European journal of pharmacology最新文献

{"title":"Amiodarone oral subacute treatment prevents cardiac dysfunction of ischemia/reperfusion in rats: Mechanisms and influence of hypothyroidism","authors":"Matías Bayley ,&nbsp;María Inés Ragone ,&nbsp;Romina G. Díaz ,&nbsp;Alicia E. Consolini","doi":"10.1016/j.ejphar.2025.177677","DOIUrl":"10.1016/j.ejphar.2025.177677","url":null,"abstract":"<div><div>The antiarrhythmic amiodarone is frequently used, but it induces a risk of hypothyroidism. Their effects on myocardial function after ischemia are unclear. The aim of this work was to evaluate the effects on cardiac recovery during ischemia and reperfusion (I/R) of a subacute oral treatment with amiodarone on rats, and the influence of hypothyroidism, as well as the underlying mechanisms. Hypothyroid rat model (HypoT) was obtained by oral intake of 0.02 % methimazole for 15 days. Amiodarone treatment (30 mg/kg/day) was administered in both HypoT and euthyroid (EuT) rats during a week. Isolated hearts were perfused inside a flow-calorimeter to measure contractile performance (P), total heat rate (Ht) and muscle economy (P/Ht). Hearts were exposed to 30 min I and 45 min R. Moreover, infarct size and western-blot were determined at the end of R. Amiodarone improved the postischemic recovery in EuT rat hearts but reduced it in HypoT rat hearts. By using several selective pharmacological tools, it was demonstrated that amiodarone cardioprotection in EuT rats was strongly reduced by blocking PI3K/AKT, PKC, iNOS and mitochondrial ATP-dependent K⁺ channels (mK_ATP). Moreover, the reduced postischemic recovery in HypoT hearts treated with amiodarone was reversed by perfusing a scavenger of oxygen reactive species. Results suggest that protective effects of amiodarone in EuT rat hearts involved a pathway with scavenging of hydroxyl radicals and activation of iNOS, PKC, PI3K/AKT and mK_ATP channels. However, ROS production was increased in hearts of HypoT rats treated with amiodarone, causing the reduced post-ischemic mechano-energetic recovery.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177677"},"PeriodicalIF":4.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882786","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":"Comparison of safety signals for ibuprofen in children and adults: A real-world pharmacovigilance analysis","authors":"Xudong Xia ,&nbsp;Jingjing Wang ,&nbsp;Xiaocan Jia ,&nbsp;Jingwen Fan ,&nbsp;Yi Zhang ,&nbsp;Ying Qiao ,&nbsp;Yongli Yang","doi":"10.1016/j.ejphar.2025.177679","DOIUrl":"10.1016/j.ejphar.2025.177679","url":null,"abstract":"<div><div>Ibuprofen is commonly used as an over-the-counter antipyretic and analgesic. However, children, as vulnerable population, are frequently excluded from pre-market clinical trials. Furthermore, there is a lack of post-marketing safety study. This study aims to evaluate the adverse events (AEs) associated with ibuprofen in both children and adults in real-world practice. The data was obtained from the Adverse Drug Reaction Monitoring Center of Henan Province, covering the period from January 1, 2010 to December 31, 2023. A disproportionality analysis was conducted using the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) to detect risk signals associated with ibuprofen in children (0–17 years) and adults (≥18 years). A total of 1399 reports were recorded for children, while 9813 reports were documented for adults. Ibuprofen-related AEs were primarily associated with gastrointestinal disorders, nervous system disorders and skin and subcutaneous tissue disorders in both children and adults. Rash and pruritus were reported more frequently among children. AEs of gastrointestinal disorders were reported more frequently among adults. White blood cell count decreased (ROR = 12.72, PRR = 12.63) has been proposed as a new AE signal in children. Headache (ROR = 1.26, PRR = 1.26) and dizziness (ROR = 2.11, PRR = 2.04) were identified only in male adults, whereas abdominal discomfort (ROR = 1.25, PRR = 1.24) and rash pruritic (ROR = 2.16, PRR = 2.16) were observed solely in female adults. The toxicity profile of ibuprofen in children and adults exhibited distinct characteristics. Clinicians should provide active monitor based on these characteristic, especially white blood cell count decreased in children.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177679"},"PeriodicalIF":4.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882785","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":"Trametinib ameliorated Adriamycin-induced podocyte injury by inhibiting METTL3 modified m6A RCAN1 RNA methylation","authors":"Feifei Miao ,&nbsp;Junjun Luan ,&nbsp;Xiaochen Feng ,&nbsp;Yonghe Zhang ,&nbsp;Zixuan Feng ,&nbsp;Zhiduo Wang ,&nbsp;Yuqing Wang ,&nbsp;Rong Yang ,&nbsp;Chen Zhang ,&nbsp;Jeffrey B. Kopp ,&nbsp;Jingbo Pi ,&nbsp;Hua Zhou","doi":"10.1016/j.ejphar.2025.177680","DOIUrl":"10.1016/j.ejphar.2025.177680","url":null,"abstract":"<div><div>N6-methyladenosine (m⁶A) plays a crucial role in kidney diseases. Methyltransferase-like 3 (METTL3) as a key m⁶A writer can be regulated by trametinib. However, the epigenetic regulation of trametinib in focal segmental glomerulosclerosis (FSGS) remains unclear. We investigated whether trametinib protects podocytes by modulating METTL3-methylated target RNAs. Regulator of calcineurin 1 (RCAN1) was predicted as a target binding RNA of METTL3 by THEW database. Immunostaining of METTL3 and RCAN1 with podocyte marker Wilm's tumor-1 (WT-1) confirmed their localization within podocytes in renal biopsy from FSGS patients. Transfection METTL3 to human podocytes reduced WT-1, synaptopodin (SYNPO), and RCAN1 protein levels. Total m⁶A, m⁶A methylated RNA of <em>RCAN1</em> increased and total <em>RCAN1</em> mRNA decreased. Inhibition of METTL3 using siRNA or trametinib reversed these changes and attenuated the ADR-induced downregulation of WT-1 and SYNPO <em>in vitro</em>. In ADR-induced FSGS mice, trametinib ameliorated proteinuria, hypoalbuminemia, renal dysfunction, glomerulosclerosis and podocyte foot process effacement. Additionally, trametinib preserved podocyte function assessed by WT-1 and SYNPO as well as delayed renal fibrosis assessed by α-smooth muscle actin and fibronectin. Consistent with results <em>in vitro</em>, trametinib also decreased the ADR-induced upregulation of METTL3 and reversed the changed levels of total m⁶A, m⁶A methylated <em>Rcan1</em> and total <em>Rcan1</em> in FSGS mice. In conclusion, trametinib may serve as a renal protective agent for FSGS by regulating METTL3-dependent RCAN1 methylation levels.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177680"},"PeriodicalIF":4.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878624","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":"Epigoitrin decreases synaptosomal glutamate release and protects neurons from glutamate excitotoxicity in rats","authors":"Yi Chang ,&nbsp;Wun-Jing Pan ,&nbsp;Su-Jane Wang","doi":"10.1016/j.ejphar.2025.177654","DOIUrl":"10.1016/j.ejphar.2025.177654","url":null,"abstract":"<div><div>Excessive synaptic glutamate levels can lead to excitotoxicity, which is implicated in various neuropathologies. This study investigates whether epigoitrin, an alkaloid abundantly found in Radix isatidis, affects glutamate release in rat cortical nerve terminals (synaptosomes) and its impact on excitotoxicity induced by the glutamate analogue kainic acid in rats. In rat cortical synaptosomes, epigoitrin reduced glutamate release induced by 4-aminopyridine in a dose-dependent manner, with an IC₅₀ value of 3 μM. Removal of extracellular Ca²⁺ or blockade of P/Q-type Ca²⁺ channels prevented epigoitrin's effect on synaptosomal glutamate release, while the N-type Ca²⁺ channel inhibitor did not. In an in vivo rat model of glutamate excitotoxicity induced by kainic acid, epigoitrin pretreatment significantly mitigated neuronal injury, glutamate elevation, and the upregulation of excitotoxicity-related proteins (DAPK1 and NMDA receptor subunit GluN2B) in the cortex of kainic acid-treated rats. Additionally, epigoitrin pretreatment reduced reactive oxygen species (ROS) production, glial activation, and levels of inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while increasing the anti-inflammatory cytokine interleutin-10 in the cortex of kainic acid-treated rats. These results suggest that epigoitrin inhibits glutamate release from cortical synaptosomes by reducing P/Q-type Ca²⁺ channel activity and provides neuroprotection against kainic acid-induced neurotoxicity by preventing oxidative stress, neuroinflammation, and glutamate elevation. This study is the first to reveal the impact of epigoitrin on the glutamatergic system.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177654"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877332","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":"Agomelatine attenuates dexamethasone-induced neurotoxicity in rats through the activation of MT1/2 receptors and attenuation of oxidative stress","authors":"Noura Ali ,&nbsp;Rehab A. Hasan ,&nbsp;Islam Ahmed Ibrahim ,&nbsp;Mona F. Mahmoud","doi":"10.1016/j.ejphar.2025.177659","DOIUrl":"10.1016/j.ejphar.2025.177659","url":null,"abstract":"<div><div>Previous studies showed that agomelatine ameliorates doxorubicin-induced brain injury in rats. Furthermore, it protects neurons against oxidative stress triggered by acute ischemia reperfusion injury. So, this study aimed to investigate the possible neuroprotective effects of agomelatine on dexamethasone-induced neurotoxicity in rats and the underlying mechanisms. Subcutaneous injections of dexamethasone (10 mg/kg, 4 days) were used to induce neurotoxicity in rats. Agomelatine (10 mg/kg), luzindole (2.5 mg/kg, a melatonin receptor blocker), and luzindole plus agomelatine treatment commenced 3 days before dexamethasone injections and concurrent with dexamethasone injections. Elevated plus maze test, Y-maze test and open field test were carried out after 1 h of the last dose of dexamethasone on day 7. On 8th day of the experiment, brain tissues were collected. Brain oxidative stress markers, immunohistochemical expression of β-amyloid and glial fibrillary acidic protein (GFAP) were measured. Moreover, histopathological changes in the cerebral cortex and hippocampus were recorded and the number of damaged cells was counted. Dexamethasone increased anxiety and memory impairment but decreased locomotor exploration activity. Furthermore, it increased brain oxidative stress, expression of β-amyloid and GFAP, increased the number of damaged neurons, and caused structural changes in cerebral cortex and hippocampus. All these deleterious changes were mitigated by agomelatine. Luzindole prior administration to agomelatine reversed the protective effects of agomelatine except its effect on lipid peroxidation. Collectively, these findings suggest that agomelatine can protect against dexamethasone-induced neurotoxicity partially by activating melatonin receptors in addition to exerting antioxidant effects.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177659"},"PeriodicalIF":4.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881594","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":"HMGB1 derived from macrophages and enteric glial cells contributes to the butyrate-induced colonic hypersensitivity in mice","authors":"Maho Tsubota ,&nbsp;Kana Sasaki ,&nbsp;Eunkyung Shin ,&nbsp;Yuta Okamura ,&nbsp;Ayaka Nishimura ,&nbsp;Ayumu Yamagata ,&nbsp;Yui Nonaka ,&nbsp;Fumiko Sekiguchi ,&nbsp;Yasuko Tomono ,&nbsp;Masahiro Nishibori ,&nbsp;Takuya Okada ,&nbsp;Naoki Toyooka ,&nbsp;Atsufumi Kawabata","doi":"10.1016/j.ejphar.2025.177660","DOIUrl":"10.1016/j.ejphar.2025.177660","url":null,"abstract":"<div><div>High mobility group box1 (HMGB1), a nuclear protein, once acetylated by histone acetyltransferase, is released into the extracellular space, and causes pain signals, thereby contributing to pathological pain. Repeated intracolonic administration of butyrate, known to inhibit histone deacetylase (HDAC), produces colonic hypersensitivity in rodents, being widely used as models for irritable bowel syndrome (IBS). Thus, we asked whether HMGB1 would participate in the butyrate-induced colonic hypersensitivity in mice, and analyzed the underlying mechanisms. Repeated butyrate treatment caused colonic hypersensitivity to distension and intraluminal sulfide, a functional enhancer of Ca_v3.2 channels, in mice, which was prevented by repeated treatment with an anti-HMGB1-neutralizing antibody, thrombomodulin alfa (TMα) capable of causing thrombin-dependent degradation of HMGB1, antagonists for RAGE, TLR4 and CXCR4, membrane receptors of HMGB1, liposomal clodronate, a macrophage depletor, and ethyl pyruvate capable of inhibiting HMGB1 release from macrophages. Butyrate treatment increased the number of Iba1-positive macrophages, but not S100B-positive enteric glial cells (EGCs), and the rate of cytosolic/whole cell HMGB1 levels in both types of cells in the colonic mucosa. In macrophage-like RAW264.7 cells and EGC-like CRL-2690 cells, butyrate as well as trichostatin A, a well-known HDAC inhibitor, at the same concentrations that increased histone acetylation, evoked cytoplasmic translocation and extracellular release of nuclear HMGB1. Together, butyrate is considered to cause HMGB1 release from macrophages and EGCs most probably by inhibiting HDAC, resulting in colonic hypersensitivity in mice. HMGB1 and its membrane receptors might serve as drug targets for colonic hypersensitivity in IBS patients.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177660"},"PeriodicalIF":4.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878564","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":"David de Wied, a visionary scientist with a drive","authors":"Willem Hendrik Gispen ,&nbsp;Marian Joëls","doi":"10.1016/j.ejphar.2025.177656","DOIUrl":"10.1016/j.ejphar.2025.177656","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177656"},"PeriodicalIF":4.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873677","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 possible role of neurogenesis activators in temporal lobe epilepsy: State of art and future perspective","authors":"Ahmed salem Al-Dhahi ,&nbsp;Hayder M. Al-kuraishy ,&nbsp;Ali K. Albuhadily ,&nbsp;Ali I. Al-Gareeb ,&nbsp;Ahmed M. Abdelaziz ,&nbsp;Athanasios Alexiou ,&nbsp;Marios Papadakis ,&nbsp;Mubarak Alruwaili ,&nbsp;Gaber El-Saber Batiha","doi":"10.1016/j.ejphar.2025.177646","DOIUrl":"10.1016/j.ejphar.2025.177646","url":null,"abstract":"<div><div>Neurogenesis is a complex process by which the neurons and supporting cells of the central nervous system (CNS) are generated by neural stem cells. Adult hippocampal neurogenesis (AHN) in the human brain is an active process during life and plays a critical role in the regulation of memory, cognition, and mood. It has been shown that epilepsy is linked with dysregulation of AHN. Of note, AHN is very sensitive to the pathological electrical stimuli during epileptic seizures, which result in the induction of neurogenesis in acute epilepsy and inhibition of neurogenesis in chronic epilepsy. Epileptic seizure-induced neurodegeneration activates the mobilization of neural stem cells during neurogenesis to substitute for neural loss in temporal lobe epilepsy (TLE), which is the most refractory type of epilepsy. Moreover, recurrent epileptic seizures in TLE trigger neurogenesis in certain brain regions. However, AHN is a transient acute epileptic seizure that terminated with 1–4 weeks following status epilepticus (SE). Nevertheless, adult AHN is dramatically reduced in chronic epilepsy and associated with the development of cognitive impairment in TLE. These findings indicate that impairment of AHN is linked with the severity of epileptic seizures. Hence, neurogenesis activators may attenuate the pathogenesis of TLE. Therefore, this review aims to discuss and explain the beneficial role of AHN in TLE and how neurogenesis activators could be effective in the management of epilepsy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177646"},"PeriodicalIF":4.2,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863834","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":"Acacetin reverses hypoxic pulmonary hypertension by inhibiting hypoxia-induced proliferation of pulmonary artery smooth muscle cells via SIRT1-HMGB1 pathway","authors":"Hui Wang ,&nbsp;Li-Jing Peng ,&nbsp;Wang Lu ,&nbsp;Gui-Rong Li ,&nbsp;Peng-Tao Zhao ,&nbsp;Xing Lv ,&nbsp;Ming-Qing Dong ,&nbsp;Man-Ling Liu","doi":"10.1016/j.ejphar.2025.177650","DOIUrl":"10.1016/j.ejphar.2025.177650","url":null,"abstract":"<div><div>Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary arterial pressure and vascular remodeling. The present study is to investigate the efficacy of acacetin on HPH and its potential molecular mechanism. C57/BL6 mice were exposed to hypobaric hypoxia for six weeks. At 4th week of hypoxia exposure, mice were administrated with the water-soluble prodrug of acacetin (5, 10, 20 mg/kg) or equivalent normal saline for another two weeks. The haemodynamic and pathohistological assessment were performed. Primary pulmonary artery smooth muscle cells (PASMCs) were cultured to examine the anti-proliferation efficacy of acacetin (0.3–3 μM). The activity and expression of sirtuin1 (SIRT1) acetylation and distribution of high-mobility group box 1 (HMGB1) were determined in lungs and/or cultured PASMCs with or without RNA interference of SIRT1. Macromolecular docking and molecular dynamics simulation were done to explore the potential binding between acacetin and SIRT1. Results showed that acacetin prodrug significantly reversed the increased pulmonary pressure and vascular remodeling in HPH mice, which is associated with inhibiting the reduction in SIRT1 and the increase in HMGB1, and inhibiting the nucleocytoplasmic translocation of HMGB1. In cultured PASMCs, acacetin inhibited the hyper-proliferation induced by hypoxia, reversed the SIRT1 reduction and inhibited the nucleocytoplasmic translocation of HMGB1 and HMGB1 increase. Silencing SIRT1 abolished all the beneficial effects of acacetin. These results demonstrate that acacetin is very effective in reversing HPH by inhibiting PASMC hyper-proliferation via regulating SIRT1-HMGB1 signaling, suggesting that acacetin is likely a promising drug candidate for treating patients with HPH.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177650"},"PeriodicalIF":4.2,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863659","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":"Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors","authors":"Giorgia Corli ,&nbsp;Fabrizio De Luca ,&nbsp;Sabrine Bilel ,&nbsp;Marta Bassi ,&nbsp;Elisa Roda ,&nbsp;Paola Rossi ,&nbsp;Liana Fattore ,&nbsp;Carlo Alessandro Locatelli ,&nbsp;Matteo Marti","doi":"10.1016/j.ejphar.2025.177633","DOIUrl":"10.1016/j.ejphar.2025.177633","url":null,"abstract":"<div><h3>Rationale</h3><div>To date, the exposure to Synthetic Cannabinoids (SCs) has been linked to unanticipated psychiatric symptoms such as agitation, psychosis, and aggressive behavior. In line with this, preclinical studies have shown that acute and long-term exposure to these compounds can result in psychostimulant effects that may be related to CB₁-mediated and dopamine-dependent mechanisms.</div></div><div><h3>Objectives</h3><div>This study focuses on the progressive effects induced by repeated injection of 1-pentyl-3-(1-naphthoyl)indole JWH-018 (6 mg/kg, i.p.) on the locomotor activity and aggressive behavior in adult male ICR-CD1® mice. Thus, the interaction with the cannabinoid CB₁ receptor-preferring antagonist/inverse agonist AM-251 (6 mg/kg, i.p.), the dopamine D_1/5 receptor antagonist SCH23390 (0.1 mg/kg, i.p.), and the dopamine D_2/3 receptor antagonist haloperidol (0.05 mg/kg, i.p.) have been evaluated. Expression and distribution of D₁ and D₂ receptors and tyrosine hydroxylase (TH) have been also investigated by immunohistochemistry on brain and cerebellar samples to explore potential neuroplastic events.</div></div><div><h3>Results</h3><div>The repeated treatment with JWH-018 lead to the exacerbation of unanticipated psychomotor agitation, progressively increasing spontaneous locomotion and aggressiveness. Pre-treatment with AM-251 prevents the effects induced by the SC first, third and seventh injection. SCH23390 and haloperidol significantly attenuate and fully prevent the effects induced by JWH-018 seventh injection when pre-administered, respectively, alone and in combination. Behavioral changes observed in JWH-018-treated mice are accompanied by alterations in cortical, hippocampal, striatal and cerebellar D₁, D₂ and TH gene expression levels.</div></div><div><h3>Conclusion</h3><div>The present results demonstrated that repeated treatment with high dosage of JWH-018 induces psycho-stimulants effects via both CB₁ receptor-mediated and dopamine-dependent mechanisms.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"998 ","pages":"Article 177633"},"PeriodicalIF":4.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870172","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}