CNS Neuroscience & Therapeutics最新文献

{"title":"Protective Effects of Mdivi-1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization","authors":"Chen Hong,&nbsp;Li Wang,&nbsp;Xiaowei Zhou,&nbsp;Liyong Zou,&nbsp;Xinming Xiang,&nbsp;Haoyue Deng,&nbsp;Qinghui Li,&nbsp;Yue Wu,&nbsp;Liangming Liu,&nbsp;Tao Li","doi":"10.1111/cns.70149","DOIUrl":"10.1111/cns.70149","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neuroinflammation is one of the essential pathogeneses of cognitive damage suffering from sepsis-associated encephalopathy (SAE). Lots of evidences showed the microglia presented mitochondrial fragmentation during SAE. This study investigated the protective effects and novel mechanisms of inhibiting microglia mitochondrial fragmentation via mitochondrial division inhibitor 1 (Mdivi-1) on cognitive damage in SAE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The SAE model was performed by cecal ligation and puncture (CLP), and Mdivi-1 was administrated via intraperitoneal injection. Morris water maze was performed to assess cognitive function. Mitochondrial morphology was observed by electron microscope or MitoTracker staining. The qRT-PCR, immunofluorescence staining, and western blots were used to detect the inflammatory factors and protein content, respectively. Flow cytometry was used to detect the polarization of hippocampal microglia. Bioinformatics analysis was used to verify hypotheses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mdivi-1 administration alleviated sepsis-induced mitochondrial fragmentation, microglia activation, polarization, and cognitive damage. The mechanisms study showed neuroinflammation and oxidative stress were suppressed via NF-κB and Keap1/Nrf2/HO-1 pathways following Mdivi-1 administration; meanwhile, pyroptosis in microglia was reduced, which was associated with enhanced autophagosome formation via p62 elevation following Mdivi-1 administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Inhibition of microglia mitochondrial fragmentation is beneficial to SAE cognitive disturbance, the mechanisms are related to alleviating neuroinflammation, oxidative stress, and pyroptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic Hydrogel-Based Strategy for Traumatic Brain Injury Modeling and Therapy","authors":"Xin He,&nbsp;Meng Lei,&nbsp;Xuewen Chen,&nbsp;Feng Xu,&nbsp;Heng Liu,&nbsp;Zhao Wei","doi":"10.1111/cns.70148","DOIUrl":"10.1111/cns.70148","url":null,"abstract":"<p>Traumatic brain injury (TBI) is one of the most traumatizing and poses serious health risks to people's bodies due to its unique pathophysiological characteristics. The investigations on the pathological mechanism and valid interventions of TBI have attracted widespread attention worldwide. With bio-mimic mechanic cues, the dynamic hydrogels with dynamic stiffness changes or reversible crosslinking have been suggested to construct the in vitro disease models or novel therapeutic agents for TBI. However, there is a lack of clarification on the dynamic hydrogels currently reported and their biomedical applications on TBI. Our review starts with introducing the native mechanical characters and changes in TBI and then summarizes the common chemical strategies of the dynamic hydrogels with dynamically tunable stiffness and reversible networks for in vitro modeling and therapy. Finally, we prospect the future development of dynamic hydrogels in the mechanical modeling of TBI, providing new mechanical insights for TBI and guidance for tailored brain-targeted biomaterials.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Locus Coeruleus Degeneration in Essential Tremor With Mild Cognitive Impairment: A Neuromelanin MRI Study","authors":"Yuelin Fang,&nbsp;Cheng Zhou,&nbsp;Bingting Zhu,&nbsp;Jiasi Liu,&nbsp;Sicheng Liu,&nbsp;Xiaojun Guan,&nbsp;Tao Guo,&nbsp;Xiaojun Xu,&nbsp;Minming Zhang,&nbsp;Jun Tian,&nbsp;Xinzhen Yin,&nbsp;Baorong Zhang,&nbsp;Guohua Zhao,&nbsp;Yaping Yan","doi":"10.1111/cns.70214","DOIUrl":"10.1111/cns.70214","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Our aim was to research the neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features of the locus coeruleus (LC) in essential tremor (ET) patients of various cognitive states and to explore the relationships between these features and cognition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recruited three groups of participants, including 30 ET patients with mild cognitive impairment (ET-MCI), 57 ET patients with normal cognition (ET-NC), and 105 healthy controls (HCs). All participants underwent MRI scanning and clinical evaluation. Through NM-MRI images, we compared the contrast-to-noise ratio of LC (CNR_LC) between groups and evaluated the relationships between CNR_LC and cognitive scales.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to HCs, ET-MCI patients had a substantially lower CNR_LC value (<i>p</i> = 0.017). The CNR_LC of ET-NC patients was intermediate between that of ET-MCI patients and HCs. Furthermore, a partial correlation analysis in ET-MCI patients, controlling for age, gender, and education level, showed that higher CNR_LC values correlate with better performance on the Montreal cognitive assessment test and the trail making test A.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>LC degeneration in ET patients may partially contribute to cognitive decline, suggesting that the LC norepinephrine system deserves further research on the mechanism of cognitive decline of ET patients as well as the development of targeted drugs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin","authors":"Chengkun Kou,&nbsp;Xu Zhao,&nbsp;Xin Fan,&nbsp;Runmin Sun,&nbsp;Wenting Wang,&nbsp;Miaomiao Qi,&nbsp;Lulu Zhu,&nbsp;Xin Lin,&nbsp;Jing Yu","doi":"10.1111/cns.70210","DOIUrl":"10.1111/cns.70210","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed microarray data analysis and integrated bioinformatics databases to identify a novel E3 ligase, Rnf40, that targets Parkin. To understand the role of RNF40 in hypertension-induced cerebrovascular endothelial cell damage, we used pAAV-hFLT1-MCS-EGFP-3×Flag-mir30shRnf40 to establish an Rnf40-deficient model in spontaneously hypertensive rats (SHRs). We also evaluated the cerebrovascular endothelial barrier function, cerebral blood flow, and cognitive performance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed reduced mitophagy in cerebrovascular endothelial cells of SHRs compared with that in Wistar-Kyoto rats. Rnf40 facilitated K48-linked polyubiquitination and degradation of Parkin, thereby inhibiting mitophagy. In the Rnf40-deficient SHR model, knocking down Rnf40 restored mitophagy in cerebrovascular endothelial cells. Additionally, levels of tight junction proteins and cerebrovascular endothelial barrier function improved following Rnf40 downregulation. Rnf40 depletion also improved global cognitive performance and restored cerebral blood flow in SHRs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clozapine Induces Agranulocytosis via Inflammatory and Hematopoietic Cytokine Induction of the JAK–STAT Signaling Pathway: Evidence From Network Pharmacology and Molecular Docking","authors":"Ying Zhang,&nbsp;Ranli Li,&nbsp;Ximing Chen,&nbsp;Yachen Li,&nbsp;Qiuyu Zhang,&nbsp;Lei Yang,&nbsp;Lina Wang,&nbsp;Yun Sun,&nbsp;Fuqiang Mao,&nbsp;Chuan Jun Zhuo","doi":"10.1111/cns.70206","DOIUrl":"10.1111/cns.70206","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Clozapine exhibits significant therapeutic efficacy in schizophrenia, especially treatment-resistant schizophrenia. However, clozapine can cause agranulocytosis, a fatal adverse effect, and the aim of this study is to explore this mechanism based on network pharmacology and molecular docking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Six and two databases were used to identify targets associated with clozapine and agranulocytosis, respectively. The bioinformatics online platform was used to identify overlaps between the drug and disease targets. The protein–protein interaction (PPI) network was characterized using Cystoscope 3.10.1 and STRING. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were analyzed using the DAVID online platform. A drug-target-pathway-disease network was constructed utilizing Cystoscope 3.10.1. The Auto Dock Vina and PyMOL software were used to verify the molecular docking of clozapine and core targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The analysis revealed 188 overlapping targets. The PPI and KEGG enrichment pathway analyses demonstrated that clozapine induces agranulocytosis by modulating the hematopoietic cell lineage and JAK–STAT signaling pathways via interleukin-3 (IL3), IL6, IL2 receptor subunit alpha (IL2RA), and granulocyte colony-stimulating factor. Binding energies between clozapine and core targets were favorable (&lt; −7.0 kcal/mol).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Clozapine-induced agranulocytosis may be linked to the JAK–STAT inflammatory signaling pathway through inflammatory and hematopoietic-related cytokines. Our findings enhance our comprehension of the potential mechanisms underlying clozapine-induced agranulocytosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination","authors":"Fuli Min,&nbsp;Zhaofei Dong,&nbsp;Shuisheng Zhong,&nbsp;Ze Li,&nbsp;Hong Wu,&nbsp;Sai Zhang,&nbsp;Linming Zhang,&nbsp;Tao Zeng","doi":"10.1111/cns.70191","DOIUrl":"10.1111/cns.70191","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein–protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Anti-Apoptotic Effects and Mechanisms of Astragaloside IV in a Rat Model of Cerebral Ischemia–Reperfusion Injury","authors":"Li Yu,&nbsp;Weifeng Jin,&nbsp;Defang Deng,&nbsp;Yiru Wang,&nbsp;Qianqian Chen,&nbsp;Yangyang Zhang,&nbsp;Haitong Wan,&nbsp;Yunxiang Chen,&nbsp;Ying Chen,&nbsp;Yu He,&nbsp;Lijiang Zhang","doi":"10.1111/cns.70209","DOIUrl":"10.1111/cns.70209","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ischemic stroke is a prevalent and life-threatening cerebrovascular disease that is challenging to treat and associated with a poor prognosis. Astragaloside IV (AS-IV), a primary bioactive component of <i>Astragali radix</i>, has demonstrated neuroprotective benefits in previous studies. This study aimed to explore the mechanisms through which AS-IV may treat cerebral ischemia–reperfusion injury (CIRI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Network pharmacology was employed to identify key targets and pathways of AS-IV in CIRI therapy, combined with molecular docking to predict binding affinity. Male Sprague–Dawley rats were randomly assigned to sham, MCAO/R, AS-IV, SP600125 (JNK inhibitor), AS-IV + SP600125, and 3-n-Butylphthalide (NBP) groups. Neurobehavioral deficits were assessed, and brain tissue damage was visualized through 2,3,5-triphenyltetrazolium chloride, H&amp;E, and TUNEL staining. Immunohistochemistry was employed to detect CytC- and caspase-3-positive cells, while Western blotting, qPCR, and ELISAs were used to analyze apoptosis-related markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 48 key targets of AS-IV predicted to be involved in the treatment of CIRI were identified, enriched in 136 pathways. AS-IV was effectively bound to the top five targets from 48 targets, and those associated with the c-Jun N-terminal kinase (JNK)/Bid pathway, with binding energy values below −5.0 kJ·mol⁻¹. JNK inhibition reduced infarcted brain areas, improved neurological function, reduced pathological brain tissue damage, and inhibited apoptosis, with AS-IV achieving similar neuroprotective effects. Both AS-IV and SP600125 reduced p-JNK, Bid, CytC, Apaf-1, caspase-3, and cleaved caspase-3 levels in rats while decreasing CytC, caspase-3, and caspase-9 levels in serum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>AS-IV may suppress apoptosis partly through the modulation of JNK/Bid signaling, exerting neuroprotective effects. These findings support the potential development of AS-IV-based therapies for stroke treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Coffee Intake and Common Mental Disorders: Insights From Genetic Analysis","authors":"Zhiqiang Du,&nbsp;Ying Jiang,&nbsp;Yuan Shen,&nbsp;Qin Zhou,&nbsp;Peng Gong,&nbsp;Haohao Zhu","doi":"10.1111/cns.70213","DOIUrl":"10.1111/cns.70213","url":null,"abstract":"<p>The study found a significant causal relationship between coffee intake and obsessive-compulsive disorder, showing a negative correlation. There was no causal relationship between coffee intake and other mental disorders. The sensitivity analysis test found no pleiotropy affecting the results, and no single nucleotide polymorphism had a major impact on the robustness of the results, indicating that the results are stable and reliable.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Demethylsinomenine Relieves Neuropathic Pain in Male Mice Mainly via Regulating α2-Subtype GABAA Receptors","authors":"Weiwei Rong,&nbsp;Xunjia Qian,&nbsp;Yujian Yin,&nbsp;Yipeng Gu,&nbsp;Weiyi Su,&nbsp;Jie-Jia Li,&nbsp;Yue Xu,&nbsp;Hongyan Zhu,&nbsp;Junxu Li,&nbsp;Qing Zhu","doi":"10.1111/cns.70197","DOIUrl":"10.1111/cns.70197","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p><i>N</i>-Demethylsinomenine (NDSM) demonstrates good analgesic efficacy in preclinical pain models. However, how NDSM exerts analgesic actions remains unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined the analgesic effects of NDSM using both pain-evoked and pain-suppressed behavioral assays in two persistent pain models. Then western blot assay and immunofluorescence staining were used to investigate the effects of NDSM on the expression of the GABA_A receptor α2 subunit (GABRA2) and inflammatory factors in the spinal cord and brain tissues of male spared nerve injury (SNI) mice. Finally, the individual subtypes of GABA_ARs (α1, α2, α3, and α5) were respectively silenced by viral-mediated knockdown to explore the involvement of subtypes of GABA_ARs in the effects of NDSM on the pain-like behaviors in male SNI mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NDSM demonstrated significant analgesic effects against chronic pain both in pain-evoked and pain-suppressed behavioral assays. NDSM treatment significantly reversed the SNI induced down-regulation of GABRA2 and up-regulation of TNF-α and IL-1β. The analgesic effects of NDSM were completely blocked by silencing GABRA2 or partially blocked by silencing GABRA3.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study provided the first evidence that the analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3, and the inhibition of neuroinflammation also contributes to the analgesic effects of NDSM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Mendelian Randomization and Single-Cell Transcriptomics Analysis Identifies Critical Blood Biomarkers and Potential Mechanisms in Epilepsy","authors":"Jianwei Shi,&nbsp;Jing Xie,&nbsp;Yanfeng Yang,&nbsp;Bin Fu,&nbsp;Zuliang Ye,&nbsp;Ting Tang,&nbsp;Quanlei Liu,&nbsp;Jinkun Xu,&nbsp;Penghu Wei,&nbsp;Yongzhi Shan,&nbsp;Guoguang Zhao","doi":"10.1111/cns.70172","DOIUrl":"10.1111/cns.70172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epilepsy has a genetic predisposition, yet causal factors and the dynamics of the immune environment in epilepsy are not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed peripheral blood samples from epilepsy patients, identifying key genes associated with epilepsy risk through Mendelian randomization, using eQTLGen and genome-wide association studies. The peripheral immune environment's composition in epilepsy was explored using CIBERSORT. An epilepsy mouse model was established to validated the expression of key genes at the transcriptomic and proteomic levels through single-cell analysis. Relevant pathways were verified. Finally, we developed a predictive model for antiepileptic drug response in epilepsy patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that <i>CDC25B</i>, <i>DNMT1</i>, <i>GZMA</i>, <i>MTX1</i>, and <i>SSH2</i> expression decreases epilepsy risk, whereas <i>FGD3</i>, <i>RAF1</i>, and <i>SH3BP5L</i> increase it. Epilepsy patients exhibited an altered peripheral immune profile, notably with increased activated mast cells and decreased CD4 memory activated T cells and γδ T cells. Eight genes were significantly related to this immune environment. In the animal model, <i>FGD3</i>, <i>SSH2</i>, and <i>DNMT1</i> were upregulated at both mRNA and protein levels in the hippocampus. FGD3 and SSH2 are specifically elevated in microglia and are primarily associated with actin regulation. The trained predictive model was deployed on an online platform.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study elucidates key genes linked to epilepsy, delineates the epilepsy immune landscape, and highlights the interaction between these domains, providing insights into potential epilepsy mechanisms and treatments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}