Neuropharmacology最新文献

{"title":"Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats","authors":"Shivani P. Vaidya ,&nbsp;Roberta G. Anversa ,&nbsp;Paulo Pinares-Garcia ,&nbsp;Leigh C. Walker ,&nbsp;Natasha Pracejus ,&nbsp;Christopher A. Reid ,&nbsp;Andrew J. Lawrence","doi":"10.1016/j.neuropharm.2025.110371","DOIUrl":"10.1016/j.neuropharm.2025.110371","url":null,"abstract":"<div><div>Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested <em>in vivo</em> through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110371"},"PeriodicalIF":4.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472604","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":"Spinal astrocyte-derived M-CSF mediates microglial reaction and drives visceral hypersensitivity following DSS-induced colitis","authors":"Ke Wu ,&nbsp;Shuai Shao ,&nbsp;Yu-ting Dong ,&nbsp;Yue-ying Liu ,&nbsp;Xing-han Chen ,&nbsp;Peng Cheng ,&nbsp;Xia Qin ,&nbsp;Xiao-han Peng ,&nbsp;Yong-mei Zhang","doi":"10.1016/j.neuropharm.2025.110373","DOIUrl":"10.1016/j.neuropharm.2025.110373","url":null,"abstract":"<div><div>Visceral hypersensitivity is one of the most prevalent symptoms of inflammatory bowel disease (IBD), and it can be difficult to cure despite achieving endoscopic remission. Accumulating studies have described that macrophage colony-stimulating factor (M-CSF) modulates neuroinflammation in the central nervous system (CNS) and the development of chronic pain, while the underlying mechanism for whether and how M-CSF/CSF1R signaling pathway regulates visceral hypersensitivity following colitis remains unknown. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we determined that microglial accumulation occurred in the spinal dorsal horn during remission phase. The reactive microglia released inflammatory factor, increased neuronal excitability in the dorsal horn, and produced chronic visceral pain behaviors in DSS-treated adult male mice. In addition, we also found significantly increased signaling mediated by astrocytic M-CSF and microglial CSF1R in dorsal horn in the mice with colitis. Exogenous M-CSF induced microglial activation, neuronal hyperactivity and behavioral hypersensitivity in the control group, inhibition of astrocyte/microglia by fluorocitrate/minocycline significantly suppressed microglial and neuronal activity, and relieved the visceral hypersensitivity in the model mice. Overall, our experimental study uncovers the critical involvement of spinal astrocyte-derived M-CSF and reactive microglia in the initiation and maintenance of visceral hypersensitivity following colitis, thereby identifying spinal M-CSF as a target for treating chronic visceral pain. This may provide more accurate theoretical guidance for clinical patients with IBD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110373"},"PeriodicalIF":4.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464819","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":"Disrupted maternal behavior in morphine-dependent pregnant rats and anhedonia in their offspring","authors":"Christopher T. Searles ,&nbsp;Meghan E. Vogt ,&nbsp;Iyanuoluwa Adedokun,&nbsp;Anne Z. Murphy","doi":"10.1016/j.neuropharm.2025.110372","DOIUrl":"10.1016/j.neuropharm.2025.110372","url":null,"abstract":"<div><div>It is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. For the first two postnatal weeks, maternal behavior was examined for fragmentation and unpredictability. Unpredictable behavioral patterns were quantitatively characterized as entropy scores. Offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic cells of mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure promotes anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110372"},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454162","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":"Δ9-tetrahydrocannabinol induces blood-brain barrier disruption: Involving the activation of CB1R and oxidative stress","authors":"Qianyao Zhang,&nbsp;Wenxin Huang,&nbsp;Taokun Li,&nbsp;Xuemei Wang,&nbsp;Ximin Lai,&nbsp;Wei Hu,&nbsp;Zhihong Li,&nbsp;Xiaofeng Zeng,&nbsp;Jian Huang,&nbsp;Ruilin Zhang","doi":"10.1016/j.neuropharm.2025.110366","DOIUrl":"10.1016/j.neuropharm.2025.110366","url":null,"abstract":"<div><div>Cannabis abuse has increased with the continuous relaxation of cannabis policies. However, the mechanism by which Δ⁹-tetrahydrocannabinol (THC) negatively affects the central nervous system, especially the blood-brain barrier (BBB), remains unclear. THC exposure models were established <em>in vivo</em> and <em>in vitro</em>. The BBB properties were examined using Western blotting (WB), immunofluorescence staining (IF), transendothelial electrical resistance (TEER), and flux of sodium fluorescein (SF). The oxidative stress regulators were examined using IF and assay kits. The activation of cannabinoid receptor 1 (CB1R) was examined using WB and IF. The THC exposure caused barrier integrity damage and endothelial dysfunction in murine and hCMEC/D₃ cells, conclude albumin leakage, increased SF permeability and reduced TEER value. The expression of tight junction proteins, including claudin 5, occludin, and junctional adhesion molecules, was decreased. Additionally, key oxidative stress regulators, including reactive oxygen species, hydrogen peroxide, malonaldehyde levels, and antioxidant enzyme activities, including catalase, glutathione peroxidase, glutathione S-transferase, and superoxide dismutase, and heme oxygenase 1, were increased. Activation of CB1R has been detected in brain microvascular endothelial cells <em>in vivo</em> and <em>in vitro</em>. Furthermore, inhibition of oxidative stress and CB1R could mitigate the aforementioned conditions and BBB damage after THC exposure. The effect of THC on murine and human brain microvascular endothelial cells revealed that THC-induced BBB damage was partly mediated by CB1R activation, triggering the oxidative stress response. This study provides new theoretical insights into the mechanisms of THC-induced BBB damage and offers novel scientific evidence for the potential neurotoxicity and adverse reactions induced by THC.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110366"},"PeriodicalIF":4.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427917","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":"Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2 – Implications for transmitter co-release from dopamine neurons","authors":"Sivakumar Srinivasan ,&nbsp;Fabian Limani ,&nbsp;Michaela Hanzlova ,&nbsp;Ségolène La Batide-Alanore ,&nbsp;Sigrid Klotz ,&nbsp;Thomas S. Hnasko ,&nbsp;Thomas Steinkellner","doi":"10.1016/j.neuropharm.2025.110367","DOIUrl":"10.1016/j.neuropharm.2025.110367","url":null,"abstract":"<div><div>Midbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2.</div><div>Here, we used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from male and female mice to determine whether GABA qualifies as substrate at VMAT2. We found that GABA reduced uptake of VMAT2 substrates in mouse synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing HEK-293 cells. Interestingly, while the closely related amino acid glycine did not affect substrate uptake at VMAT2 in mouse synaptic vesicles, the amino sulfonic acid taurine reduced uptake similar to GABA. Lastly, we discovered that the majority of mouse and human midbrain DA neurons in the substantia nigra of either sex expressed VMAT2 and GAT1 suggesting that most of them could be capable of co-releasing DA and GABA. Together, our findings suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110367"},"PeriodicalIF":4.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal exposure to methadone or buprenorphine alters transcriptional networks associated with synaptic signaling in newborn rats","authors":"Henriette Nyberg ,&nbsp;Inger Lise Bogen ,&nbsp;Nur Duale ,&nbsp;Jannike Mørch Andersen","doi":"10.1016/j.neuropharm.2025.110368","DOIUrl":"10.1016/j.neuropharm.2025.110368","url":null,"abstract":"<div><div>While the use of methadone or buprenorphine during pregnancy is beneficial for the mother's health compared to illicit opioid use, prenatal exposure to these medications may have adverse consequences for the unborn child. However, the underlying molecular mechanisms of prenatal opioid exposure on neurodevelopment remain poorly understood. Hence, this study aimed to investigate gene expression changes, focusing on synapse-related genes, in cerebral tissue from newborn rats prenatally exposed to methadone or buprenorphine. Female Sprague-Dawley rats were exposed to methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day), or sterile water through osmotic minipumps during pregnancy. Total RNA was isolated from the cerebrum on postnatal day 2 and analyzed using RNA-sequencing. Analyses of differentially expressed genes (DEGs) and enriched biological processes were conducted to compare the gene expression profiles between treatment groups within each sex. Prenatal buprenorphine exposure resulted in 598 DEGs (333 up- and 265 downregulated) in males and 175 (75 up- and 100 downregulated) in females, while prenatal methadone exposure resulted in 335 DEGs (224 up- and 111 downregulated) in males and 201 (57 up- and 144 downregulated) in females. Gene ontology analyses demonstrated that enriched biological processes included synaptic signaling, immune responses, and apoptosis. Analysis of the DEGs using the synapse database SynGO revealed that males prenatally exposed to buprenorphine displayed the highest number of enriched synapse-related biological process terms. Understanding gene expression changes following prenatal methadone or buprenorphine exposure is crucial to uncover the mechanisms underlying behavioral alterations and to develop interventions to mitigate the impact of opioid exposure on neurodevelopment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110368"},"PeriodicalIF":4.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432839","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":"Modulation of spinal morphine pharmacokinetics and antinociception by α2-adrenergic agonists in the male rat","authors":"Radu G. Copie ,&nbsp;Kim Blomqvist ,&nbsp;Melina Farzaneh Kari ,&nbsp;Mika Kurkela ,&nbsp;Mikko Niemi ,&nbsp;Pekka V. Rauhala ,&nbsp;Terhi J. Lohela ,&nbsp;Marko Rosenholm ,&nbsp;Tuomas O. Lilius","doi":"10.1016/j.neuropharm.2025.110369","DOIUrl":"10.1016/j.neuropharm.2025.110369","url":null,"abstract":"<div><div>The synergistic antinociceptive effects of α₂-adrenergic agonists and intrathecal (i.t.) opioids were initially linked to pharmacodynamics. However, the α₂-agonist dexmedetomidine also enhances brain delivery of CSF-administered drugs by increasing glymphatic influx. Here, fadolmidine, a hydrophilic α₂-agonist designed for spinal analgesia, was studied for its sedative, antinociceptive, and pharmacokinetic effects with co-administered lumbar intrathecal morphine. Subcutaneous and i.t. dexmedetomidine served as comparators.</div><div>Forty-eight male Sprague-Dawley rats received i.t. lumbar catheters. Sedative effects of i.t. fadolmidine (1–10 μg) and i.t. dexmedetomidine (1–10 μg) were assessed by open field and rotarod tests. The antinociceptive effects of morphine alone (1.5 μg i.t.) and co-administered with i.t. fadolmidine (3 and 10 μg) were evaluated using the tail-flick test. Effects of i.t. fadolmidine and subcutaneous dexmedetomidine (0.2 mg/kg) on morphine concentration within CNS were assessed by liquid chromatography-tandem mass spectrometry at 60 min.</div><div>While i.t. dexmedetomidine was sedating, i.t fadolmidine was not. The antinociceptive effects of other treatment regimens weaned at latest after 90 min, whereas the combination of fadolmidine 10 μg i.t. and morphine 1.5 μg i.t. provided antinociception until the end of the measurement period (%maximum possible effect of 77.5 ± 11.5 vs saline 10.6 ± 11.1, p = 0.0002 at 120 min). Subcutaneous dexmedetomidine effectively targeted lumbar morphine towards the injection site resulting in a 3335-fold (95% CI: 929−11978) lower brain-to-injection site ratio, versus a 355-fold (95% CI: 196−641) difference with saline.</div><div>By improving spinal opioid targeting, α₂-adrenergic agonists dexmedetomidine and fadolmidine may reduce supraspinal side effects, enabling safe and efficacious intrathecal analgesia.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110369"},"PeriodicalIF":4.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of an astrocyte calcium exporter on orbitofrontal cortex neuron excitability, astrocyte-synaptic interaction, and alcohol consumption","authors":"A.R. Kastner-Blasczyk ,&nbsp;S.W. Hester ,&nbsp;S.E. Reasons ,&nbsp;M.D. Scofield ,&nbsp;J.J. Woodward","doi":"10.1016/j.neuropharm.2025.110365","DOIUrl":"10.1016/j.neuropharm.2025.110365","url":null,"abstract":"<div><div>Previous electrophysiology studies show that acute ethanol inhibits firing of orbitofrontal (OFC) cortex neurons while chronic intermittent ethanol (CIE) exposure increases firing accompanied by enhanced ethanol drinking. The acute ethanol inhibition of OFC neuronal firing is mediated by inhibitory glycine receptors and is reduced by expressing a plasma membrane calcium ATPase (PMCA) in OFC astrocytes. In this study, we tested the effects of astrocyte PMCA on CIE-induced increases in excitability and alcohol consumption and the physical interaction between OFC astrocytes and neurons. CIE increased neuronal firing in male mice as compared to Air controls while PMCA itself increased firing in Air control male mice. In contrast, PMCA reduced CIE-mediated hyperexcitability of firing in females. CIE did not affect OFC astrocyte size in control or PMCA male mice but increased astrocyte size in female mice. Similar to spiking, PMCA and CIE both increased the number of GluA1 containing synapses within the vicinity of virally labeled astrocytes in male mice but had differential effects in females. The astrocytic interaction with GluA1 labeled synapses was not affected by CIE treatment in male or female control mice, but there was a treatment-dependent effect of PMCA in male mice. CIE increased alcohol consumption in control but not PMCA male mice and had no effect on drinking in female mice. Lastly, OFC astrocyte PMCA expression had no effect on behavioral measures of locomotion, anxiety, spontaneous alternation, or spatial memory. These findings reveal important sex-dependent differences in the physiological, structural and behavioral actions of OFC astrocytes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110365"},"PeriodicalIF":4.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZLN005, a PGC-1α agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa","authors":"Chengyu Hu ,&nbsp;Chengda Ren ,&nbsp;Yan Wu ,&nbsp;Ruoyi Lin ,&nbsp;Tianyi Shen ,&nbsp;Tingting Li ,&nbsp;Donghui Yu ,&nbsp;Lei Jiang ,&nbsp;Zhongqi Wan ,&nbsp;Yunhong Luo ,&nbsp;Tu Su ,&nbsp;Jing Yu ,&nbsp;Yaoyan Qiu","doi":"10.1016/j.neuropharm.2025.110361","DOIUrl":"10.1016/j.neuropharm.2025.110361","url":null,"abstract":"<div><div>Retinitis pigmentosa (RP) is a hereditary neurodegenerative disease characterized by the degeneration of photoreceptors caused by mutations in various genes. Increasing evidence suggests that mitochondrial biogenesis plays a critical role in many neurodegenerative diseases. This study investigated the role of mitochondrial biogenesis in rd1 mice, a widely recognized model of RP. Male C57BL/6 mice and age-matched rd1 mice were used for in vivo experiments, while H₂O₂ was employed on 661w cells to establish an in vitro model. Our findings revealed that mitochondrial biogenesis and the regulatory PGC-1α/NRF-1/TFAM pathway were significantly downregulated in rd1 mice. Treatment with ZLN005, a PGC-1α agonist, markedly improved visual function in rd1 mice and alleviated thinning of the retinal outer nuclear layer. Additionally, ZLN005 enhanced mitochondrial biogenesis and restored mitochondrial function in photoreceptors. Further analysis in vitro confirmed that ZLN005 rescued photoreceptor degeneration by promoting mitochondrial biogenesis through the PGC-1α/NRF-1/TFAM pathway. In summary, our results highlight the critical role of mitochondrial biogenesis and the PGC-1α/NRF-1/TFAM pathway in the progression of RP. This offers a potential strategy to delay photoreceptor degeneration in RP by maintaining mitochondrial function and could be combined with existing therapies for improving treatment outcomes through synergistic pathways.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110361"},"PeriodicalIF":4.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-α1/CREB pathway","authors":"Mu Xu ,&nbsp;Jialiang Wang ,&nbsp;Jia Shi ,&nbsp;Xiuyun Wu ,&nbsp;Qin Zhao ,&nbsp;Hui Shen ,&nbsp;Jingli Chen ,&nbsp;Jianbo Yu","doi":"10.1016/j.neuropharm.2025.110362","DOIUrl":"10.1016/j.neuropharm.2025.110362","url":null,"abstract":"<div><div>Esketamine (ES) has been shown to confer neuroprotection partly by exerting anti-inflammation, alleviating oxidative stress, enhancing neuronal vitality, and promoting synaptic remodeling. Nonetheless, its precise function in SAE and the associated mechanisms are not understood. In this study, we investigated the neuroprotective potential of ES at behavioral, structural, and functional levels <em>in vivo</em> and <em>in vitro</em>. C57BL/6J mice administered with lipopolysaccharide (LPS) served as the research model and were injected with 10 mg/kg ES intraperitoneally. Fiber photometry was performed to record Ca²⁺ transients during behavioral assays. The neuronal dendritic architecture and synaptic plasticity were examined using the Golgi staining and transmission electron microscopy. Stereotactic administration of siRNA was performed to suppress the NF-α1 expression and determine the role of the NF-α1/CREB pathway <em>in vitro</em>. The neuroprotective effects of ES were verified in primary neurons and HT22 cells using a conditioned culture. The ES treatment alleviated sepsis symptoms, cognitive impairment, and decreased mortality. It also upregulated the NF-α1 expression in the hippocampal CA1 region and reduced neuroinflammation, oxidative stress, and neuronal loss. Moreover, ES treatment normalized the Ca²⁺ transients and improved dendritic structure as well as synaptic plasticity. However, NF-α1 knockdown p-CREB downregulation abolished the protective effects of ES. This also reversed the phenotypic characteristics of Ca²⁺ transients, dendritic structure, and post-synaptic plasticity. ES can abolish the LPS-induced hippocampal neurotoxicity <em>in vitro</em> and <em>in vivo</em> models and modulate neuronal Ca²⁺ transients and post-synaptic plasticity via the NF-α1/CREB signaling pathway. These findings provide a theoretical basis that will guide the future application of ES to treat hippocampal injury in sepsis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110362"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414156","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}