European journal of pharmacology最新文献

{"title":"The cannabinoid CB2 receptor: improvement of sleep or memory in rotenone model of Parkinson's disease","authors":"Adriano D.S. Targa ,&nbsp;Gustavo Z. dos Santos-Lima ,&nbsp;Lais S. Rodrigues ,&nbsp;Samantha F. Cavalcante ,&nbsp;John Fontenele-Araújo ,&nbsp;Pablo Torterolo ,&nbsp;Juliane Fagotti ,&nbsp;Jéssica Ilkiw ,&nbsp;Ana Carolina D. Noseda ,&nbsp;Marina Trombetta-Lima ,&nbsp;Flávia Dorieux ,&nbsp;Patricia S. Dominico ,&nbsp;Mari C. Sogayar ,&nbsp;Monica Levy Andersen ,&nbsp;Cristina Aparecida Stern ,&nbsp;Marcelo M.S. Lima","doi":"10.1016/j.ejphar.2025.177745","DOIUrl":"10.1016/j.ejphar.2025.177745","url":null,"abstract":"<div><div>The impact of cannabinoid CB₂ receptor modulation on the non-motor symptoms of Parkinson's disease remains unknown. We investigated the role of nigrostriatal CB₂ receptors modulation in reversing alterations in sleep macrostructure, inter-hemispheric synchronization dynamics, and memory consolidation in the rotenone model of Parkinson's disease. Male Wistar rats (n = 65) underwent stereotaxic surgery for the administration of either rotenone (12 μg/μl) or dimethyl sulfoxide (vehicle, 10 % v/v) into the substantia nigra pars compacta. Seven days later, the rotenone-treated animals received intrastriatal injections of either dimethyl sulfoxide (vehicle, 10 % v/v), GW405833 (partial agonist of CB₂ receptors, 10 μg/μl), or AM630 (antagonist/inverse agonist of CB₂ receptors, 3 μg/μl). One group of animals underwent 6 h of sleep-wake recording, while another group performed object recognition and open field tests. Real-time polymerase chain reaction was conducted to determine striatal transcript levels of CB₁ and CB₂ receptors. Infusion of AM630 reversed the rotenone-induced alterations in sleep macrostructure and inter-hemispheric synchronization dynamics. This modulation led to increased sleep efficiency (p &lt; 0.01), higher probability of shorter desynchronization events (p &lt; 0.01), and reduced transition rate from synchronized to desynchronized states (p &lt; 0.05). Conversely, GW405833, but not AM630, reversed the rotenone-induced impairment in object recognition memory (p &lt; 0.01). No significant effects were observed on striatal cannabinoid receptors transcripts levels. These findings suggest that CB₂ receptors modulation is associated with paradoxical outcomes in terms of non-motor signs of Parkinson's disease, indicating somewhat independent mechanisms underlying sleep and memory alterations in the rotenone model of the disease.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177745"},"PeriodicalIF":4.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093054","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":"Ameliorative effect of GLP1 agonist on vascular calcification in normoglycemic aged rat aorta via miR34a/SIRT6/NRF2/HO-1 signalling pathway","authors":"Amira Mohammed Abdelfattah ,&nbsp;Hanim M. Abdelnour ,&nbsp;Eman M. Askar ,&nbsp;Amira Mohamed Abdelhamid ,&nbsp;Reham I. Elgarhi","doi":"10.1016/j.ejphar.2025.177741","DOIUrl":"10.1016/j.ejphar.2025.177741","url":null,"abstract":"<div><div>Medial arterial calcification (MAC), an age related vascular histological alteration, accounts for cardiovascular mortality, where cellular senescence and disturbed redox haemostasis play a role. Liraglutide (LRGT), an approved anti-diabetic agent, recently showed vascular benefits. So, we examined the probable protective impact of LRGT against aging-induced MAC and in addition, the role of MiR-34a/SIRT6 pathway is delineated.</div><div>Rats were classified into two groups; young (3–4 months old) and aged (24 months old n = 24). Eight rats from the aged group were sacrificed at the beginning of the experiment and the remaining rats completed the study with or without LRGT for 8 weeks.</div><div>Administration of LRGT ameliorated medial calcification, as shown by Alizarin red staining and calcium content assay, and downregulated runt-related transcription factor 2 (RUNX2) and osteocalcin, while enhancing α-SMA immunoexpression and improving histological appearance in aged rats’ aorta. Additionally, mitigation of aging-induced elevation of blood pressure (SBP and DBP), the senescent p53 and p16 proteins, and senescence-associated secretory phenotype including TNFα and IL-6 was also evident with LRGT. Moreover, LRGT treatment was associated with decline in MDA, 8-OHdG and Keap1 and increased GSH, NRF2, and its targeted antioxidants such as HO-1, NQO1, and GCLC. LRGT also enhanced eNOS immunoexpression in aged rats. At the molecular level, LRGT upregulated aortic SIRT6 mRNA epression and downregulated its upstream MiR-34a transcript level. We concluded that LRGT alleviated MAC during physiological aging mostly through MiR-34a/SIRT6-mediated repression of cellular senescence and repairing the Keap1/NRF2/antioxidants cascades.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1001 ","pages":"Article 177741"},"PeriodicalIF":4.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093047","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 potential effects of ticagrelor and/or sodium butyrate on imiquimod-induced psoriasis in mice model: The role of NLRP3 inflammasome signaling pathway","authors":"Hanan M. Elkhouly,&nbsp;Amany A. Abdin,&nbsp;Ahmed M. Kabel,&nbsp;Alshimaa Aboalsoud,&nbsp;Fleur F. Abd Elmonem","doi":"10.1016/j.ejphar.2025.177738","DOIUrl":"10.1016/j.ejphar.2025.177738","url":null,"abstract":"<div><h3>Background</h3><div>Psoriasis is a chronic immune-mediated inflammatory skin disease with a huge negative impact on patients’ quality of life and an increasing need to discover new alternatives for psoriasis treatment with better efficacy and fewer adverse effects. This study was designed to investigate the immunomodulatory and anti-inflammatory effects of ticagrelor (TICA) and/or sodium butyrate (NaB) in imiquimod (IMQ)-induced psoriasis model.</div></div><div><h3>Methods</h3><div>Mice were randomly allocated into five equal groups: control group, untreated IMQ group, IMQ + TICA group, IMQ + NaB group, and IMQ + TICA + NaB group. IMQ cream (62.5 mg) was applied topically on the shaved dorsal skin and 5 mg on the right ear for 7 consecutive days. The treatment protocol started post-induction and for 10 days with daily intraperitoneal injection of (10 mg/kg TICA) and (500 mg/kg NaB). The effects of these drugs on inflammatory, immune-modulatory, pyroptosis, and multi drug resistance 1 (MDR1) levels were assessed.</div></div><div><h3>Results</h3><div>IMQ + TICA + NaB group showed enhanced amelioration of disease activity, with significant improvements in body weight, Psoriasis area severity index (PASI) score, ear thickness, and spleen index. The levels of the inflammatory and immune markers [interleukin-1β (IL-1β) and IL-17] and MDR1 level, as well as the immunohistochemical expression of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and nuclear factor-kappa B (NF-κB/p65), were significantly alleviated. Moreover, the superiority of the combination extended to histopathological findings, epidermal thickness, and Baker's scoring.</div></div><div><h3>Conclusion</h3><div>TICA and NaB might be considered promising candidates for psoriasis treatment via modulation of IL-17 and NF-κB/NLRP3/IL-1β pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177738"},"PeriodicalIF":4.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093102","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":"Comparative efficacy of febuxostat and vitamin E in the management of MASLD: Insights from a randomized parallel clinical study","authors":"Hadier El-Sheikh ,&nbsp;Sahar El-Haggar ,&nbsp;Rehab Badawi ,&nbsp;Eslam Habba","doi":"10.1016/j.ejphar.2025.177735","DOIUrl":"10.1016/j.ejphar.2025.177735","url":null,"abstract":"<div><h3>Aim</h3><div>We aimed to determine whether inhibiting xanthine oxidase (XO) activity and NLRP-3 activation in the liver with febuxostat could influence the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>Sixty-four MASLD patients were divided into two groups: 32 patients received 80 mg of febuxostat daily, while the other 32 patients received 400 mg of vitamin E twice daily for 24 weeks. A gastroenterologist assessed the degree of steatosis using Fibroscan and controlled attenuation parameter (CAP) measurements at baseline and after six months. Additionally, hepatic steatosis index (HSI), HAIR-score, and levels of NLRP-3, TIM-3, HOMA-IR, MDA, uric acid, lipid profile, and liver function tests were measured before and after treatment.</div></div><div><h3>Results</h3><div>Improvement in steatosis was observed in 50 % of febuxostat group and 46.9 % of vitamin E group. Both groups showed a significant reduction in CAP scores, with more pronounced decrease in vitamin E group (p &lt; 0.001) compared to febuxostat group (p = 0.001). Febuxostat group exhibited significantly lower levels of NLRP-3, MDA, TIM-3, and uric acid compared to vitamin E group. HSI, HAIR score, and liver functions improved similarly in both groups.</div></div><div><h3>Conclusion</h3><div>Febuxostat appears to be effective in reducing steatosis in MASLD patients, suggesting its potential as a treatment option for non-cirrhotic MASLD.</div><div>ClinicalTrials.gov identifier is <span><span>NCT05574036</span><svg><path></path></svg></span>, Registered October 6, 2022 — Retrospectively</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177735"},"PeriodicalIF":4.2,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092954","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":"Cinnamaldehyde enhances the intervention effect of puerarin on stroke from the perspectives of pharmacokinetics and pharmacodynamics","authors":"Shuai Wang ,&nbsp;Yue Liu ,&nbsp;Mengyao Cui ,&nbsp;Xingyu Zou ,&nbsp;Mengjun Pan ,&nbsp;Dayuan Jiang ,&nbsp;Tingting Chang ,&nbsp;Hongye Xu ,&nbsp;Deling Wu ,&nbsp;Xiaoqin Chu","doi":"10.1016/j.ejphar.2025.177732","DOIUrl":"10.1016/j.ejphar.2025.177732","url":null,"abstract":"<div><div>The low oral bioavailability of puerarin (Pue) affects its therapeutic effect. The aim of this study is to enhance the absorption of Pue and improve therapeutic efficacy by adding cinnamaldehyde (CA). The pharmacokinetics of Pue in rats were studied using oral administration: CA + Pue, and single Pue. The Caco-2 cell model was used to investigate the effect of CA on the absorption and transport of Pue. The absorption sensitivity of TSG to P-gp inhibitors verapamil (Ver), Ko143, and MK-571 in vivo were simultaneously evaluated, and assessed the effects of ATP binding cassette (ABC) transporter inhibitors (such as P-gp inhibitors verapamil, MK-571, and BCRP inhibitor Ko143) on predicting targeted transport of active ingredients to explore the relationship between Pue transport and inhibition of these efflux proteins. A rat model of middle cerebral artery occlusion (MCAO) was established to explore the therapeutic effect of single Pue and Pue with CA on ischemic stroke (IS). The results showed that compared with Pue suspension, CA increased the absorption of Pue in rats, with C_max and AUC_(0-t) being 4.84 times and 11.54 times higher, respectively. Both P-gp and MRP play a role in the transport mechanism of Pue. Compared with single Pue, the transmembrane transport from Basolateral (BL) to Apical (AP) side of Pue was significantly reduced when Pue was applied in combination with CA. In addition, the efflux ratio (ER) value also significantly decreased. This discovery suggests that CA may reduce the secretion of Pue, thereby enhancing its absorption and transport by inhibiting exocytosis mediated by efflux transporters, similar to the effect of Ver. On the other hand, in the MCAO rat model, Pue + CA reduced the extent of cerebral infarction, alleviated pathological damage, significantly reduced the level of inflammatory mediators, and increased the release of anti-inflammatory factors, suggesting that CA can synergize with Pue to exert a better therapeutic effect on IS. Therefore, the combination of Pue and CA for the treatment of IS has profound scientific significance and rationality from the points of disposition and pharmacodynamics in vivo.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177732"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092971","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":"Morphine exacerbates myocardial ischemia/reperfusion injury by overactivation of NLRP3 inflammasome via suppression of p-TRPV1 in male rats","authors":"Bo Jiang ,&nbsp;Xiao-Xi Li ,&nbsp;Yi Lei ,&nbsp;Xin-Meng Wang ,&nbsp;Tian-Qi Wang ,&nbsp;Zheng Guo","doi":"10.1016/j.ejphar.2025.177736","DOIUrl":"10.1016/j.ejphar.2025.177736","url":null,"abstract":"<div><div>The pathology of early MIRI (myocardial ischemia/reperfusion injury) is characterized by sterile inflammation. TRPV1 (transient receptor potential vanilloid 1) and NLRP3 inflammasome sense harmful stimulation and modulate inflammation in cardiomyocytes. We recently demonstrated morphine downregulated p-TRPV1 and exacerbated MIRI. In this study, we investigate the potential crosstalk of TRPV1 and NLRP3 inflammasome activities and a potential modulatory effect of morphine on the interaction in MIRI. In vivo and in vitro experiments were conducted. Coding RNA and pharmacological modulations were used in this study. We found MI/R (myocardial ischemia and reperfusion) upregulated p-TRPV1 without change in expression of NLRP3 inflammasome. Giving morphine during myocardial ischemia increased ventricular arrythmia, reduced heart rate and +dp/dt Max in reperfusion, and increased serum cTnI (cardiac troponin I) and infarct size. Suppression of p-TRPV1 but enhancement of NLRP3 inflammasome activity at the end of MI/R were detected. The alterations were reversed by an opioid μ-receptor antagonist or a NLRP3 inhibitor. Giving TRPV1 antagonist or knockdown of TRPV1 in cultured primary cardiomyocytes inhibited p-TRPV1 but increased NLRP3 inflammasome and the downstream cytokines and LDH (lactate dehydrogenase) in the supernatants. Conversely, treatment with capsaicin (a TRPV1 agonist) or upregulation of TRPV1 via transfection of <em>Ad</em>-TRPV1 elevated p-TRPV1 and reduced NLRP3 and LDH. The results indicated morphine treatment during myocardial ischemia aggravates MIRI by increasing the activity of NLRP3 inflammasome, via suppressing the inhibitory effect of p-TRPV1 on NLRP3 inflammasome. Targeting the signal chain of opioid μ-receptor agonist/TRPV1/NLRP3 inflammasome may find a novel way to improve MIRI.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177736"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089797","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":"Damnacanthal exerts anti-cancer effects in breast cancer cells via NAG-1 upregulation, CRM1 downregulation, and induction of autophagy","authors":"Jiyoung Moon ,&nbsp;Jaehak Lee ,&nbsp;Thararat Nualsanit ,&nbsp;Junsun Ryu ,&nbsp;Seung Joon Baek","doi":"10.1016/j.ejphar.2025.177734","DOIUrl":"10.1016/j.ejphar.2025.177734","url":null,"abstract":"<div><div>Breast cancer continues to be a major cause of cancer-related deaths worldwide, emphasizing the urgent need for innovative treatments. This study investigates the anti-cancer potential of damnacanthal in breast cancer cell lines BT-20 and MCF-7, highlighting its regulatory effects on key biomarkers NAG-1 (Nonsteroidal Anti-inflammatory Drug-Activated Gene-1) and CRM1 (Chromosome Region Maintenance 1). NAG-1 is recognized for its pro-apoptotic and anti-tumorigenic roles, while CRM1 is associated with oncogenic activity. We found that damnacanthal treatment significantly increased NAG-1 expression and decreased CRM1 expression in a dose- and time-dependent manner. Functional assays demonstrated that damnacanthal inhibited cell proliferation, reduced colony formation, and decreased tumor spheroid size. Mechanistically, luciferase reporter assays revealed that damnacanthal activates the −133 to +41 region of the NAG-1 promoter through C/EBP-β. Real-time PCR and Western blotting analyses confirmed that NAG-1 is upregulated transcriptionally, whereas CRM1 is downregulated post-translationally via enhanced protein degradation, as evidenced by cycloheximide chase assays. Molecular docking suggested direct binding of damnacanthal to CRM1, potentially explaining its reduced stability. Additionally, damnacanthal induced autophagy by upregulating NAG-1, as indicated by increased LC3-II expression and autophagic flux, further confirmed by immunocytochemistry. These findings suggest that damnacanthal exerts potent anti-cancer effects by modulating NAG-1 and CRM1 expressions, inhibiting tumor cell growth, and inducing autophagy. This highlights its therapeutic potential as a novel agent for breast cancer treatment, warranting further clinical exploration.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177734"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093011","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":"Effects of midazolam and dexmedetomidine on liver and intestinal mitochondrial respiration","authors":"Anne Kuebart,&nbsp;Nicola Kaltenbach,&nbsp;Christina Hoffmann,&nbsp;Olaf Picker,&nbsp;Anna Herminghaus","doi":"10.1016/j.ejphar.2025.177740","DOIUrl":"10.1016/j.ejphar.2025.177740","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction frequently occurs in critically ill patients and is thought to contribute to metabolic shutdown and hepatic or gastrointestinal failure. In addition to hypoxemia and inflammation, sedatives are considered potential contributors to further impairment of mitochondrial function.</div></div><div><h3>Objective</h3><div>This study investigated the effect of the sedatives midazolam and dexmedetomidine on liver and colon mitochondrial function. Especially colon mitochondrial affection by both drugs was evaluated here for the first time.</div></div><div><h3>Design</h3><div>Liver and colon tissue homogenates from healthy Wistar rats (n = 60) were treated with therapeutical and supra-therapeutical doses of midazolam (0.25, 5, 50, 100, 500 μM) and dexmedetomidine (1, 5, 50, 100, 1000 nM). Samples were analyzed using the Clark electrode (Strathkelvin 782). Data analyses were performed via <em>GraphPad Prism® 8</em> using the Kruskal-Wallis + Dunn's post-hoc test. p &lt; 0.05 was considered significant.</div></div><div><h3>Results</h3><div>In liver homogenates, treatment with 500 μM midazolam (48.6 ± 6.6 %) showed a significantly decreased respiratory control index (RCI) compared with the control (107.1 ± 14.8 %, p &lt; 0.01) for complex II but without decreases in ADP/O ratio. Colon homogenate did not show significant alterations after midazolam treatment. Dexmedetomidine treatment did not affect colon or liver mitochondrial respiration in any dosage.</div></div><div><h3>Conclusions</h3><div>In clinical dosages on healthy organs, midazolam and dexmedetomidine did not show any effects on mitochondrial respiration in the colon and liver. However, in supra-therapeutical dosages, midazolam showed an organ-specific, dose-dependent, and complex-dependent effect on mitochondrial respiration by reducing the coupling of ETS and OXPHOS but without decreasing efficacy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1001 ","pages":"Article 177740"},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093029","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 “Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43”[Eur J Pharmacol.853(2019) 84–92/EJP-49538]","authors":"Meiling Wang ,&nbsp;Yusi Wu ,&nbsp;Yanrong Yu ,&nbsp;Yanqi Fu ,&nbsp;Hang Yan ,&nbsp;Xiaoying Wang ,&nbsp;Tingting Li ,&nbsp;Weijie Peng ,&nbsp;Dan Luo","doi":"10.1016/j.ejphar.2025.177694","DOIUrl":"10.1016/j.ejphar.2025.177694","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177694"},"PeriodicalIF":4.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947262","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":"Inhibiting 5-HT2C receptor in the hippocampus rescues EphB2-dependent memory impairment in mice","authors":"Subhajit Jana,&nbsp;Sailendrakumar Kolatt Chandran,&nbsp;Kobi Rosenblum,&nbsp;Raphael Lamprecht","doi":"10.1016/j.ejphar.2025.177729","DOIUrl":"10.1016/j.ejphar.2025.177729","url":null,"abstract":"<div><div>EphB2 is a tyrosine kinase receptor that regulates key neuronal functions such as synaptic transmission and morphogenesis. EphB2 dysfunction is associated with neurological disorders and dementia. In Alzheimer's disease, EphB2 depletion leads to memory deficits in mouse models, and its level is reduced in patients. EphB2 expression also declines with aging. Moreover, EphB2 dysfunction has been linked to autism. Here, we show that long-term memory (LTM) of auditory fear conditioning is impaired in EphB2^lacZ/lacZ male mice that lack EphB2 forward signaling. However, LTM was significantly increased when we microinjected the 5-HT_2C serotonin receptor antagonist SB 242084 into the hippocampus before fear memory retrieval. SB 242084 microinjection before testing did not affect freezing in EphB2^lacZ/lacZ when mice were exposed to the tone <em>per se</em> during training and testing. The 5-HT_2C antagonist did not affect fear LTM in wild-type mice. SB 242084 was ineffective when injected before fear conditioning training. Microinjection of the 5-HT_2C receptor agonist MK-212 into the hippocampus of wild-type mice before memory retrieval did not affect LTM. We further revealed that SB 242084 altered the intrinsic properties of pyramidal hippocampal neurons leading to increased excitability only in EphB2^lacZ/lacZ but not in wild-type mice. The results show that memory is not lost in EphB2^lacZ/lacZ mice but rather memory is inaccessible and can be recovered with 5-HT_2C antagonists. Furthermore, it may be possible to rescue such memory impairments in brain diseases where EphB2 dysfunction is involved.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177729"},"PeriodicalIF":4.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076891","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}