Neuropharmacology最新文献

{"title":"Comparison of ventilatory depression by carfentanil, fentanyl, and heroin, and reversal by opioid receptor antagonists in rats","authors":"Shawn M. Flynn ,&nbsp;Charles P. France","doi":"10.1016/j.neuropharm.2025.110601","DOIUrl":"10.1016/j.neuropharm.2025.110601","url":null,"abstract":"<div><div>Fentanyl and its analogs continue to drive the overdose crisis in the United States. It is unclear whether there are unique properties of fentanyls that increase the risk of opioid overdose compared with other opioid receptor agonists (e.g., heroin). This study compared the ventilatory depressant effects of the opioid receptor agonists heroin, fentanyl, and carfentanil, and reversal of those effects by opioid receptor antagonists. This study used whole-body plethysmography in rats to determine the ventilatory depressant effects of heroin (178–1780 μg/kg), fentanyl (5.6–56 μg/kg), and carfentanil (0.56–5.6 μg/kg) when administered alone and in mixtures, to compare the profile of effects across drugs and determine whether there are significant interactions between the drugs when co-administered. The potencies of the opioid receptor antagonists naloxone and diprenorphine to reverse opioid-induced ventilatory depression were compared across opioid agonists. All three agonists reduced minute volume with carfentanil being ∼50- and 100-fold more potent than fentanyl and heroin, respectively. The profile of effects on ventilation did not differ across agonists and no significant drug-drug interactions were detected. Naloxone and diprenorphine dose-dependently reversed the ventilatory depressant effects of each opioid agonist. Both antagonists were less potent at reversing the effects of carfentanil compared with reversing a functionally equivalent dose of heroin. These findings suggest that fentanyl might not produce unique effects on breathing that increase risk of overdose. That naloxone and diprenorphine were less potent to reverse the effects of carfentanil compared with an equivalent dose of heroin is consistent with existing literature and emphasizes the need for continued evaluation of potential differences in pharmacological properties across opioid receptor agonists.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110601"},"PeriodicalIF":4.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceftriaxone ameliorates tau phosphorylation and mislocalization in APP/PS1 AD mice by inhibiting endoplasmic reticulum stress","authors":"Niu-Niu Feng ,&nbsp;Li Li ,&nbsp;Li-Zhe Liu ,&nbsp;Ruo-Bing He ,&nbsp;Xiao-Hui Xian ,&nbsp;Li-Rong Liu ,&nbsp;Yu-Yan Hu ,&nbsp;Wen-Bin Li","doi":"10.1016/j.neuropharm.2025.110600","DOIUrl":"10.1016/j.neuropharm.2025.110600","url":null,"abstract":"<div><div>Tau phosphorylation and mislocalization are hallmark pathological features of Alzheimer's disease (AD), with endoplasmic reticulum stress (ERS) contributing to tauopathy. We previously showed that ceftriaxone (Cef) improves cognition in APP/PS1 AD mice through regulating GLT-1-mediated glutamate homeostasis. Here, we examined Cef's neuroprotection against ERS-related tauopathy. C57BL/6J and APP/PS1 AD mice were used. Cognitive functions were assessed by new object recognition (NOR), new location recognition (NLR) and Morris water maze (MWM) tests. Hippocampal synaptosomes were isolated using the Syn-PER™ Synaptic Protein Extraction Kit. Western blot analysis evaluates the protein levels of ERS markers, total and phosphorylated tau (Ser396/Ser262/Thr181), and Gsk3β. Transmission electron microscopy examined the endoplasmic reticulum ultrastructural changes of the hippocampus. Confocal 3D-reconstructed imaging assessed the phosphorylated tau (Ser396) distribution on the dendrites in the hippocampal region. The results showed that Cef treatment effectively reduced protein levels of ERS markers and restored endoplasmic reticulum ultrastructural integrity of hippocampus. Simultaneously, Cef treatment significantly alleviated tau phosphorylation levels, decreased accumulation of total and phosphorylated tau in synaptosomes, reduced phosphorylated tau (Ser396) distribution in dendritic compartments and inhibited Gsk3β activity in the hippocampus of APP/PS1 AD mice. Tunicamycin, a promoter of ERS, exacerbated cognitive impairments, tau phosphorylation levels and mislocalization, and Gsk3β activity, and notably, this exacerbation was inhibited by Cef treatment. Simultaneously, the ERS activation significantly inhibited Cef's above benefits on APP/PS1 AD mice. In conclusion, Cef improves cognitive impairment by alleviating ERS, decreasing Gsk3β activity, and reducing tau phosphorylation and mislocalization in the hippocampus of APP/PS1 AD mice.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110600"},"PeriodicalIF":4.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropharmacology adenosine A2A receptor and glial glutamate transporter GLT-1 are synergistic targets to reduce brain hyperexcitability after traumatic brain injury in mice","authors":"Mariana Alves ,&nbsp;Rogério Gerbatin ,&nbsp;Rebecca Kalmeijer ,&nbsp;Denise Fedele ,&nbsp;Tobias Engel ,&nbsp;Detlev Boison","doi":"10.1016/j.neuropharm.2025.110599","DOIUrl":"10.1016/j.neuropharm.2025.110599","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a leading cause of acquired epilepsy, with post-traumatic epilepsy (PTE) significantly contributing to morbidity and mortality. To date, there is no treatment capable to prevent the development of PTE, which remains an urgent unmet need. Previous studies suggest that adenosine A_2A receptor (A_2AR) activation and glutamate transporter 1 (GLT-1) dysregulation may contribute to epileptogenesis, however, it is unclear whether therapeutic targeting of the A_2AR or GLT-1 can attenuate TBI-induced hyperexcitability, and whether there are synergistic interactions between the two. Here, we investigated the therapeutic potential of two FDA approved drugs istradefylline (A_2AR inhibitor) and ceftriaxone (GLT-1 activator) in preventing long-lasting brain hyperexcitability in a clinically relevant rodent model of TBI. Adult male mice underwent controlled cortical impact (CCI)-induced TBI and were randomly assigned to istradefylline, ceftriaxone, istradefylline/ceftriaxone, or vehicle groups, receiving treatment during the first 24 h post-injury. Susceptibility to chemoconvulsant-evoked seizures was quantified at 4–5 weeks after CCI. We show that CCI caused a reduction in GLT-1 and an increase in A_2AR protein levels in the ipsilateral hippocampus. Transient acute treatment with istradefylline or ceftriaxone reduced brain hyperexcitability at 4–5 weeks post-TBI. Notably, mice treated with the combination of istradefylline and ceftriaxone exhibited increased GLT-1 levels, accompanied by further reductions in brain hyperexcitability, showing greater effects than either drug alone. Our findings identify a novel disease-modifying approach following TBI using a combination of two FDA-approved drugs which might be useful to mitigate the long-lasting brain hyperexcitability-induced by TBI.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110599"},"PeriodicalIF":4.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent role of Neuropeptide-S on anxiety, fear conditioning, and alcohol seeking in alcohol preferring rats","authors":"Min Li ,&nbsp;Sara De Carlo ,&nbsp;Laura Soverchia ,&nbsp;Scott P. Runyon ,&nbsp;Stewart Clark ,&nbsp;Marisa Roberto ,&nbsp;Carolina L. Haass-Koffler ,&nbsp;Roberto Ciccocioppo ,&nbsp;Douglas J. Sheffler ,&nbsp;Nazzareno Cannella","doi":"10.1016/j.neuropharm.2025.110598","DOIUrl":"10.1016/j.neuropharm.2025.110598","url":null,"abstract":"<div><div>Alcohol Use Disorder (AUD) is a global health concern, with stress playing a crucial role in its development and persistence. Currently, no pharmacotherapies specifically targeting stress are approved for AUD treatment. Neuropeptide S (NPS) plays a dual role in stress regulation, exhibiting both anxiolytic and stress-enhancing effects. While NPS reduces alcohol self-administration (ASA) in alcohol preferring rats, its role in AUD-related stress and anxiety remains unclear.</div><div>This study investigated the behavioral effects of NPS in male and female Marchigian Sardinian alcohol-preferring (msP) rats. To assess its impact on locomotion, anxiety, and fear memory, we conducted an open-field, an elevated plus maze (EPM), and a fear conditioning (FC) paradigm following intracerebroventricular administration of NPS. Furthermore, we examined the effects of NPS on ASA and yohimbine-induced reinstatement of alcohol-seeking in msP rats.</div><div>Our results indicate that NPS administration increased locomotor activity in both sexes and selectively alleviated generalized anxiety levels in male rats in the EPM test. In the FC task, administration of NPS immediately after FC test facilitated the extinction of fear memories in females but not in males. Notably, NPS reduced ASA in both female and male rats but did not alter yohimbine-induced reinstatement of alcohol-seeking. In conclusion, NPS modulates anxiety in a sex-dependent manner. Since both alcohol and NPS alleviate anxiety and fear conditioning in msP rats, NPS may reduce alcohol intake by replacing the anxiolytic properties of alcohol. These effects appear to be sex-dependent, with NPS primarily alleviating generalized anxiety in males and facilitating fear extinction in females.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110598"},"PeriodicalIF":4.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pantothenic acid-mediated inhibition of microglial inflammation via the JAK2/STAT3 pathway enhances motor function recovery after Spinal cord injury","authors":"Yuepeng Fang ,&nbsp;Ce Zhang ,&nbsp;Zhijie Yang ,&nbsp;Xiangrui Zhao ,&nbsp;yongcheng Yin ,&nbsp;zhengxin Jin ,&nbsp;Pengchong Zhu ,&nbsp;Bin Ning","doi":"10.1016/j.neuropharm.2025.110591","DOIUrl":"10.1016/j.neuropharm.2025.110591","url":null,"abstract":"<div><div>This study employed transcriptome sequencing and targeted metabolomics to delve into the molecular alterations in mouse spinal cords following spinal cord injury (SCI). Notably, a significant depletion of pantothenic acid (PA) was observed in the injured spinal cord, exhibiting an inverse correlation with microglial inflammation and activation. To further elucidate this relationship, experimental interventions using PA were conducted in SCI mouse models. The results demonstrated that PA administration effectively inhibited microglial inflammation via modulation of the JAK2/STAT3 signaling pathway. This inhibition not only mitigated the neuroinflammatory milieu but also fostered an environment conducive to axonal growth and neuronal regeneration. Consequently, SCI mice treated with PA exhibited improved motor function recovery compared to untreated controls. Our findings not only deepen the understanding of the relationship between PA and neuroinflammatory processes in SCI but also highlight the therapeutic potential of PA in promoting neuronal regeneration and functional recovery.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110591"},"PeriodicalIF":4.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosterone modulates dopamine and serotonin1A receptor mediated regulation of prepulse inhibition and startle in male rats","authors":"Wendy K. Adams ,&nbsp;Maarten van den Buuse","doi":"10.1016/j.neuropharm.2025.110594","DOIUrl":"10.1016/j.neuropharm.2025.110594","url":null,"abstract":"<div><div>The aim of this project was to investigate the role of stress in neurotransmitter modulation of prepulse inhibition (PPI), a model of sensorimotor gating which is disrupted in schizophrenia and other illnesses. We studied the effect of adrenalectomy (ADX) and low and high levels of corticosterone (CORT) replacement on the effect of pharmacological modulators of PPI in rats. In ADX rats treated with a high dose of CORT (CORT200) the disruption of PPI caused by acute treatment with the dopamine receptor agonist, apomorphine, was significantly enhanced compared to ADX rats implanted with a control cholesterol pellet. On the other hand, CORT200 rats were less sensitive to the effect of the serotonin_1A receptor agonist, 8-OH-DPAT, while ADX rats implanted with a lower dose of CORT (CORT50) showed enhanced responding to this treatment. There were no differential effects on baseline PPI, or changes in startle or habituation of startle that could explain the effects on PPI. These data suggest that prolonged CORT treatment induces a major shift in dopaminergic and serotonergic mechanisms involved in the regulation of PPI. ADX and CORT replacement were found to have no effect on dopamine D₂ receptor densities in the nucleus accumbens (NAc), striatum or cingulate cortex, suggesting that our current observations are not due to changes in the levels of these receptors. These data may provide new insight into the role of stress in psychosis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110594"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144680359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selectively counteracting cerebellar adaptations to chronic alcohol exposure reduces acute alcohol withdrawal severity in C57BL6/N mice","authors":"Nadia A. McLean ,&nbsp;Samantha N. Shippell Stiles ,&nbsp;Aspen E. Harder ,&nbsp;Chloe M. Erikson ,&nbsp;Gloria J. Lee ,&nbsp;Dominik Schnalzer ,&nbsp;Margot Ernst ,&nbsp;Marko D. Mihovilovic ,&nbsp;Giuseppe Giannotti ,&nbsp;David J. Rossi","doi":"10.1016/j.neuropharm.2025.110595","DOIUrl":"10.1016/j.neuropharm.2025.110595","url":null,"abstract":"<div><div>A critical component of Alcohol Use Disorder (AUD) is alcohol (EtOH) withdrawal and consequent aversive withdrawal symptoms that generate negative reinforcement for renewed EtOH consumption to alleviate such symptoms. Here, we simulated human binge EtOH consumption and subsequent acute withdrawal by exposing male and female C57BL6/N mice to EtOH vapor for varying durations (24–72 h). During acute withdrawal, starting 4 h after removal from EtOH vapor, we used patch-clamp recording in cerebellar slices, combined with behavioral analysis of aversive somatic/motor (performance on the accelerating rotorod) and affective/emotional (ultrasonic vocalizations and blood corticosterone) withdrawal symptoms. We found that cerebellar granule cells (GCs) exhibit a homeostatic downregulation of sIPSC frequency that parallels development of motor discoordination and negative emotional affect, all starting at ∼48–72 h of EtOH vapor exposure. Fitting with the negative reinforcement component of the AUD cycle, re-exposure to EtOH during withdrawal reduced somatic and affective withdrawal symptoms. Importantly, selective chemogenetic inhibition of GCs during withdrawal improved motor coordination, likely via actions at the GC axon terminals, and selective pharmacological inhibition of GCs via enhancement of the tonic GABA_AR current, using PZ-II-019 (Compound 6), significantly improved negative emotional affect. Collectively, these results indicate that cerebellar homeostatic adaptations mediate aspects of both somatic and affective aversive EtOH withdrawal symptoms, and that restoration of cerebellar adaptations can effectively treat such symptoms. Moreover, they highlight the cerebellum as a promising selective target for treating aversive EtOH withdrawal symptoms, a critical component of the AUD cycle.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110595"},"PeriodicalIF":4.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropharmacology editorial","authors":"James E. McCutcheon ,&nbsp;Carrie R. Ferrario","doi":"10.1016/j.neuropharm.2025.110592","DOIUrl":"10.1016/j.neuropharm.2025.110592","url":null,"abstract":"","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110592"},"PeriodicalIF":4.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imperatorin activates TRPV1/GRPR pathway to induce scratching behaviors in mice","authors":"Liyuan Bao ,&nbsp;Xinyi Gao ,&nbsp;Ting Yi,&nbsp;Yayue Yang,&nbsp;Tianchi Gao,&nbsp;Yachen Yang,&nbsp;Mengping Lou,&nbsp;Pingjing Zhou,&nbsp;Yuxin Zhang,&nbsp;Yanqing Wang,&nbsp;Wenli Mi","doi":"10.1016/j.neuropharm.2025.110593","DOIUrl":"10.1016/j.neuropharm.2025.110593","url":null,"abstract":"<div><div>Chronic itch is a prevalent and distressing symptom associated with several diseases, and significantly affects patients’ quality of life. Investigating the mechanisms underlying itch and identifying novel anti-pruritic drugs require the development of innovative preclinical animal models. In this study, an acute animal model of itch was established using an intradermal (i.d.) injection of imperatorin (IMP) into the nape of the neck or cheek of male and female mice. The i d. IMP injection in the nape elicited a robust, dose-dependent scratching behavior that was independent of histamine. IMP injection into the cheek induced both scratching and wiping behaviors. Furthermore, IMP injection upregulated the phosphorylation of extracellular signal regulated kinases (p-ERK) and calcium influx in the dorsal root ganglion (DRG), which were suppressed by the deficiency of transient receptor potential ion channel V1 (TRPV1). Scratching behaviors could also be inhibited by TRPV1 deficiency. IMP-induced scratching could be mitigated by an intrathecal injection of the GRPR antagonist RC3095, and the IMP-evoked increase in c-Fos expression in GRPR⁺ neurons in the spinal cord was attenuated by TRPV1 deficiency. These findings suggest that IMP could trigger itch-related responses, at least partially, via the activation of TRPV1⁺ neurons in the DRG and subsequently the GRPR + neurons in the spinal cord. IMP may therefore serve as an efficient nonhistaminergic model of acute itch to screen of potential anti-pruritus agents.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110593"},"PeriodicalIF":4.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anxiolytic effects of clemastine via modulation of hippocampal oligodendrocytes in a mouse model of methotrexate-induced cognitive impairment","authors":"Ryosuke Ochi,&nbsp;Jun Yamada,&nbsp;Kyoko M. Iinuma,&nbsp;Shozo Jinno","doi":"10.1016/j.neuropharm.2025.110589","DOIUrl":"10.1016/j.neuropharm.2025.110589","url":null,"abstract":"<div><div>Anxiety poses a significant psychological burden for cancer patients. Cancer-related cognitive impairment (CRCI), resulting from chemotherapy and/or peripheral malignancies, is increasingly linked to glial cell dysregulation in the brain. Therefore, the present study investigated the potential role of hippocampal oligodendrocytes in CRCI pathogenesis. Methotrexate (MTX), a chemotherapeutic anticancer drug, was administered intraperitoneally to 7-week-old male C57BL/6J mice. MTX treatment enhanced anxiety-like behavior in both open-field and elevated plus-maze tests, whereas short-term memory assessed in a Y-maze test and contextual memory in a fear conditioning test were preserved. Additionally, MTX led to a reduction in the hippocampal expression of myelin-related genes, including <em>Plp</em>, and decreased the densities of oligodendrocyte precursor cells, mature oligodendrocytes, and myelin-related proteins. In contrast, MTX did not impact the expression of genes associated with microglia and astrocytes, nor the densities of these cells in the hippocampus. The administration of clemastine fumarate (CLE), a first-generation antihistamine, reduced MTX-induced anxiety-like behavior in both open-field and elevated plus-maze tests. CLE also restored the expression of myelin-related genes and densities of oligodendrocyte precursor cells, mature oligodendrocytes, and myelin-related proteins in the hippocampus of MTX-treated mice. To further elucidate the mechanism, we analyzed gene expression in the FBD-102b oligodendrocyte precursor cell line. MTX downregulated key myelin-related genes, including <em>Sox10</em> and <em>Plp</em>, but CLE treatment effectively counteracted this. This in vitro evidence strongly supports our in vivo findings, demonstrating that CLE exerts anxiolytic effects in CRCI by modulating MTX-induced damage to hippocampal oligodendrocytes, thus identifying a specific mechanism for a novel therapeutic strategy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110589"},"PeriodicalIF":4.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}