European journal of pharmacology最新文献

{"title":"Novel mechanisms of metformin-induced vasorelaxation of mesenteric arterioles via endothelium-dependent hyperpolarization to treat murine colitis","authors":"Luyun Zhang ,&nbsp;Zhiming Zhu ,&nbsp;Hui Dong","doi":"10.1016/j.ejphar.2025.177900","DOIUrl":"10.1016/j.ejphar.2025.177900","url":null,"abstract":"<div><h3>Research purpose</h3><div>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.</div></div><div><h3>Materials and methods</h3><div>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.</div></div><div><h3>Results</h3><div>Metformin-induced vasorelaxation of human and mouse mesenteric arterioles through endothelium-dependent hyperpolarization <strong>(</strong>EDH) predominantly. 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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 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 ,&nbsp;H. Asci ,&nbsp;S. Asci ,&nbsp;M.A. Sevuk ,&nbsp;H.S. Sarikaya ,&nbsp;O. Ozmen","doi":"10.1016/j.ejphar.2025.177913","DOIUrl":"10.1016/j.ejphar.2025.177913","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 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 ,&nbsp;Yiyin Zhang ,&nbsp;Bohan Wu ,&nbsp;Ruijing Qiu ,&nbsp;Chen Zhao ,&nbsp;Buxing Chen ,&nbsp;Hongcai Shang","doi":"10.1016/j.ejphar.2025.177883","DOIUrl":"10.1016/j.ejphar.2025.177883","url":null,"abstract":"<div><h3>Objective</h3><div>To provide evidence-based dosing recommendations for doxorubicin (DOX)-induced acute and chronic cardiotoxicity models in mice.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 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,&nbsp;Becky Hackett,&nbsp;Almudena Otálora-Alcaraz,&nbsp;Eric J. Downer","doi":"10.1016/j.ejphar.2025.177878","DOIUrl":"10.1016/j.ejphar.2025.177878","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 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}

{"title":"Rosmarinic acid attenuates blood-brain barrier dysfunction to improve cerebral ischemia/reperfusion injury in mice","authors":"Chao Guo ,&nbsp;Jianbo Li ,&nbsp;Yucheng Liao ,&nbsp;Ying Yin ,&nbsp;Zhongying Ma ,&nbsp;Shan Liang ,&nbsp;Wei Quan ,&nbsp;Jingwen Wang","doi":"10.1016/j.ejphar.2025.177882","DOIUrl":"10.1016/j.ejphar.2025.177882","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral ischemia/reperfusion (CI/R) has detrimental effects in cases of ischemic stroke. This notably triggers the blood-brain-barrier (BBB) to break. Known for its ability to provide neuroprotective benefits, rosmarinic acid (RosA) is a phenolic acid compound in the <em>Lamiaceae family</em> of plants. However, the relevance between the neuroprotective effect of RosA on CI/R and its direct protective effect on the BBB remains unclear. This study aimed to investigate how RosA regulates BBB integrity after CI/R injury and explore its underlying pharmacological mechanism in mice.</div></div><div><h3>Methods</h3><div>The mouse model of middle cerebral artery occlusion (MCAO) was established by subjecting the animals to 1 h of ischemia followed by a 24-h reperfusion period. Neurological scoring, infarct size, BBB permeability, histological examination, and biochemical parameters were subsequently assessed.</div></div><div><h3>Results</h3><div>Our study showed that RosA improved neurofunction and reduced infarct size by protecting BBB permeability, alleviating CI/R-induced neuronal loss and apoptosis. Molecular docking, molecular dynamics (MD) simulationand surface plasmon resonance (SPR) suggested that RosA may directly bind to matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2). Furthermore, RosA significantly enhanced tight junction proteins, including zonula occludens-1 (ZO-1), occludin and claudin 5, while simultaneously decreasing the levels of MMP-9 and MMP-2 mRNA and proteins.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that RosA significantly mitigates CI/R-induced BBB disruption in middle cerebral artery occlusion (MCAO) mice by enhancing tight junction protein expression and down-regulating MMP-9 and MMP-2 levels.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 177882"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549271","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":"Nitrous oxide increases peripheral blood flow and decreases plasma adrenaline and noradrenaline concentrations in human volunteers: An in vivo nonrandomized clinical and in vitro chromaffin cell culture study","authors":"Yoshitaka Shimizu ,&nbsp;Masahiro Irifune ,&nbsp;Tamayo Takahashi ,&nbsp;Aya Oda ,&nbsp;Hisanobu Kamio ,&nbsp;Serika Imamura ,&nbsp;Utaka Sasaki ,&nbsp;Eiji Imado ,&nbsp;Yoshiyuki Okada ,&nbsp;Yukio Ago ,&nbsp;Katsuya Morita ,&nbsp;Norio Sakai","doi":"10.1016/j.ejphar.2025.177899","DOIUrl":"10.1016/j.ejphar.2025.177899","url":null,"abstract":"<div><div>Our understanding of the effects of nitrous oxide (N₂O) on the peripheral circulation is incomplete. Therefore, we investigated its effects on peripheral blood flow, skin temperature, and plasma adrenaline (AD) and noradrenaline (NAd) concentrations, which reflect sympathetic nerve activity, in human volunteers and on AD and NAd release from cultured bovine adrenal chromaffin cells. Twenty-three subjects were allocated to three groups based on measurement items. Peripheral blood flow, palm skin temperature, and plasma AD and NAd levels were evaluated using modern laser-Doppler flowmetry, thermography, and high-performance liquid chromatography with a fluorescence detector, respectively. In the <em>in vitro</em> study, cultured bovine adrenal chromaffin cells were used to examine the effects of N₂O on AD and NAd release. The inhalation of N₂O significantly increased peripheral blood flow and palm skin temperature. It also significantly decreased plasma AD and NAd concentrations. The <em>in vitro</em> study revealed that N₂O significantly inhibited acetylcholine (ACh)-induced AD and NAd release from cultured cells, while a high concentration did not affect excess KCl-induced AD and NAd release, suggesting that N₂O interfered with the process between the activation of ACh receptors and opening of voltage-operated Ca²⁺ channels in the plasma membrane. These changes in the peripheral circulation by N₂O were attributed to a decrease in plasma AD and NAd concentrations, which may have been due to the inhibition of sympathetic activity. In addition, the ability of N₂O to reduce plasma AD and NAd concentrations was mediated, at least in part, by the inhibition of their release from the adrenal medulla.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 177899"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559578","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":"Cilostazol and SB203580 combination: Targeting ER stress and p38MAPK signaling in Alzheimer's disease mouse model","authors":"May Magdy Ali ,&nbsp;Rabab Hamed Sayed ,&nbsp;Walaa Wadie ,&nbsp;Reham Atef Mohammed","doi":"10.1016/j.ejphar.2025.177897","DOIUrl":"10.1016/j.ejphar.2025.177897","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (p38MAPK) signaling contribute to neuronal inflammation, oxidative stress, and apoptosis, driving neurodegeneration in Alzheimer's disease (AD). These pathways present potential therapeutic targets. This study evaluates the neuroprotective effects of cilostazol (CLZ), a selective phosphodiesterase 3 inhibitor, and its modulation of ER stress and p38MAPK signaling in an AD mouse model induced by AlCl₃ (10 mg/kg/day, i.p.) and D-galactose (150 mg/kg/day, i.p.) for 8 weeks. CLZ (30 mg/kg, p.o.), SB203580 (a p38MAPK inhibitor, 1 mg/kg, i.p.), or their combination were administered during the final 4 weeks. Results demonstrated that CLZ, alone or in combination with SB203580, mitigated cognitive decline, preserved hippocampal neurons, reduced Tau phosphorylation, and alleviated histopathological alterations. Mechanistically, CLZ suppressed ER stress by inhibiting both the IRE1α and PERK arms of ER stress. Inhibition of IRE1α inhibited p38MAPK, leading to NF-κB suppression and decreased TNF-α levels, thereby attenuating neuroinflammation. Simultaneously, PERK inhibition downregulated CHOP/GADD153, shifting the Bax/Bcl2 balance to prevent apoptosis. Additionally, CLZ reduced oxidative stress and enhanced survival signaling via p-CREB activation. Notably, combining CLZ with SB203580 further enhanced these neuroprotective effects in an additive manner. These findings underscore CLZ's potential in targeting ER stress and neuroinflammatory pathways in AD, particularly when combined with selective p38MAPK inhibition. This study highlights a promising therapeutic strategy, warranting further investigation to develop effective treatments for AD and other neurodegenerative disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1003 ","pages":"Article 177897"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534795","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}