European journal of pharmacology最新文献

{"title":"Therapeutic S100A8/A9 inhibition reduces NADPH oxidase expression, reactive oxygen species production and NLRP3 inflammasome priming in the ischemic myocardium","authors":"Mihaela-Loredana Vlad ,&nbsp;Razvan Gheorghita Mares ,&nbsp;Gabriel Jakobsson ,&nbsp;Simona-Adriana Manea ,&nbsp;Alexandra-Gela Lazar ,&nbsp;Mihai Bogdan Preda ,&nbsp;Mirel Adrian Popa ,&nbsp;Maya Simionescu ,&nbsp;Alexandru Schiopu ,&nbsp;Adrian Manea","doi":"10.1016/j.ejphar.2025.177575","DOIUrl":"10.1016/j.ejphar.2025.177575","url":null,"abstract":"<div><div>Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies on cultured macrophages (Mac), important cellular effectors in MI. Compared to sham-operated animals, we detected significant increases in the Nox1, Nox2, Nox4 catalytic subunits at mRNA and protein levels, and NADPH-dependent ROS production in the left ventricle of MI mice. S100A8/A9 blockade prevented the up-regulation of Nox1/2/4 expression, reduced ROS formation, suppressed NF-kB activation and prevented NLRP3 inflammasome priming and activation, leading to reduced levels of active IL-1β. In-vitro, S100A8/A9 induced gene expression of Nox catalytic subtypes and NLRP3 in Mac in a TLR4-dependent and dose-dependent manner. These effects were counteracted by pharmacological inhibition of S100A8/9, TLR4, Nox1/4 and Nox2. In conclusion, we show that Nox upregulation and ROS formation triggered by S100A8/A9 contributes to NLRP3 inflammasome priming and increased IL-1β production in the infarcted myocardium. These mechanisms can be therapeutically targeted to prevent inflammatory and oxidant myocardial damage in acute MI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177575"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779450","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":"Preconditioning and post-preconditioning states of mesenchymal stem cells with deferoxamine: A comprehensive analysis","authors":"Basak Isildar ,&nbsp;Serbay Ozkan ,&nbsp;Duygu Neccar ,&nbsp;Meral Koyuturk","doi":"10.1016/j.ejphar.2025.177574","DOIUrl":"10.1016/j.ejphar.2025.177574","url":null,"abstract":"<div><div>Mesenchymal stem cells (MSCs) derive their therapeutic potential from their secretomes, which can be modulated by external stimuli. Hypoxia is one such stimulus, and research on preconditioning MSCs with hypoxia-mimetic agents is rising. However, the effects of these preconditioning processes and the resulting metabolic status require further investigation. This study evaluated the effects of deferoxamine (DFX), a hypoxia-mimetic agent, preconditioning on MSCs in serum and serum-free environments. The influence of hypoxia on cell metabolism was examined during and after preconditioning by assessing cytotoxicity, proliferation, migration, secretomes, senescence, autophagy, and apoptosis mechanisms. The optimal DFX dose and duration for preconditioning were determined as 150 μM and 24 h based on cytotoxicity testing. Accordingly, DFX preconditioning significantly upregulated HIF-1α expression, increasing protein secretion and reducing total oxidant status. DFX appears to enhance the therapeutic potential of MSCs by increasing their secretome and antioxidant capacity. However, upon DFX removal, HIF-1α levels returned to normal, and the associated positive effects diminished. Autophagy was markedly enhanced during DFX preconditioning, potentially improving metabolic activity, preserving cellular integrity, and preparing MSCs for ischemic environments. Autophagy returned to baseline after DFX withdrawal, indicating a temporary hypoxia-mimetic response. In a serum-containing medium, specific effects of preconditioning were relatively weak to be observed. This study demonstrates that DFX-preconditioning increases MSCs' metabolic activity and enhances their adaptive cellular response. However, the effect may be transient, which provides insights into the behavior of MSCs in ischemic environments and emphasizes the need to evaluate the long-term effects of hypoxia-mimetic agents.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177574"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779427","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":"Overview of M-LP/MPV17L, a novel atypical PDE and possible target for drug development","authors":"Reiko Iida ,&nbsp;Toshihiro Yasuda","doi":"10.1016/j.ejphar.2025.177569","DOIUrl":"10.1016/j.ejphar.2025.177569","url":null,"abstract":"<div><div>M-LP/Mpv17L (Mpv17-like protein) was initially identified as a novel protein during screening of age-dependently expressed genes in mouse kidney. Previous findings suggested that human Mpv17-like protein (M-LP/MPV17L) is involved in the maintenance of mitochondrial DNA (mtDNA), thus playing a role in cell defense against mitochondrial dysfunction, although its molecular mechanism of action has remained unknown. Recently, generation of <em>M-LP/MPV17L</em>-knockout (KO) cells using CRISPR-Cas9 technology has revealed that M-LP/MPV17L exerts cyclic nucleotide phosphodiesterase (PDE) activity despite lacking the conserved catalytic region and other structural motifs characteristic of the PDE family, and is one of the key components of pathways such as cAMP/cAMP-dependent protein kinase A (PKA) signaling. Moreover, generation of <em>M-LP/Mpv17L</em>-KO mice has revealed that deficiency of M-LP/Mpv17L results in development of β-cell hyperplasia and improved glucose tolerance, as well as physiological afferent cardiac hypertrophy. M-LP/MPV17L is a protein of great interest as it is a potential target for drug development. Therefore, in this review, we overview the molecular characteristics, regulation of expression, cellular functions, phenotypes detected in KO mice, and disease relevance of M-LP/MPV17L.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177569"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777262","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":"Acevaltrate overcomes myeloma resistance to bortezomib via pyroptosis by promoting BAX translocalization to mitochondria","authors":"Yaner Wang ,&nbsp;Yaoli Cui ,&nbsp;Ziyang Liu ,&nbsp;Longlong Liu ,&nbsp;Zhenqian Huang ,&nbsp;Qi Wang ,&nbsp;Xinliang Mao","doi":"10.1016/j.ejphar.2025.177572","DOIUrl":"10.1016/j.ejphar.2025.177572","url":null,"abstract":"<div><div>Bortezomib is a mainstay drug for the treatment of myeloma, a malignancy of plasma cells, but resistance frequently develops. Overcoming bortezomib resistance is urgently needed. In the present study, we found that acevaltrate, an active ingredient from a traditional Chinese medicine, exhibits potent activity in triggering pyroptosis in bortezomib-resistant myeloma cells. Mechanistically, acevaltrate induces myeloma cells pyroptosis in a Caspase-3 and GSDME-dependent manner. When Caspase-3 is inhibited by its specific inhibitor or GSDME is knocked out, myeloma cells fail to undergo pyroptosis triggered by acevaltrate. Moreover, acevaltrate promotes the production of reactive oxygen species and strikingly reduces mitochondrial membrane potential. Consistent with this finding, acevaltrate dissociates BAX from its inhibitor, Bcl-2, thereby promoting BAX translocalization to mitochondria. Furthermore, IFIT3, an IFN-inducible protein, is upregulated by acevaltrate. Interestingly, while IFIT3 fails to directly induce myeloma cells pyroptosis, it markedly enhances acevaltrate-induced pyroptosis. IFIT3 binds to Bcl-2 and prevents it from interacting with BAX. Lastly, acevaltrate effectively triggers pyroptosis in bortezomib-resistant myeloma cells. Pre-treatment with acevaltrate significantly restores the sensitivity of resistant myeloma cells to bortezomib. Therefore, acevaltrate strongly induces myeloma cell pyroptosis and overcomes bortezomib resistance. Given its potent activity against myeloma and its established safety profile, acevaltrate warrants further evaluation in clinical settings for its potential to overcome myeloma resistance to bortezomib.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177572"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767915","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":"Pharmaco-toxicological effects of the synthetic cannabinoids 4F-ABUTINACA, SDB-005, and JWH-018 in mice. In vitro and in vivo studies","authors":"Xuwen Luo ,&nbsp;Lixin Kuai ,&nbsp;Xuesong Shi ,&nbsp;Yanling Qiao ,&nbsp;Kaixi Li ,&nbsp;Deli Xu ,&nbsp;Bin Di ,&nbsp;Fang Yan ,&nbsp;Peng Xu","doi":"10.1016/j.ejphar.2025.177586","DOIUrl":"10.1016/j.ejphar.2025.177586","url":null,"abstract":"<div><h3>Background</h3><div>Synthetic cannabinoids (SCs) are currently one of the most severely abused new psychoactive substances in the world. However, there remains a notable lack of pharmacological data on the newly emerged synthetic cannabinoids. In the present study, the in vitro and in vivo pharmacological effects of the fourth-generation synthetic cannabinoids 4F-ABUTINACA and SDB-005 are determined and compared to those of the first-generation synthetic cannabinoid JWH-018.</div></div><div><h3>Methods</h3><div>In this study, the affinities of three SCs for CB1 receptors were evaluated using surface plasmon resonance (SPR) experiments. The acute toxicity of these three SCs was assessed through the up-and-down procedure, while their cannabinoid-specific pharmacological effects were determined through tetrad assays, which examined parameters such as temperature regulation, analgesia, locomotor activity, and catalepsy. Additionally, conditioned place preference (CPP) experiments and a precipitated withdrawal tests were conducted to assess the psychoactive effects and physical dependence of the SCs.</div></div><div><h3>Results</h3><div>SPR experiments and acute toxicity tests demonstrated that in vitro KD values were positively correlated with in vivo ED₅₀ potency estimates. All SCs were found to induce the classical “tetrad effects” in a dose-dependent manner. Notably, all SCs displayed significant biphasic effects in CPP experiments. Following the administration of the CB1 receptor antagonist rimonabant, a significant increase in head twitches and paw tremors was observed, indicating that the physical dependence manifested after the ingestion of SCs is mediated by the CB1 receptor.</div></div><div><h3>Conclusions</h3><div>These findings suggest that these SCs have cannabinoid-specific pharmacological effects and abuse potential, providing robust experimental data to support future regulatory efforts.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177586"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779425","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 antibacterial efficacy of nitroxoline against multidrug resistant Escherichia coli associated with copper binding","authors":"Xiaoyong Huang ,&nbsp;Qianqian Li ,&nbsp;Shiqi Yan ,&nbsp;Chenli Wang ,&nbsp;Xiaomin Ren ,&nbsp;Jianzhong Wang ,&nbsp;Jia Cheng ,&nbsp;Zilong Sun","doi":"10.1016/j.ejphar.2025.177576","DOIUrl":"10.1016/j.ejphar.2025.177576","url":null,"abstract":"<div><div>Nitroxoline (NIT) has been approved for the treatment of uncomplicated urinary tract infections (UTIs) for more than half a century, yet its antimicrobial properties remain incompletely understood. Here, we determined the intricate connections between NIT's metal-chelating capabilities and its antibacterial activity. Metal ion binding characteristics were measured by Ultraviolet–visible (UV–vis) spectroscopy. Biochemical assays and molecular docking studies were performed to elucidate the underlying mechanism. We found that NIT could interact with a diverse array of metal ions, including Cu²⁺, Fe²⁺, Zn²⁺ and Mn²⁺. While, the addition of Cu²⁺ significantly decreased NIT's antibacterial effect against uropathogenic <em>Escherichia coli</em> (UPEC) strain J96 and multidrug resistant <em>E coli</em> B2, with the minimum inhibitory concentration (MIC) increased from 8 mg/L to 64 mg/L. Mechanically, NIT significantly decreased the intracellular copper ion levels and reduced bacterial transmembrane electrical potential. Furthermore, NIT promoted production of nitric oxide, peroxynitrite (ONOO-), and reactive oxygen species (ROS). However, the interaction of Cu²⁺ with NIT suppressed the induced generation of ROS but not the generation of ONOO- in <em>E coli</em>, suggesting that the antibacterial activity of NIT arose from multiple functional groups within its molecular structure. Moreover, NIT triggered intracellular acidification concomitant with enhanced glucose uptake, yet paradoxically suppressed ATP generation, suggesting a potential uncoupling between glycolytic flux and oxidative phosphorylation. Finally, the action of NIT was predicted to bind to the <em>CuB</em>-metal redox centers of cytochrome bo(3) ubiquinol oxidase through molecular docking analyses. Collectively, these data illuminate the antibacterial activity of NIT as a potent copper-related metalloantibiotic against UPEC.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177576"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779443","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":"Microglia modulate integrity of myelin and proliferation of oligodendrocyte precursor cells in murine model of bone cancer pain","authors":"Li Jiang ,&nbsp;Yu Wang ,&nbsp;Qing-zi Wu ,&nbsp;Jia-cheng Yu ,&nbsp;Yu-lin Huang ,&nbsp;Rui Xu ,&nbsp;Kun Ni ,&nbsp;Xiao-ping Gu ,&nbsp;Zheng-liang Ma","doi":"10.1016/j.ejphar.2025.177585","DOIUrl":"10.1016/j.ejphar.2025.177585","url":null,"abstract":"<div><div>Cancer pain, a frequent complication in patients with cancer, adversely affects quality of life and survival rates. Microglia promote nociceptive information transmission by modulating myelin integrity during pain perception. However, the specific mechanisms by which microglia regulate myelin in the context of cancer pain remain poorly understood. In this study, we developed a bone cancer pain model to examine the interactions among microglia, myelin, and oligodendrocyte precursor cells and their roles in cancer pain. Our study found that mice with bone cancer pain had oligodendrocyte differentiation defects and myelin loss, and that promoting myelination did not relieve pain. In addition, we observed that reactive microglia and inflammatory cytokines increased and microglia phagocytosed myelin in mice with bone cancer pain. Inhibition of microglia not only alleviated pain behaviors in mice with bone cancer but also mitigated myelin phagocytosis and the proliferation of oligodendrocyte precursor cells. Our study suggests that microglia-mediated myelin loss and oligodendrocyte precursor cell proliferation may be one of the pathological mechanisms underlying pain in mice with bone cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177585"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779401","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":"Sinomenine alleviates experimental autoimmune uveitis in rats: Possible involvement of PI3K/AKT and NF-κB signaling pathways","authors":"Qing Gao ,&nbsp;Jun Peng ,&nbsp;Meng Xiong ,&nbsp;Shunhua Zhou ,&nbsp;Xiaojuan Wang ,&nbsp;Jing Lu ,&nbsp;Yuanyi Guo ,&nbsp;Qinghua Peng ,&nbsp;Meiyan Zeng ,&nbsp;Houpan Song","doi":"10.1016/j.ejphar.2025.177571","DOIUrl":"10.1016/j.ejphar.2025.177571","url":null,"abstract":"<div><div>Uveitis is an inflammatory ocular condition characterized by an autoimmune etiology. Sinomenine (SIN), the main active constituent of the rhizome of <em>Sinomenium acutum</em> (Thunb.) Rehd. et Wils., exhibits both anti-inflammatory and immunosuppressive properties. The present study sought to investigate the therapeutic effects of SIN on experimental autoimmune uveitis (EAU) in rats and to elucidate its underlying mechanisms. A bioinformatics analysis was conducted to identify signaling pathways implicated in the pathogenesis of uveitis, leading to the identification of the PI3K/AKT and NF-κB pathways for further experimental validation. An EAU model was subsequently established, and the ocular surface morphology was examined using slit lamp microscopy and hematoxylin-eosin staining. Immunofluorescence was utilized to measure the protein expression and distribution. Enzyme-linked immunosorbent assay was used to determine the expression of inflammatory cytokines. Experimental findings demonstrated that SIN significantly decreased ocular inflammation scores. Further validation revealed that SIN significantly elevated levels of interleukin-10 (IL-10) while reducing levels of IL-17, tumor necrosis factor-α (TNF-α), and IL-1β in EAU rats. SIN significantly suppressed the expression of phosphorylated proteins in the PI3K/AKT and NF-κB pathways. In addition, it reduced the expression of RORγt while enhancing the expression of Foxp3, the transcription factors associated with Th17 cells and Tregs, respectively. In summary, our data demonstrate that SIN alleviates EAU inflammation by inhibiting the activation of the PI3K/AKT and NF-κB signaling pathways and restoring the balance between Th17 and Tregs. These findings highlight SIN as a promising therapeutic agent for the treatment of uveitis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177571"},"PeriodicalIF":4.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779439","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":"Diacerein's antiproliferative effects alone and with 5-fluorouracil in an Ehrlich solid tumour model: Molecular docking, molecular dynamics Simulation studies, and experimental Verification","authors":"Mohamed S. Abdel-Maksoud ,&nbsp;Renad Abdullah Alatawi ,&nbsp;Sarah Saad A. Albalawi ,&nbsp;Maram N. Alrashidi ,&nbsp;Nader E. Abo-Dya ,&nbsp;Nehal Elsherbiny ,&nbsp;Yasser M. Ragab ,&nbsp;Aeshah A. Awaji ,&nbsp;Mohamed El-Sherbiny ,&nbsp;Hassabelrasoul Elfadil ,&nbsp;Mohammad M. Abd-Alhaseeb","doi":"10.1016/j.ejphar.2025.177564","DOIUrl":"10.1016/j.ejphar.2025.177564","url":null,"abstract":"<div><div>The current study used an experimental model of mammary gland carcinoma to assess the chemo-sensitizing effectiveness of the combined administration of diacerein and 5-Fluorouracil (5-FU). With docking scores of −8.1, −7.6, and −9.2 kcal/mol, respectively, the molecular docking experiments showed that diacerein exhibits significant binding affinities to Caspase-3, NF-κB, and AKT1. Molecular dynamics Simulations revealed that diacerein has favourable binding free energy (ΔGbind) of −26.7 kcal/mol for Caspase-3, -24.2 kcal/mol for NF-κB, and −39.9 kcal/mol for AKT1, combined with low root mean square deviation (RMSD) values of 3.1 Å, 1.6 Å, and 2.1 Å for the three targets respectively. To validate these findings <em>in vivo</em>, Ehrlich solid tumor (EST) was induced in female Swiss mice. Four groups of animals were randomly assigned: EST + vehicle, EST + 5-FU, EST + diacerein, and EST + combination. Diacerein and 5-FU combination treatment increased EST mice's life span and reduced the solid tumor's weight and volume. Furthermore, diacerein and 5-FU combination significantly suppressed oxidative stress, inhibited AKT phosphorylation, decreased downstream inflammation (NF-κB, TNF-α, IL-1β), and increased apoptosis by modulating Bax, Bcl2, P53, and caspase-3 levels in tumor tissues. In conclusion, by inhibiting the AKT/NF-κB axis, diacerein and 5-FU combination showed possible antiproliferative effectiveness in the EST model.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177564"},"PeriodicalIF":4.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742620","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":"Effect of apigenin on seizure susceptibility, parvalbumin immunoreactivity, and GABAA receptor expression in the hippocampal neurons in mice","authors":"Katarzyna Socała ,&nbsp;Edyta Kowalczuk-Vasilev ,&nbsp;Małgorzata Komar ,&nbsp;Radosław Szalak ,&nbsp;Elżbieta Wyska ,&nbsp;Piotr Wlaź","doi":"10.1016/j.ejphar.2025.177548","DOIUrl":"10.1016/j.ejphar.2025.177548","url":null,"abstract":"<div><div>Apigenin is a flavonoid compound found in many fruits, vegetables, and medicinal herbs. It possesses a wide range of biological activities including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects. Some initial evidence also suggests that apigenin may have antiseizure properties. In this study, we aimed at providing more insight into the potential influence of apigenin on seizure susceptibility in mice and its influence on parvalbumin and GABA_A receptor immunoreactivity (PV-IR and GABA_AR-IR) in the hippocampus. We also assessed the pharmacokinetic profile of apigenin after intraperitoneal route of administration and its possible side effects. Acute administration of apigenin, at doses of 100 and 150 mg/kg, significantly increased the threshold for various types of seizures, i.e., the myoclonic twitch in the <em>iv</em>PTZ test, the 6 Hz-induced seizure, and hindlimb tonus in the maximal electroshock seizure test. A 14-day treatment with apigenin at a lower dose of 50 mg/kg also increased the threshold for maximal electroshock-induced seizures. Pharmacokinetic profiling revealed a very slow elimination of apigenin from serum, and even slower from the brain, after intraperitoneal administration. In consequence, a relatively high accumulation of this compound in the brain can be expected. In addition, apigenin given repeatedly increased the mean number of GABA_AR-IR and PV-IR neurons in hippocampal fields suggesting its potential influence on neuronal Ca²⁺ metabolism. This study indicates that apigenin has a relatively minor effect on acute seizures in mice. However, modifying the quantity of GABA_AR-IR and PV-IR hippocampal neurons provides further support for the neuroprotective effects of apigenin.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"996 ","pages":"Article 177548"},"PeriodicalIF":4.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742724","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}