European journal of pharmacology最新文献

{"title":"Effectiveness and safety of the SREBP1/2 inhibitor, fatostatin, in a preclinical model of metabolic dysfunction-associated steatotic liver disease progression.","authors":"Mahak Arora, Nikolina Canová, Tijana Šopin, Zuzana Pavlíková, Tomáš Kučera, Tomáš Vacík, Ondřej Slanař","doi":"10.1016/j.ejphar.2025.177890","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177890","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder that can progress to metabolic dysfunction-associated steatohepatitis (MASH), potentially leading to liver fibrosis, cirrhosis, and cancer. As there is no sufficient specific pharmacological treatment for the progression of MASLD to MASH, we focused on the study of master transcriptional regulators involved in energy, cholesterol and lipid metabolism and adipogenesis. Therefore, our experimental work aimed to investigate the possible hepatoprotective effects and safety of fatostatin, which is the inhibitor of sterol regulatory element binding proteins 1 and 2 (SREBP1/2), in preclinical dietary models of the MASLD progression. Pretreatment of primary hepatocytes with fatostatin improved in vitro lipotoxicity produced by palmitic acid. To induce MASLD-to-MASH progression in vivo, male C57BL6J mice received a special western-type atherogenic diet with fructose and glucose in drinking water for 12 weeks. Despite the simultaneous administration of the diet to mice, an additional 4-week fatostatin treatment significantly improved the oral glucose tolerance test and reduced body, adipose tissue and liver weights, fasting glycemia, alkaline phosphatase, total cholesterol, liver conjugated dienes, nitrites and triglycerides, steatosis, and histopathological total MASLD activity score. These effects were related to the beneficial modulatory effect of fatostatin on liver expression of genes involved in lipid metabolism. Although fatostatin remarkably slowed the progression of MASLD, it produced elevated serum TNF-alpha, representing systemic inflammation, and severe skin adverse reactions similar to eczema, previously not reported. Therefore, we assume that liver-targeted specific inhibition of SREBP1/2 could be valuable in treating the progression of MASLD to MASH without concomitant skin toxicity.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177890"},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567298","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: \"Involvement of protein A and IL-16 in the hyperalgesia and allodynia evoked by Staphylococcus aureus in mice\" [Eur J Pharmacol. 2025 1002:177861].","authors":"Luis Menéndez, Alejandro Álvarez-Artime, Sara González-Rodríguez, Gemma Fernández-García, María González-Amor, Ángel Manteca, Ana Baamonde","doi":"10.1016/j.ejphar.2025.177876","DOIUrl":"10.1016/j.ejphar.2025.177876","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177876"},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564710","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":"Computational and Experimental Validation of 4-Amino-3- Hydroxynaphthalene-1-Sulfonic Acid as a Novel Antibiofilm Agent.","authors":"Minsa Mini, Praveen Kumar","doi":"10.1016/j.ejphar.2025.177892","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177892","url":null,"abstract":"<p><p>Pseudomonas aeruginosa (PA) is a gram-negative opportunistic pathogen, and is well-known for its biofilm-forming ability and antimicrobial resistance, challenging the treatment of infections, particularly in immunocompromised individuals. Biofilms are the complex communities of bacterial cells encased in a protective extracellular matrix, serving as a key survival strategy for PA and enabling them to resist antimicrobial therapies and evade host immune defense mechanisms effectively. This study aims to explore the antibiofilm potential of 4-amino-3-hydroxynaphthalene-1-sulfonic acid (ANS) and its derivatives by targeting the major biofilm-forming pathway, the quorum sensing (QS) system in PA, through in vitro and in silico approaches. Biochemical assays and confocal imaging demonstrated the dose-dependent biofilm-inhibitory activity of ANS in both clinical and standard PA strains. Growth curve analysis further confirmed that ANS exhibited antibiofilm effects without significant antimicrobial activity. Additionally, violacein quantification assays using Chromobacterium violaceum revealed the ANS interferes with the QS pathway. In silico analyses, encompassing molecular docking and molecular dynamic (MD) simulations, confirmed the stable interactions between ANS and LasR regulator, demonstrating higher binding energy compared to other QS regulators (LasI, RhlR, PqsA, PqsC, PqsD). In silico structure-based modifications predicted ANS derivative (L19) with potential antibiofilm activity, further experimental validation is required to confirm the activity of L19. Notably, ANS is non-toxic to HepG2 cells at concentrations up to 800 μg/mL, indicating its potential safety for therapeutic applications. These findings underscore the significance of ANS and its derivatives as promising candidates for the development of novel antibiofilm agents targeting the QS system in PA.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177892"},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567287","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":"Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis.","authors":"Luyun Zhang, Zhiming Zhu, Hui Dong","doi":"10.1016/j.ejphar.2025.177900","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177900","url":null,"abstract":"<p><strong>Research purpose: </strong>Metformin, an FDA-approved medication for type 2 diabetes mellitus (T2DM), has been previously reported to have anti-colitis effects via anti-inflammatory, antioxidant, and gut microbiota modulation. However, the precise mechanisms of metformin-induced vasorelaxation in intestinal resistance vessels in health and ulcerative colitis (UC), remain largely unknown.</p><p><strong>Materials and methods: </strong>Mulvany-style wire myograph was used to determine metformin-induced vasorelaxation of human submucosal arterioles and mesenteric arterioles from wild-type C57BL/6 mice and transient receptor potential vanilloid 4 knockout mice (TRPV4 KO mice). Ca²⁺ imaging and patch clamp were applied in human umbilical vein endothelial cells (HUVEC). DSS-induced mouse UC model was used to examine the role of metformin-induced vasorelaxation in its anti-colitis effects.</p><p><strong>Results: </strong>Metformin-induced vasorelaxation of human and mouse mesenteric arterioles through endothelium-dependent hyperpolarization (EDH) predominatly. Metformin induced endoplasmic reticulum (ER)/Ca²⁺ release via PLC/IP₃/IP₃R pathway in HUVEC. Metformin also promoted Ca²⁺ influx and membrane currents via store-operated Ca²⁺ entry (SOCE) and TRPV4 channels. Metformin/EDH-mediated vasorelaxation almost remained intact in colitis while acetylcholine (ACh)/EDH-mediated vasorelaxation was almost impaired totally. Importantly, metformin/EDH-mediated vasorelaxation could rescue the impaired ACh/EDH-mediated vasorelaxation and ameliorate the destructive colitis mucosae.</p><p><strong>Conclusions: </strong>Metformin/EDH-mediated vasorelaxation protects intestinal mucosae against colitis by rescuing the impaired ACh-induced vasorelaxation to recover mucosal hemoperfusion. We reveal an innovative action mode and underlying mechanisms of metformin on microvascular activities in health and colitis. Our data strongly suggest that metformin could be repurposed as a safe and effective medication to prevent/treat colitis, especially as a choice of drug for patients suffering from T2DM and UC.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177900"},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567299","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":"FS145 exerts anti-inflammatory and analgesic effects through blocking integrin αvβ3 on macrophages","authors":"Jianxi Yang ,&nbsp;Yihan Gao ,&nbsp;Junfang Liu ,&nbsp;Qingye Zeng ,&nbsp;Zhijian Xiao ,&nbsp;Jinwei Chai ,&nbsp;Ahmed A.K. Osman ,&nbsp;Wancheng Lu ,&nbsp;Xin Chen ,&nbsp;Xueqing Xu","doi":"10.1016/j.ejphar.2025.177891","DOIUrl":"10.1016/j.ejphar.2025.177891","url":null,"abstract":"<div><div>Macrophages exert a crucial role in the initiation and regulation of inflammation, and certain proteins derived from the saliva of blood-feeding arthropods have been proven to have potent anti-inflammatory and analgesic properties by regulating macrophages’ functions. We previously identified and characterized FS145, a disintegrin from the saliva of the flea <em>Xenopsylla cheopis</em>, which was demonstrated as an antiangiogenesis factor <em>in vivo</em> and <em>in vitro</em> by specific blockage of the integrin α_vβ₃ function. Here, we investigated its anti-inflammatory and analgesic effects as well as the molecular mechanism of action of this ectoparasitic peptide. FS145 could bind to RAW264.7 cells at a concentration-dependent manner and significantly attenuate the adhesion of LPS-activated RAW264.7 cells to fibrinogen, fibronectin, and vitronectin but not to laminin. Furthermore, FS145 was shown to inhibit macrophage migration and the production of NO, TNF-α, IL-1β and IL-6 by suppressing MAPK/NF-κB signaling cascades in LPS-induced macrophages. Notably, FS145 was also exhibited the potent anti-inflammatory and anti-nociceptive effects <em>in vivo</em>. These findings suggest that FS145 may exert a therapeutic effect by blocking integrin α_vβ₃ and suppressing MAPK/NF-κB ing pathways and the subsequent inflammatory response of macrophages. Therefore, FS145 holds promise as a novel anti-inflammatory and analgesic agent, warranting further investigation into its potential clinical applications.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 177891"},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549199","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":"\"Dapagliflozin mitigates lipopolysaccharide-induced neuroinflammation through potential involvement of the IL-17A/GSK3β signaling pathway and modulation of inflammatory cytokines\".","authors":"O Imeci, H Asci, S Asci, M A Sevuk, H S Sarikaya, O Ozmen","doi":"10.1016/j.ejphar.2025.177913","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177913","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation drives neuronal degeneration and cognitive decline through various mechanisms. Interleukin (IL)-17A, secreted by Th17 cells, activates glycogen synthase kinase 3 beta (GSK3β), worsening neuroinflammation via the nuclear factor kappa B (NF-κB) pathway. Dapagliflozin (DPG), a sodium/glucose cotransporter 2 inhibitor with neuroprotective effects, reduces oxidative stress, apoptosis, and inflammation. This study examines DPG's molecular impact on neuroinflammation in an LPS-induced rat model.</p><p><strong>Methods: </strong>The experiment was designed with four groups as control, lipopolysaccharide (LPS) (5 mg/kg, intraperitoneal), LPS+DPG (10 mg/kg via oral gavage), and DPG, with a total of thirty-two female Wistar Albino rats. After five days of treatment, the rats were euthanized. Brain and cerebellum tissues were gathered for biochemical analysis to examine oxidative stress parameters spectrophotometrically; histological and immunostaining analysis focusing on caspase-9 (Cas-9), NF-κB, and IL-10 immunoexpressions, and genetic analysis as IL-17A, GSK3β, IL-6, and cyclooxygenase 2 gene expressions by qRT-PCR.</p><p><strong>Results: </strong>Histopathological evaluation revealed hyperemia, edema, mild degeneration, neuronal death, and modest gliosis in the LPS group. Increment of Cas-9 and NF-κB immunoexpressions, oxidative stress parameters, and the mRNA expressions of all four genes, in addition to the decrement of IL-10 and total antioxidant status, have been observed. DPG treatment significantly reversed all these findings and protected the neuronal tissues against LPS-induced substantial neuronal damage.</p><p><strong>Conclusion: </strong>In conclusion, DPG may exert neuroprotective effects through the involvement of the IL-17A/GSK3β pathway and reduction of oxidative stress; however, further studies are needed to clarify causal mechanisms and broader anti-inflammatory actions.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177913"},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564708","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":"Optimizing Dose Selection for Doxorubicin-Induced Cardiotoxicity in Mice: A Comprehensive Analysis of Single and Multiple-Dose Regimens.","authors":"Min Li, Yiyin Zhang, Bohan Wu, Ruijing Qiu, Chen Zhao, Buxing Chen, Hongcai Shang","doi":"10.1016/j.ejphar.2025.177883","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177883","url":null,"abstract":"<p><strong>Objective: </strong>To provide evidence-based dosing recommendations for doxorubicin (DOX)-induced acute and chronic cardiotoxicity models in mice.</p><p><strong>Methods: </strong>A systematic literature search was conducted in PubMed, Web of Science, CNKI, Wanfang, and VIP databases (January 2015-October 2024) for studies on DOX-induced cardiotoxicity in mice.</p><p><strong>Results: </strong>Analysis of 808 studies from 736 articles revealed 182 unique mouse models, including 21 single-dose and 161 multiple-dose regimens. For single-dose protocols, the most common administered doses were 10, 15, and 20 mg/kg. Cardiotoxicity was effectively induced at a single dose of 15-20 mg/kg, with higher mortality observed at 20 mg/kg compared with 15 mg/kg. For multiple-dose regimens, the most prevalent protocol is 5 mg/kg administered weekly for 4 weeks, accounting for 21.23% of relevant studies. Besides, across different dosing intervals, the median single dose ranged from 2.5 to 5.5 mg/kg, given 3-6 times, with a median cumulative dose of 15-20 mg/kg. Notably, cumulative doses of 15-24 mg/kg reliably induced cardiac injury, but survival rates declined at doses ≥20 mg/kg.</p><p><strong>Conclusion: </strong>For acute cardiotoxicity, a single dose of 15 mg/kg is recommended. For chronic cardiotoxicity, two regimens are proposed: (a) the widely used 5 mg/kg weekly for 4 weeks, or (b) a flexible regimen of 2.5-5.5 mg/kg per dose, administered 3-6 times, with a cumulative dose of 15-20 mg/kg, adjustable based on experimental requirements.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177883"},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564711","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 1:1 combination of cannabidiol and Δ⁹-tetrahydrocannabinol inhibit toll-like receptor 7- and 8-mediated inflammation in human immune cells.","authors":"Melody Cui Sun, Becky Hackett, Almudena Otálora-Alcaraz, Eric J Downer","doi":"10.1016/j.ejphar.2025.177878","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177878","url":null,"abstract":"<p><p>Cannabinoid regulation of endosomal signalling via innate immune toll-like receptors (TLRs) is understudied. Endosomal cell signalling via TLR7 and TLR8 governs cellular responses to infection with viral and bacterial single-stranded RNA. TLR7/8 activation is associated with neuroinflammation, with inappropriate activation of TLR7/8 linked to the propagation of autoimmune disease. Following activation, TLR7 and TLR8 control the cellular production of cytokines, chemokines and type I interferons (IFNs). In this study we focused on two clinically relevant plant-derived (phyto) cannabinoids, cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), given that cannabinoid-based therapeutics containing these compounds are currently available in the form of sativex® (nabiximols) and epidiolex®. The study aim was to determine the anti-inflammatory effects of CBD and THC, when delivered in isolation and in a sativex-like combination (1:1), on TLR7/8-induced inflammation in immune cells. We employed the use of CL075 (3M-002), a thiazoloquinolone derivative that acts as an agonist of both TLR7 and TLR8. Using THP-1-derived macrophages and primary peripheral blood mononuclear cells (PBMCs) from healthy control subjects, we demonstrate that TLR7/8 activation promoted the time- and concentration-dependent production of the chemokine CXCL10, cytokine TNFα and type I IFNs in both macrophages and PBMCs. TLR7/8 activation promoted nuclear factor (NF)-κB activation, p38 MAPK phosphorylation and the transcription of interferon regulator factor 7 (IRF7). We assessed the anti-inflammatory effects of CBD and THC, when delivered alone and in a 1:1 combination, on CL075-stimulated inflammatory mediator production in macrophages/PBMCs. Data presented herein indicate that CBD and THC, particularly when delivered in a 1:1 combination, can act as TLR7/8 immunomodulatory drugs to dampen inflammation in macrophages and PBMCs. This study provides evidence that phytocannabinoids target TLR7/8-induced viral signalling on endosomal compartments to control inflammation in immune cells.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177878"},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564709","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 Effects of GLP-1 Receptor Agonists on Body Composition in Patients with Type 2 Diabetes, Overweight or Obesity: A Meta-Analysis of Randomized Controlled Trials.","authors":"Jieying Lu, Shen Zou, Xinyi Liu, T I N G Y A T P A T R I C K Wong, Xiaomin Zhang, Xu Ka Shing, Yanchen Zhao, Yuanjia Hong, Aiying Cen, Yingxue Wang","doi":"10.1016/j.ejphar.2025.177885","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177885","url":null,"abstract":"<p><strong>Aim: </strong>The objective is to evaluate the impacts of glucagon-like peptide 1 receptor agonists on body composition among patients with type 2 diabetes, overweight or obesity.</p><p><strong>Methods: </strong>We conducted an extensive search in the PubMed, Embase, and Cochrane Library databases, scanning the literature related to GLP-1RAs from the establishment of the databases to October 15, 2024, without language restrictions. Ignoring heterogeneity, a random effects model is adopted. I² is utilized to assess the heterogeneity among studies. The weighted mean difference and 95% confidence interval are employed to evaluate the differences in outcomes. The Cochrane risk of bias assessment tool is applied to evaluate the quality of randomized controlled trials. Statistical analysis is conducted using Review Manager version 5.4.</p><p><strong>Results: </strong>36 randomized controlled trials were included, involving 2555 participants. The study demonstrated that GLP-1RAs conspicuously decreased fat-related outcomes, encompassing fat mass, body fat percentage, visceral fat area and subcutaneous fat area. When placebo was adopted as a control, GLP-1RAs decreased the lean mass. No significant discrepancies were detected when oral antidiabetic drugs, insulin, and lifestyle interventions were employed as controls. There was no disparity in the effect of GLP-1RAs on the lean mass percentage.</p><p><strong>Conclusion: </strong>This study indicates that the treatment of GLP-1RAs can decrease fat mass. Lean mass loss was observed in the majority of studies, and the effect is more prominent in overweight and obese patients as well as in those with long-term treatment. However, there was no disparity in the effect of GLP-1RAs on the lean mass percentage.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177885"},"PeriodicalIF":4.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564712","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":"Concentration-Dependent Cellular Effects of VU0364572 on Medium Spiny Neurons in the Nucleus Accumbens of Male and Female Mice.","authors":"Chao Wu, Cesar R Romero-Leguizamón, Morgan Thomsen, Kristi A Kohlmeier","doi":"10.1016/j.ejphar.2025.177915","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.177915","url":null,"abstract":"<p><p>Selective targeting of M1 receptors (M1R) presents a promising therapeutic approach for managing cocaine use disorder. In this study, we investigated the acute cellular and synaptic effects of the M1R modulator VU0364572 on medium spiny neurons (MSNs) in the core of the nucleus accumbens. MSNs are targets of dopaminergic projections from the ventral tegmental area, which play a key role in signaling saliency of drug-related stimuli, and they receive glutamatergic inputs from the cortex that regulate the development, reinstatement, and extinction of drug dependence. For the first time, we demonstrate that VU0364572 modulates both the excitability of MSNs and excitatory neurotransmission onto these neurons in a concentration- and sex-dependent manner. In female C57/BL/6J mice, at 90 μM, VU0364572 increased postsynaptic and presynaptic excitability, while 30 μM reduced MSNs excitability without significantly affecting neurotransmission. In male C57/BL/6J mice, 60 μM enhanced glutamatergic neurotransmission, while 90 μM resulted in a reduction of excitatory synaptic activity. At all three concentrations cellular excitability was decreased in MSNs from male mice. These findings provide novel insight into the cellular and synaptic actions of VU0364572 and highlight the potential for sex-specific treatment strategies in cocaine use disorder.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177915"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559574","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}