inflammatory signaling. This study evaluated the protective effects of spinosin in dextran sulfate sodium (DSS)-induced colitis in rats.</div></div><div><h3>Methods</h3><div>Colitis was induced using 2% DSS in drinking water. Rats received oral spinosin (5, 10, or 20 mg/kg) or sulfasalazine once daily. Clinical indices, macroscopic injury, oxidative/nitrosative stress, inflammatory mediators, Nrf2/HO-1-related markers, TLR4/NFKB1-associated markers, apoptosis-related proteins, MCP-1, and tight junction gene expression were assessed.</div></div><div><h3>Results</h3><div>DSS caused body-weight loss, colon shortening, splenomegaly, increased disease activity index (DAI), oxidative/nitrosative stress, inflammatory mediator upregulation, and reduced tight junction gene expression. Spinosin improved day-8 body weight at 10 mg/kg (p &lt; 0.05) and 20 mg/kg (p &lt; 0.001), restored colon length at 10 and 20 mg/kg (p &lt; 0.001), reduced spleen index at 20 mg/kg (p &lt; 0.001), and decreased DAI at all doses (p &lt; 0.001). Spinosin reduced LDH at 5 mg/kg (p &lt; 0.05) and 10–20 mg/kg (p &lt; 0.001), and reduced MPO, MDA, NO, COX-2, iNOS, and MCP-1. Spinosin reduced IL-6, TNF-α, TGF-β, PGE₂, Bax, NFKB1 p105/p50 protein levels, and TLR4 mRNA expression, with the most consistent effects observed at 10 and 20 mg/kg. Spinosin also increased antioxidant defenses, HO-1, Nrf2, IL-10, Bcl-2, and ZO-1/occludin mRNA expression, mainly at 10–20 mg/kg (p &lt; 0.001).</div></div><div><h3>Conclusions</h3><div>Spinosin attenuates DSS-induced colitis in rats, with effects associated with improved redox balance, increased Nrf2/HO-1-related cytoprotective markers, reduced inflammatory mediators, and restored barrier-associated gene expression.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179117"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419852","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":"Y320 suppresses non-small cell lung cancer growth by triggering autophagy-dependent pyroptosis through ubiquitin/proteasome-mediated c-FLIP degradation","authors":"Shuohan Xi,&nbsp;Wendie Wang,&nbsp;Yue Shang,&nbsp;Chaoyang Zeng,&nbsp;Qin Liu,&nbsp;Xiyan Zhang,&nbsp;Ling Su,&nbsp;Shu-zhen Chen","doi":"10.1016/j.ejphar.2026.179121","DOIUrl":"10.1016/j.ejphar.2026.179121","url":null,"abstract":"<div><div>Y320, initially identified as an immunomodulator, has been reported to reverse multidrug resistance to chemotherapeutic agents in breast and liver cancers. However, its antitumor activities and underlying mechanisms remain poorly elucidated. In this study, we first investigated the antitumor effects and mechanisms of Y320 in non-small cell lung cancer (NSCLC). Y320 exerted potent antitumor activities against NSCLC both in vitro and in vivo. It induced excessive autophagy, as evidenced by increased autophagosome and autolysosome formation, reduced sequestosome 1 (SQSTM1) protein levels, and conversion of microtubule-associated protein 1 light chain 3 beta (LC3B) from type I to type II. Concurrently, Y320 significantly triggered pyroptosis via the caspase-3/GSDME pathway, as indicated by cellular swelling, membrane blebbing, lactate dehydrogenase (LDH) release, increased propidium iodide (PI) uptake, and elevated levels of cleaved caspase-3 and GSDME-NT. Y320-induced pyroptosis depended on autophagy, and blockade of autophagy at the early stage reversed the occurrence of pyroptosis. Additionally, Y320 downregulated cellular FLICE-like inhibitory protein (c-FLIP) expression through the proteasomal pathway. Importantly, we were the first to verify that knockdown of c-FLIP induced pyroptosis via activation of the caspase-3/GSDME axis. Overexpression of c-FLIP reversed Y320-induced autophagy-dependent pyroptosis. Thus, Y320 induced excessive autophagy-dependent pyroptosis in NSCLC cells by downregulating c-FLIP, ultimately leading to cell death. In conclusion, our study identifies Y320 as a promising therapeutic candidate for NSCLC and elucidates that autophagy-dependent pyroptosis is involved in its antitumor mechanism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179121"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419858","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 Hbα deficiency induces neuronal apoptosis by promoting the accumulation of AGEs","authors":"Yuning Zhou,&nbsp;Lin Jiang,&nbsp;Yi Zhang,&nbsp;Yiying Wang,&nbsp;Lei Zhang,&nbsp;Chunni Zhou,&nbsp;Shun Wang,&nbsp;Jing Li,&nbsp;Chunnian Hu,&nbsp;Yanmin Luo,&nbsp;Jing Tang,&nbsp;Xin Liang,&nbsp;Peilin Zhu,&nbsp;Qian Xiao,&nbsp;Yong Tang,&nbsp;Fenglei Chao","doi":"10.1016/j.ejphar.2026.179139","DOIUrl":"10.1016/j.ejphar.2026.179139","url":null,"abstract":"<div><div>Hemoglobin alpha (Hbα) is localized to neuronal mitochondria, but its role in neuronal health remains unclear. We investigated the impact of Hbα deficiency in hippocampal neurons, focusing on advanced glycation end products (AGEs). Using adeno-associated virus‌-mediated silencing, we found hippocampal Hbα-deficient mice showed spatial memory deficits and pyramidal neuron loss. Molecular analysis revealed that Hbα depletion downregulated mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1α) and disrupted mitochondrial membrane proteins. This was accompanied by increased accumulation of AGEs, elevated levels of the inflammatory factor interleukin-1β and enhancing pro-apoptotic signaling. Consistently, Hbα depletion in HT22 hippocampal neuronal cells compromised cell viability, and this deficit was rescued by treatment with the AGEs inhibitor alagebrium (ALT711). Furthermore, ALT711 treatment modulated mitochondrial membrane integrity and attenuated pro-apoptotic signaling. Our findings indicate Hbα maintains neuronal health by modulating AGEs and inhibiting apoptosis, suggesting AGEs inhibition as a therapeutic strategy for Hbα deficiency-related damage.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179139"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419869","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":"Erianin ameliorates liver fibrosis through the PRDX3/NLRX1 axis","authors":"Mengqi Zhu,&nbsp;Xi Yang,&nbsp;Jingmin Xie,&nbsp;Xiaojing Shi,&nbsp;Jiajing Li,&nbsp;Yuhua Shi,&nbsp;Lijiang Zhang,&nbsp;Xinyao Tian,&nbsp;Yang Li,&nbsp;Jihong Yao,&nbsp;Ruimin Sun","doi":"10.1016/j.ejphar.2026.179110","DOIUrl":"10.1016/j.ejphar.2026.179110","url":null,"abstract":"<div><div>Liver fibrosis constitutes a central pathological hallmark of advanced chronic liver diseases. However, effective therapeutic targets and pharmacological interventions remain insufficiently defined. Mitochondrial oxidative stress plays a pivotal role in the pathogenesis of hepatic stellate cells (HSCs) activation during liver fibrosis. While erianin, a natural bibenzyl compound extracted from the stems of <em>Dendrobium chrysotoxum Lindl.</em>, exerts antioxidant effects in various diseases, its protective effect against liver fibrosis remains elusive. Thus, this study aimed to evaluate the therapeutic potential of erianin against liver fibrosis and to explore the underlying molecular mechanisms. The results revealed that erianin markedly attenuated CCl₄-and TGF-β1-induced HSCs activation and liver fibrosis. Molecular docking analyses identified PRDX3 as a specific binding target of erianin, with a subsequent increase in PRDX3 expression. However, PRDX3 knockdown abolished the protective effects of erianin on liver fibrosis. Mechanistically, RNA-seq and molecular assays demonstrated that PRDX3 alleviated liver fibrosis by activating NLRX1 and that erianin mediated its protection through the PRDX3/NLRX1 pathway. Collectively, these findings demonstrate that erianin alleviates liver fibrosis via the PRDX3/NLRX1 axis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179110"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374936","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":"Bergapten promotes angiogenesis by enhancing endothelial autophagy and reducing pyroptosis in ischemic skin flap","authors":"Xian Liu,&nbsp;Jingwei Shi,&nbsp;Liang Chen,&nbsp;Ningning Yang,&nbsp;Yuzhi Zhang,&nbsp;Yi Wang,&nbsp;Chenhao Ye,&nbsp;Yuhang Zhu,&nbsp;Liquan An,&nbsp;Xuwei Zhu,&nbsp;Jian Ding","doi":"10.1016/j.ejphar.2026.179091","DOIUrl":"10.1016/j.ejphar.2026.179091","url":null,"abstract":"<div><h3>Background</h3><div>Necrosis of distal flap tissue is often attributed to ischemic injury. Previous research has indicated that Bergapten (BeG), known for its anti-inflammatory and antioxidant activities, protects tissues from ischemic injury. This investigation aimed to ascertain the beneficial effects of BeG on ischemic flap survival and explore its underlying mechanisms.</div></div><div><h3>Methods</h3><div>To assess the survival of ischemic skin flaps, analyses of flap viability were conducted utilizing survival rate evaluations and laser Doppler blood flow (LDBF) detection. RNA sequencing was performed to clarify the underlying molecular processes involved. In addition, angiogenesis, oxidative stress (OS), pyroptosis, transcription factor EB (TFEB)-mediated autophagy, and adenosine AMP-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin (CaN) signaling were assessed using molecular docking (MD), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR), Western blot (WB) assays, immunofluorescence, and dihydroethidium (DHE) staining.</div></div><div><h3>Results</h3><div>The improvement in flap viability due to BeG was associated with the stimulation of autophagy, reduction of OS, and inhibition of pyroptosis. Notably, BeG-mediated enhancement of autophagic flux and increased resistance to OS were crucial for alleviating pyroptosis in vascular endothelial cells (VECs). BeG promoted autophagy flux and reduced endothelial oxidative stress by activating TFEB in ischemic flaps. However, the therapeutic effects of BeG were abolished by adeno-associated virus (AAV)-mediated TFEB knockdown. Additionally, BeG regulated TFEB activity through the AMPK-TRPML1-CaN pathway.</div></div><div><h3>Conclusions</h3><div>BeG enhences autophagy and alleviates OS through stimulation of the AMPK-TRPML1-CaN-TFEB signaling cascade, hence improving the survival of ischemic flaps and potentially offering significant clinical implications.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179091"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327717","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":"Early prediabetes aggravates neuroinflammatory and cognitive dysfunctional responses to chlorpyrifos exposure: Possible amelioration by arachidonic acid","authors":"Rowan E. Arida,&nbsp;Heba-Tallah Abd Elrahim Abd Elkader,&nbsp;Salwa A. Abuiessa,&nbsp;Mahmoud Agami,&nbsp;Salwa M. Abdallah,&nbsp;Mai M. Helmy,&nbsp;Ahmed I. El-Mallah,&nbsp;Ahmed F. El-Yazbi","doi":"10.1016/j.ejphar.2026.179097","DOIUrl":"10.1016/j.ejphar.2026.179097","url":null,"abstract":"<div><div>Chronic exposure to organophosphorus pesticides (OPs) is increasingly implicated in neuroinflammatory and cognitive disorders, yet susceptibility factors and pharmacological modulators remain poorly defined. Given the global rise in metabolic dysfunction, this study investigated whether prediabetes amplifies the neurotoxic impact of chronic chlorpyrifos (CPF) exposure and examined arachidonic acid (AA) as a potential modulator of the associated detrimental phenotype, with emphasis on endocannabinoid system (ECS) perturbation. Male Sprague–Dawley rats were rendered prediabetic and dermally exposed to CPF for 35 days, in the absence or presence of oral AA supplementation (3 mg/kg/day). Chronic CPF exposure induced systemic metabolic dysfunction, cerebrovascular hypoperfusion, adipose inflammation, and marked neuroinflammation accompanied by cognitive and motor impairment, as assessed by behavioral testing, laser speckle imaging, biochemical assays, histopathology, immunohistochemistry, and LC–MS/MS. These effects were exacerbated in prediabetic rats. CPF accumulated preferentially in adipose depots and brain tissue and was associated with elevated IL-1β and oxidative stress. Molecularly, CPF disrupted ECS homeostasis, with increased hippocampal 2-arachidonoylglycerol levels, downregulation of CB1 receptors, and upregulation of CB2 receptors, consistent with a stress-induced but functionally impaired endocannabinoid response. AA supplementation significantly mitigated CPF- and prediabetes-induced dysfunctional phenotype, and rebalanced ECS signaling. Collectively, these findings identify early prediabetes as a critical vulnerability state that aggravates OP neurotoxicity and demonstrate that AA exerts broad neuroprotective and metabolic benefits, in part through modulation of endocannabinoid and inflammatory signaling. This work highlights the ECS–adipose–brain axis as a pharmacologically relevant interface linking environmental toxicant exposure to metabolic and neurocognitive decline.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179097"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338327","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}