Neuropharmacology最新文献

{"title":"Antibiotic treatment improves gut dysbiosis and depression-like behavior induced by morphine withdrawal","authors":"Dong-yu Yu ,&nbsp;Jing-qi Gao ,&nbsp;Xi-xi Yang ,&nbsp;Fei-fei Gao ,&nbsp;Jun-lin Liu ,&nbsp;Meng-qing Shen ,&nbsp;Bo-yuan Gu ,&nbsp;Yu-xiang Zhang ,&nbsp;Chun-xia Yan","doi":"10.1016/j.neuropharm.2025.110579","DOIUrl":"10.1016/j.neuropharm.2025.110579","url":null,"abstract":"<div><div>Opioid withdrawal poses a significant neuropsychiatric challenge, notably contributing to the onset of depression. Depression intertwines with gut flora richness and diversity, frequently coinciding with synaptic plasticity alterations in the brain. Gut microbiota dysbiosis potentially contributes to withdrawal-triggered depression via gut-brain axis. This research delves into the impact of antibiotic-induced gut microbiota alteration on behavioral and synaptic protein variations in mice subjected to morphine withdrawal-induced depression. A murine model was established using escalating doses of morphine followed by naloxone-precipitated withdrawal. Depression-like behaviors were assessed through tail suspension, sucrose preference, forced swimming tests, while histopathology evaluated ileocolonic inflammation. Synaptic markers, Synaptophysin (SYP) and Synapsin 1 (SYN1), in the hippocampus were analyzed via Western blotting, and gut microbiota composition was assessed through 16S rRNA sequencing. An antibiotic intervention model was employed to explore microbiota-dependent mechanisms. Morphine withdrawal induced characteristic depression-like behaviors, including prolonged immobility in forced swimming and reduced sucrose preference. Microbiota diversity metrics demonstrated significant declines in α-diversity. Histological analysis revealed marked inflammatory infiltration in ileal tissues, accompanied by reduction in hippocampal SYP expression. Antibiotic administration attenuated behavioral impairments, mitigated gut dysbiosis, reduced intestinal inflammation, and partially rescued SYP expression. These findings establish that morphine withdrawal induces intestinal dysbiosis, hippocampal synaptic plasticity deficits and depression-like behaviors, which are reversible through microbiota modulation. The results highlight the antibiotic treatment as a potential therapy for opioid withdrawal sequelae.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110579"},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513638","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":"Perinatal fentanyl exposure drives enduring addiction risk and central amygdala gene dysregulation","authors":"Courtney P. Wood ,&nbsp;Yeji Shin ,&nbsp;Maria G. Balaguer ,&nbsp;Paola Campo ,&nbsp;Selen Dirik ,&nbsp;Bryan A. Montoya ,&nbsp;Gregory M.R. Cook ,&nbsp;Gabrielle M. Palermo ,&nbsp;Parsa K. Naghshineh ,&nbsp;Alex Morgan ,&nbsp;Sara R.M.U. Rahman ,&nbsp;Abraham A. Palmer ,&nbsp;Francesca Telese ,&nbsp;Giordano de Guglielmo","doi":"10.1016/j.neuropharm.2025.110581","DOIUrl":"10.1016/j.neuropharm.2025.110581","url":null,"abstract":"<div><div>The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure in heterogeneous stock (HS) rats characterized by high genetic diversity, to investigate NOWS symptoms and its long-term effects on adult fentanyl self-administration, drug-seeking behavior, and central amygdala (CeA) transcriptomic changes, addressing a critical gap in understanding synthetic opioid impacts. Offspring born to fentanyl-exposed dams exhibited reduced survival, lower body weight, spontaneous withdrawal symptoms, and mechanical hypersensitivity during adolescence. These rats displayed negative affect in adolescence, while they showed increased fentanyl self-administration, heightened drug-seeking during reinstatement, and elevated corticosterone levels during withdrawal in adulthood. To explore the molecular underpinnings of these physiological and behavioral outcomes, we conducted RNA-seq in the CeA of adult rats, revealing dysregulated pathways related to GPCR signaling, adaptive immune response and neurodevelopmental processes. These transcriptional changes provide insights into the mechanisms driving addiction vulnerability and stress-related behaviors following early fentanyl exposure. Our findings highlight the lasting impact of perinatal opioid exposure in an experimental system that avoids many of the confounds that plague studies in humans, underscoring the need for preclinical models to study NOWS and its long-term consequences. This model offers translational relevance for developing therapeutic strategies to mitigate NOWS and reduce neuropsychiatric risks associated with perinatal opioid exposure.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110581"},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514183","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":"Mice lacking the endocannabinoid-synthesizing enzyme NAPE-PLD exhibit sex-dependent dysregulations in responsiveness to oxycodone and a natural reward","authors":"Taylor J. Woodward ,&nbsp;Emily Sizemore ,&nbsp;Ananya Balaji ,&nbsp;Ada Port ,&nbsp;John Hainline ,&nbsp;Hasaan Kazi ,&nbsp;Serge Luquet ,&nbsp;Ken Mackie ,&nbsp;Andrea G. Hohmann","doi":"10.1016/j.neuropharm.2025.110573","DOIUrl":"10.1016/j.neuropharm.2025.110573","url":null,"abstract":"<div><div>The endogenous cannabinoid (endocannabinoid) and opioid systems are highly interconnected in the context of drug reward. Bioactive lipids known as <em>N</em>-acylethanolamines (NAEs), and, specifically, anandamide (AEA), influence several unwanted side effects of opioids, including dependence and tolerance. AEA undergoes degradation catalyzed by the enzyme fatty-acid amide hydrolase (FAAH), whereas the biosynthesis of AEA <em>in vivo</em> is catalyzed by the enzyme <em>N</em>-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD). AEA and FAAH are implicated in opioid reward, but the impact of genetic deletion of NAPE-PLD on responsiveness to opioids remains unknown. Here we explored the role of NAPE-PLD in behavioral sensitivity to the opioid analgesic oxycodone. We evaluated NAPE-PLD knockout (KO) and wild type (WT) mice of both sexes in assays that assess opioid-induced psychomotor responses and voluntary oral consumption of oxycodone. In our studies, genetic deletion of NAPE-PLD produced a shift in sexually dimorphic responses to oxycodone. Psychomotor response to oxycodone was reduced in female but not male NAPE-PLD KO mice. Female NAPE-PLD KO mice consumed more oral oxycodone that female WT mice, while no genotypic differences in consumption were observed in males. Oxycodone consumption also increased the number of striatal ΔFosB positive cells in female WT mice, but not in male WT mice or NAPE-PLD KO mice of either sex. Additionally, NAPE-PLD KO mice of both sexes consumed more sucrose than WT mice. Together, these findings suggest that NAPE-PLD may regulate responses to opioids in a sexually dimorphic manner as the impact of genetic deletion of NAPE-PLD was greater in females than males.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110573"},"PeriodicalIF":4.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517721","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":"Neuroprotective effects of Crocus sativus-mediated cerium oxide nanoparticles in a rat model of sciatic nerve crush injury","authors":"Fatemeh Asghari ,&nbsp;Abolfazl Bayrami ,&nbsp;Arash Abdolmaleki ,&nbsp;Shima Rahim Pouran ,&nbsp;Aziz Habibi-Yangjeh","doi":"10.1016/j.neuropharm.2025.110567","DOIUrl":"10.1016/j.neuropharm.2025.110567","url":null,"abstract":"<div><div>This study aimed at integrating the outstanding medicinal traits of Crocus sativus L. (saffron) with ceria nanoparticles (CeO₂ NPs) to assess the neuroprotective potential of their combination in rats with nerve crush injury. With this aim, ceria NPs were prepared using saffron extract (S-CeO₂), and the acquired nanoceria were characterized via XRD, DRS, FTIR, SEM, and TGA and compared to the traits of the nanoceria prepared in the absence of saffron extract (CeO₂). The GC-MS analysis was also conducted to reveal the bioactive compounds of the saffron extract. Subsequently, comparative studies were carried out on the motor nerve recovery effectiveness of the nanoceria samples on the peripheral nerve injury model rats using sciatic functional index and walking track analysis. Later, the hot plate test was performed to assess the pain-like behavior and subsequent sensory recovery of the sciatic nerve of the rats under study. The atrophy of the gastrocnemius muscles of the sacrificed rats was then studied using the muscle mass ratio values. In the end, the physiological conditions of the myelin sheath, nerve fiber, and muscle recovery were analyzed via histological morphometric patterns. As per the results, the postoperative administration with S-CeO₂ accelerated peripheral nerve regeneration and improved the recovery of motor function, which could potentially be due to the antioxidant and anti-inflammatory activities of the engaged constituents. Altogether, our findings emphasize the therapeutic potential of ceria nanoparticles encompassing the phytomolecules of the saffron extract in addressing neurological disorders, thereby enabling the development of cutting-edge therapies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110567"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490881","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":"Kcc-ReHo and Cohe-ReHo in bipolar disorder: their associated genes and potential for diagnosis and treatment prediction","authors":"Dan Lv ,&nbsp;Hao-hao Yan ,&nbsp;Chun-guo Zhang ,&nbsp;Xiao-ling Li ,&nbsp;Le-yi Zhang ,&nbsp;Jia-quan Liang ,&nbsp;Chao-hua Tang ,&nbsp;Wei-bin Wu ,&nbsp;Wen Deng ,&nbsp;Guo-jun Xie ,&nbsp;Wen-bin Guo","doi":"10.1016/j.neuropharm.2025.110575","DOIUrl":"10.1016/j.neuropharm.2025.110575","url":null,"abstract":"<div><div>The neural mechanisms underlying resting-state cerebral functional activity in bipolar disorder (BD) and the effects of pharmacotherapy on it remain unclear. This study investigated changes in local brain activity in BD patients (BDPs) following treatment, evaluated the diagnostic and prognostic potential of regional homogeneity (ReHo), and explored associated genes and biological processes. Resting-state fMRI data and clinical variables were collected from 68 BDPs (at baseline and after 3 months of pharmacotherapy) and 80 healthy controls (HCs). Local brain activity was assessed using Kendall's coefficient of concordance ReHo (KCC-ReHo) and Coherence ReHo (Cohe-ReHo). Support Vector Machine (SVM) and Support Vector Regression (SVR) were employed for classification and treatment response prediction. Neuroimaging-transcriptomic analysis was conducted to explore the relationship between altered ReHo and gene expression profiles from the Allen Human Brain Atlas. BDPs exhibited greater KCC-ReHo and Cohe-ReHo values in the striatum and cerebellum circuit, but lower values in the prefrontal cortex compared to HCs. Following pharmacotherapy, KCC-ReHo values in the cerebellum circuit decreased. Classification accuracy was 68 % (AUC: 0.76 and 0.75 for KCC-ReHo and Cohe-ReHo, respectively), with predicted treatment response moderately correlating with actual outcomes (<em>r</em> = 0.34 and 0.31). Twenty-seven genes were found to be associated with ReHo group differences. Our findings underscore the dysfunction of the prefrontal-striatum and cerebellar circuits as key neuropathological mechanisms in BD. The observed reduction in cerebellar activity post-pharmacotherapy suggests a potential therapeutic mechanism, while neuroimaging-transcriptomic analysis highlights the genetic underpinnings of these alterations in BDPs.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110575"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502329","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":"Neuroprotective potential of novel CARTp analogs in the hippocampus of THY-Tau22 mouse model of Tau pathology","authors":"Vilém Charvát ,&nbsp;Petra Vaculová ,&nbsp;Blanka Železná ,&nbsp;Lenka Maletínská ,&nbsp;Andrea Pačesová","doi":"10.1016/j.neuropharm.2025.110578","DOIUrl":"10.1016/j.neuropharm.2025.110578","url":null,"abstract":"<div><div>Anorexigenic neuropeptides have shown a remarkable potential in the treatment of neurodegenerative disorders, such as Alzheimer's disease (AD). One of the strong anorexigenic neuropeptides is called cocaine- and amphetamine-regulated transcript peptide (CARTp), which is the third most abundant transcript in the hypothalamus. Previously, we introduced a novel palmitoylated analog of 2-SS-CART(61–102), a specific analog of natural CART(61–102) with two disulfide bridges, with anorexigenic and neuroprotective properties. This study explores the impact of 2-SS-CART(61–102) and its palmitoylated analog, palm-2-SS-CART(61–102), on the early progression of Tau pathology characteristic of AD, utilizing the THY-Tau22 transgenic mouse model. Chronic subcutaneous treatment with CARTp analogs improved short-term spatial memory in the Y-maze, reduced the number of neurofibrillary tangles (NFT) in the hippocampal CA1 region, and decreased the level of GFAP + astrocytes in the hippocampus of THY-Tau22 mice. Furthermore, treatment with CARTp analogs showed increased levels of synaptic markers in the hippocampus. A beneficial effect on these attributes makes CARTp analogs promising for AD therapy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110578"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510743","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":"Temporal and Spatial Patterns of Secondary Motor Cortex Calcium Activity in Cocaine Self-Administration: A Study Using MiniScope Imaging and Machine Learning.","authors":"Amith Korada, Yingying Chen, Ziqian Bi, Haoying Fu, Michal A Lange, Joreylis Michelle F Montgomery, Chandrashekar Rayanki, Changyong Guo, Shiaofen Fang, Yao-Ying Ma","doi":"10.1016/j.neuropharm.2025.110574","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110574","url":null,"abstract":"<p><p>Addiction is a chronic mental disorder caused by disruptions in brain function. While most research has focused on the medial prefrontal cortex, our recent findings highlight the secondary motor cortex (M2) as a key region modulating cocaine-seeking behaviors during relapse. Mechanisms underlying the role of M2 in addiction remain unclear. We hypothesize that initial drug-taking behaviors directly reshape M2 neuronal activity. This study investigated the effects of five 1-hr daily intravenous self-administration (IVSA) sessions on M2 neuronal activity in male C57BL/6J mice using in vivo Ca²⁺ imaging via miniScopes. Temporal and spatial patterns of Ca²⁺ transients were analyzed across three IVSA factors: IV substance (i.e., saline vs. cocaine), IVSA days, and within-session stages. Machine learning models, including Recurrent Neural Networks for temporal patterns, and Neural Networks, Support Vector Machines, and Extreme Gradient Boosting for spatial patterns, were employed. RESULTS: Cocaine-treated mice displayed consistent drug-taking behaviors within sessions and increased intake on Day 5 compared to Day 1, unlike saline-treated mice, which showed reduced operant behaviors within each daily session. IV substance was the most sensitive factor influencing both temporal and spatial patterns of M2 Ca²⁺ transients, characterized by frequency and frequency-amplitude interactions, but not amplitude alone. A 15-second bin size optimized differentiation between saline and cocaine groups. CONCLUSION: Both temporal and spatial alterations in M2 neuronal activity were detected during early cocaine exposure, revealing early changes that may contribute to later drug relapse. These findings underscore the importance of advanced imaging and machine learning techniques in advancing addiction research.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110574"},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512185","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":"Hydroxysafflor yellow A attenuates the blood-brain barrier dysfunction and neuroinflammation through anti-inflammatory microglial polarization after intracerebral hemorrhage","authors":"Fei Zheng ,&nbsp;Xiaohang Guo ,&nbsp;Qiuju Yan ,&nbsp;Yaya Zhou ,&nbsp;En Hu ,&nbsp;Haonan Zhu ,&nbsp;Menghan Cheng ,&nbsp;Zhe Yu ,&nbsp;Mingrui Hu ,&nbsp;Ruoqi Ding ,&nbsp;Haigang Li ,&nbsp;Wei Zhang ,&nbsp;Tao Tang ,&nbsp;Yang Wang ,&nbsp;Teng Li ,&nbsp;Changqing Deng","doi":"10.1016/j.neuropharm.2025.110576","DOIUrl":"10.1016/j.neuropharm.2025.110576","url":null,"abstract":"<div><div>The destruction of the blood-brain barrier (BBB) is the most common life-threatening event of intracerebral hemorrhage (ICH). Balancing microglia polarization is a prospective therapeutic strategy for BBB injury. This study aims to explore the neuroprotective effects and the underlying mechanisms of Hydroxysafflor yellow A (HSYA) from the perspective of BBB disruption and neuroinflammation. ICH was induced by intracerebral injection of collagenase Ⅶ in C57BL/6J male mice, and HSYA was injected through the tail vein for three days. We established three oral concentrations for HSYA and found that the administration of HSYA (20 mg/kg/d) significantly improved the neurological deficits of ICH mice and reversed the histopathological damage of the brain. Using IgG and Evans Blue staining, we demonstrated that HSYA prominently facilitated the BBB repair after ICH with no bleeding risk. HSYA greatly enhanced the expression of tight junction proteins (ZO-1, occludin, and claudin-5) but decreased MMP9. HSYA also significantly reduced the CD68⁺ microglia with pro-inflammation mediators (IL-1β, IL-6, TNF-α, iNOS, HO-1, and COX2) and increased the Arg-1⁺ microglia with anti-inflammation mediators (IL-10, and TGF-β). We identified the PI3K/Akt signaling pathway through database mining and bioinformatics analysis and verified the activation of PI3K/Akt by HSYA intervention. Further, employing the PI3K-specific antagonist LY294002 confirmed that the pre-administration of LY294002 mostly negated the neuroprotective effects of HSYA. HSYA activates the PI3K/Akt/mTOR signaling pathway, balancing microglial polarization and improving BBB integrity, highlighting its potential to be an effective drug option for ICH treatment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110576"},"PeriodicalIF":4.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490880","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":"Bioinformatics and validation reveal spinal cord cathepsin S potential degradation of perineuronal nets in neuropathic pain","authors":"Jiahui Pang ,&nbsp;Ziwei Hu ,&nbsp;Yubai Zhao ,&nbsp;Xinli Liu ,&nbsp;Bo Wang ,&nbsp;Qian Fang ,&nbsp;Yin Xu ,&nbsp;Yingxuan Hu ,&nbsp;Hui Zeng ,&nbsp;Wen Wu","doi":"10.1016/j.neuropharm.2025.110577","DOIUrl":"10.1016/j.neuropharm.2025.110577","url":null,"abstract":"<div><div>Neuropathic pain (NP), resulting from nerve damage or diseases, significantly impacts patients’ quality of life. Bioinformatics analysis can assist researchers in identifying key molecular pathways involved disease progression. This study aims to investigate the hub genes in the spinal cord of NP rats, with a particular focus on the relationship between Cathepsin S (CTSS) and perineuronal nets (PNNs). Bioinformatics analysis identified <em>Ctss</em> as a hub gene in NP dataset GSE18803. After injury, CTSS expression was significantly upregulated in the spinal cord of NP rats, and the immunofluorescence staining confirmed the degradation of PNNs in the ipsilateral spinal cord lamina V of NP rats. Furthermore, in vitro experiment demonstrated that CTSS promoted the degradation of PNNs. Finally, knockdown CTSS expression spinal cord relived pain and PNNs degradation in NP rats. These findings suggest that CTSS is upregulated in the spinal cord of NP rats and reveal CTSS potential degradation of PNNs.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110577"},"PeriodicalIF":4.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507098","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":"Irisin ameliorates cognitive impairment in a lipopolysaccharide-induced neuroinflammation mouse model by inhibiting the NLRP3 inflammasome pathway in microglia","authors":"Da-Qi Zhang ,&nbsp;Ge Li ,&nbsp;Zong-Dong Fu ,&nbsp;Yu-Sheng Huang ,&nbsp;Xiao-Li Feng ,&nbsp;Li-Jun Chen ,&nbsp;Rong Wang ,&nbsp;Wen-Jie Zhao ,&nbsp;Qifu Li","doi":"10.1016/j.neuropharm.2025.110572","DOIUrl":"10.1016/j.neuropharm.2025.110572","url":null,"abstract":"<div><div>Neuroinflammation is implicated in the development of neurodegenerative diseases. Irisin was first identified as an exercise-induced skeletal muscle-secreted glycosylated protein. The main physiological functions of irisin were initially thought to include the promotion of angiogenesis; improvement of oxidative metabolism; and regulation of glucose, lipid, and mitochondrial metabolism. However, despite its demonstrated neuroprotective effects in Alzheimer's disease, the precise role of irisin in neuroinflammation, particularly in lipopolysaccharide (LPS)-induced cognitive impairment, remains unclear. This study was performed to investigate the protective effects and mechanisms of irisin on LPS-induced inflammatory cognitive impairment both <em>in vivo</em> and <em>in vitro</em>. We induced cognitive impairment in mice using LPS and evaluated cognitive function by employing the Morris water maze test. Further, we used immunofluorescence staining and flow cytometry to assess microglial activation and polarization in the cortex and hippocampus, two brain regions involved in cognitive behaviors. Western blotting was used to detect the levels of proteins related to the NLRP3 signaling pathway. Furthermore, we measured tumor necrosis factor -α, interleukin (IL)-6, CCL2, IL-4 and IL-10 levels in BV2 cells using a mouse enzyme-linked immunosorbent assay kit and characterized M1 and M2 polarization using flow cytometry. Irisin administration improved learning and cognitive abilities but inhibited microglial activation and M1 polarization in LPS-treated mice. Irisin significantly decreased the expression of NLRP3 inflammasome signaling pathway molecules in LPS-treated mice. Further, irisin suppressed microglial activation and reduced the production of proinflammatory cytokines in BV2 cells. Moreover, irisin protected PC12 cells from LPS-activated BV2 microglia-induced neurotoxicity and inhibited apoptosis in PC12 cells induced by BV2 conditioned medium. Irisin mitigated inflammatory cognitive dysfunction and suppressed microglial activation and M1-type polarization by inhibiting the NLRP3 signaling pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110572"},"PeriodicalIF":4.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366882","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}