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Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition 星形胶质细胞HIF-1α/VEGF诱导内皮细胞PI3K/Akt激活,在LCN2抑制下加速缺血后血管生成。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-14 DOI: 10.1016/j.neuint.2025.106078
Ning Tian , Xiaoxia Li , Yanlin Jiang , Jungang Deng , Hao Wang , Bing Guo , Meiling Chen , Rujia Liao
{"title":"Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition","authors":"Ning Tian ,&nbsp;Xiaoxia Li ,&nbsp;Yanlin Jiang ,&nbsp;Jungang Deng ,&nbsp;Hao Wang ,&nbsp;Bing Guo ,&nbsp;Meiling Chen ,&nbsp;Rujia Liao","doi":"10.1016/j.neuint.2025.106078","DOIUrl":"10.1016/j.neuint.2025.106078","url":null,"abstract":"<div><div>Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106078"},"PeriodicalIF":4.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway. 精神药物和神经退行性药物通过PAF途径调节血小板活性。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-13 DOI: 10.1016/j.neuint.2025.106073
Savvato Kosidou, Zisis Zannas, Anna Ofrydopoulou, Dimitra A Lambropoulou, Alexandros Tsoupras
{"title":"Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway.","authors":"Savvato Kosidou, Zisis Zannas, Anna Ofrydopoulou, Dimitra A Lambropoulou, Alexandros Tsoupras","doi":"10.1016/j.neuint.2025.106073","DOIUrl":"https://doi.org/10.1016/j.neuint.2025.106073","url":null,"abstract":"<p><p>Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets possess both hemostatic and immunomodulatory roles in these situations, with sharing key molecular pathways with the central nervous system, offering thus a valuable peripheral model for evaluating psychotropic drug effects. Platelet-activating factor (PAF), a potent thrombo-inflammatory mediator, has emerged as a potential link between the two systems, yet its involvement in drug responses remains understudied. This study systematically investigates the effects of psychotropic drugs (i.e. antidepressants, antipsychotics and anxiolytics), and neuroprotective (anti-Alzheimer's/Anti-Parkinson's) drugs on platelet aggregation, focusing on PAF-pathway in comparison to a control platelet agonist, ADP. Using ex vivo light transmission aggregometry, we determined IC<sub>50</sub> values for each drug and analyzed the impact of selected drug combinations, in which the NSAID diclofenac was also included. Results revealed that most of the compounds assessed inhibited more effectively the PAF-induced aggregation of platelets compared to their effect on the ADP-pathway, with perphenazine showing the greatest anti-PAF potency. Several drug combinations, notably those including alprazolam and diclofenac, demonstrated significant synergistic effects. These findings suggest that commonly prescribed psychotropic drugs and medications for neurodegenerative disorders can influence platelet activity, mostly through the PAF-pathway, and that their interactions with NSAIDs may amplify their efficacy. Nevertheless, some drugs and their combinations induced lysis of platelets at much higher concentrations than their IC50 values, which stems safety concerns for their use.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106073"},"PeriodicalIF":4.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neuronal FSTL4 negatively regulates BDNF-mediated neuron-glioma interaction 神经元FSTL4负调控bdnf介导的神经元-胶质瘤相互作用。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-11 DOI: 10.1016/j.neuint.2025.106072
Yan Sun , Mi Xiao , Xunhui Wang , Yanchun Xu , Anbin Chen , Bin Li , Baohui Feng , Bangbao Tao
{"title":"Neuronal FSTL4 negatively regulates BDNF-mediated neuron-glioma interaction","authors":"Yan Sun ,&nbsp;Mi Xiao ,&nbsp;Xunhui Wang ,&nbsp;Yanchun Xu ,&nbsp;Anbin Chen ,&nbsp;Bin Li ,&nbsp;Baohui Feng ,&nbsp;Bangbao Tao","doi":"10.1016/j.neuint.2025.106072","DOIUrl":"10.1016/j.neuint.2025.106072","url":null,"abstract":"<div><div>Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it's unclear whether and how the BDNF-mediated cross-talk between neurons and gliomas is regulated. FSTL4 is reported to negatively regulate BDNF maturation. Here, we hypothesized that neuronal FSTL4 may negatively regulate BDNF-mediated neuron-glioma cross-talk. By using a combination of approaches like chemogenetic activation of primary neurons and CRISPR knockout/activation of endogenous FSTL4, we show that activated primary neurons support the proliferation of co-cultured glioma cells and neuronal BDNF secretion mediates this neuron-glioma interaction via activating TrkB in glioma cells. In addition, this process is negatively regulated by neuronal FSTL4 as its CRISPR KO in primary neurons further supports the proliferation of co-cultured glioma cells. Importantly, CRISPR activation of endogenous FSTL4 expression in primary neurons results in impaired ability to support co-cultured glioma cells, highlighting the therapeutic potential of activating endogenous FSTL4 for glioma treatment. Taken together, our study shows that the FSTL4/BDNF/TrkB axis plays an essential role in fine-tuning the neuron-glioma interaction and targeting this interplay with CRISPR tools may help to develop novel therapeutic strategies.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106072"},"PeriodicalIF":4.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Regional and cell type-specific activation of the unfolded protein response after kainate injection in mice 海碱盐注射后未折叠蛋白反应的区域和细胞特异性激活。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-09 DOI: 10.1016/j.neuint.2025.106071
Ly Huong Nguyen , Loc Dinh Nguyen , Dat Xuan Dao , Tsuyoshi Hattori , Hiroshi Ishii , Mika Takarada-Iemata , Osamu Hori
{"title":"Regional and cell type-specific activation of the unfolded protein response after kainate injection in mice","authors":"Ly Huong Nguyen ,&nbsp;Loc Dinh Nguyen ,&nbsp;Dat Xuan Dao ,&nbsp;Tsuyoshi Hattori ,&nbsp;Hiroshi Ishii ,&nbsp;Mika Takarada-Iemata ,&nbsp;Osamu Hori","doi":"10.1016/j.neuint.2025.106071","DOIUrl":"10.1016/j.neuint.2025.106071","url":null,"abstract":"<div><div>The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcription factor 6 (ATF6), and its downstream molecular chaperones in the endoplasmic reticulum (ER) have neuroprotective properties against excitotoxicity. In this study, we examined the temporal and spatial changes in the UPR activation after administration of an excitotoxic reagent, kainate (KA), into mice. RT-qPCR revealed enhanced expression of UPR genes, with peaks either on day 1 or day 3 after intrahippocampal KA injection. The status of the UPR was analyzed using ER stress-activated indicator (ERAI)-transgenic mice, in which the spliced form of XBP-1, downstream of the IRE1 branch of the UPR, can be monitored. ERAI-derived GFP signals were strongly observed in CA3 neurons and moderately observed in dentate gyrus neurons, but not in CA1 neurons, after KA injection. A small portion of the activated astrocytes was also positive for ERAI signals. Further studies revealed that ERAI signals were observed in both the soma and dendrites of neurons in regions with enhanced neuronal activity and resistance to KA toxicity. These results suggest that the UPR may be associated with the neuronal activity and survival after KA injection.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106071"},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Crossing the Borders: the amino acid transporter LAT1 (SLC7A5) in the Blood-Brain Barrier 跨越边界:血脑屏障中的氨基酸转运体LAT1 (SLC7A5)。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-08 DOI: 10.1016/j.neuint.2025.106070
Mariafrancesca Scalise , Raffaella Scanga , Lara Console , Michele Galluccio , Flaviana Marzano , Andrea Magrì , Lorena Pochini , Cesare Indiveri
{"title":"Crossing the Borders: the amino acid transporter LAT1 (SLC7A5) in the Blood-Brain Barrier","authors":"Mariafrancesca Scalise ,&nbsp;Raffaella Scanga ,&nbsp;Lara Console ,&nbsp;Michele Galluccio ,&nbsp;Flaviana Marzano ,&nbsp;Andrea Magrì ,&nbsp;Lorena Pochini ,&nbsp;Cesare Indiveri","doi":"10.1016/j.neuint.2025.106070","DOIUrl":"10.1016/j.neuint.2025.106070","url":null,"abstract":"<div><div>The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinated action of specific ion channels and membrane transporters belonging to the SLC and ABC superfamilies. Indeed, membrane transporter expression in the BBB is less redundant than in other parts of the body. Therefore, any alteration to one of these proteins may pose a threat to the brain. The fifth member of the SLC7 family, which is expressed at the BBB has been the subject of much research over the years. SLC7A5, also known as LAT1, is a plasma membrane transporter of essential amino acids, whose role in brain development is well recognised. The protein is expressed in the membranes of BBB vessels, neurons, and microglia, creating a connection between different areas of the human brain. LAT1 received significant attention in the context of brain tumor treatment, particularly for glioblastoma multiforme, a malignancy with a poor prognosis characterised by fatal relapses. Since several drugs are also substrates of LAT1, its expression at the BBB could be exploited to deliver drugs that target brain diseases. This review describes the functional, structural, and regulatory features of LAT1, focusing on pharmacology in the context of brain homeostasis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106070"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia 活化星形胶质细胞重编程为gaba能神经元治疗三叉神经痛。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-08 DOI: 10.1016/j.neuint.2025.106067
Shuangyin Xia , Kai Chen , Xin Li , Dingquan Zou , Meng Wang , Yaping Wang
{"title":"Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia","authors":"Shuangyin Xia ,&nbsp;Kai Chen ,&nbsp;Xin Li ,&nbsp;Dingquan Zou ,&nbsp;Meng Wang ,&nbsp;Yaping Wang","doi":"10.1016/j.neuint.2025.106067","DOIUrl":"10.1016/j.neuint.2025.106067","url":null,"abstract":"<div><div>Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors <em>Sox2</em> and <em>Mash1</em> in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing <em>Sox2</em> and <em>Mash1</em> in astrocytes led to a significant transdifferentiation into GABAergic neurons, which − improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing <em>Sox2</em> and <em>Mash1</em> in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106067"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Histone lactylation is associated with METTL3-dependent LCN2 m6A modification and astrocyte activation after intracerebral hemorrhage 脑出血后,组蛋白乳酸化与mettl3依赖性LCN2 m6A修饰和星形胶质细胞活化有关。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-06 DOI: 10.1016/j.neuint.2025.106069
Ling Gao , Xiaobin Zheng , Cong Tan , Li Peng , Chuang Wang , Zhongtao Zheng , Jiangli Han , Jian Wang , Zhao Yang , Weiming Chen
{"title":"Histone lactylation is associated with METTL3-dependent LCN2 m6A modification and astrocyte activation after intracerebral hemorrhage","authors":"Ling Gao ,&nbsp;Xiaobin Zheng ,&nbsp;Cong Tan ,&nbsp;Li Peng ,&nbsp;Chuang Wang ,&nbsp;Zhongtao Zheng ,&nbsp;Jiangli Han ,&nbsp;Jian Wang ,&nbsp;Zhao Yang ,&nbsp;Weiming Chen","doi":"10.1016/j.neuint.2025.106069","DOIUrl":"10.1016/j.neuint.2025.106069","url":null,"abstract":"<div><h3>Background</h3><div>Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated with unfavorable outcome in ICH patients. However, the role of lactate in ICH-induced SBI remain poorly understood.</div></div><div><h3>Method</h3><div>An autologous blood injection mouse model of ICH and lactate-treated C8D1A cells were employed as the <em>in vivo</em> and <em>in vitro</em> models, respectively. The establishment of ICH model was validated by behavior tests, and brain injury was assessed by H&amp;E and Nissel staining. qRT-PCR, Western blot and IHC analysis were used to detect the expression of key molecules. Immunofluorescent (IF) staining was employed to evaluate astrocyte activation. Pro-inflammatory cytokine release was monitored by ELISA assay. The interaction between H3K18la and METTL3 was assessed by ChIP assay, and the association between METTL3 and LCN2 mRNA was assessed by RNA immunoprecipitation (RIP) assay.</div></div><div><h3>Results</h3><div>The levels of lactate, METTL3 and LCN2 are elevated in ICH model in mice. The inhibition of lactate decreased METTL3 expression and alleviated ICH-induced SBI. Mechanistically, histone H3K18 lactylation was associated with the upregulated levels of METTL3 and m<sup>6</sup>A in mouse brains. METTL3 regulated the m<sup>6</sup>A modification of LCN2 and upregulated its expression. In ICH mice, silencing of LCN2 inhibited A1 astrocyte activation. Histone lactylation-modulated LCN2 m<sup>6</sup>A modification is involved in astrocyte activation and the regulation of SBI in ICH mice.</div></div><div><h3>Conclusion</h3><div>These results suggested a mechanism whereby histone lactylation is implicated in the activation of A1 astrocytes through METTL3-mediated LCN2 m<sup>6</sup>A modification.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106069"},"PeriodicalIF":4.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differences in presynaptic hippocampal GABAergic terminals at the early stage of life in female and male mice: effect of an acute early inflammatory challenge 雌性和雄性小鼠早期海马突触前gaba能终端的差异:急性早期炎症的影响
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-04 DOI: 10.1016/j.neuint.2025.106062
Cristina Benatti , Alessandra Roggeri , Ylenia Toscano , Veronica Torre , Nicoletta Brunello , Fabio Tascedda , Johanna Maria Catharina Blom , Anna Pittaluga
{"title":"Differences in presynaptic hippocampal GABAergic terminals at the early stage of life in female and male mice: effect of an acute early inflammatory challenge","authors":"Cristina Benatti ,&nbsp;Alessandra Roggeri ,&nbsp;Ylenia Toscano ,&nbsp;Veronica Torre ,&nbsp;Nicoletta Brunello ,&nbsp;Fabio Tascedda ,&nbsp;Johanna Maria Catharina Blom ,&nbsp;Anna Pittaluga","doi":"10.1016/j.neuint.2025.106062","DOIUrl":"10.1016/j.neuint.2025.106062","url":null,"abstract":"<div><div>GABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the efficiency of mechanisms of GABA storage and exocytosis in hippocampal terminals of male and female mice during the juvenile period (PND21), adolescence (PND36) or adulthood (PND90). The expression of mRNA encoding for the presynaptic GABA transporter type 1, (GAT1) and the vesicular GABA transporter (VGAT1) was analysed. A significant scaling-down in the GAT1 mRNA levels (SLC6A1) was detected at PND21 in both sexes until adulthood, while the SLC32A1-VGAT mRNA level was conserved. We also analysed the density of GAT1 and VGAT proteins. Western blot analysis unveiled the presence of a monomeric and an oligomeric form of GAT1. The density of the monomeric form was conserved at the different stages of development in both sexes. Differently, the oligomeric assembly was significantly overexpressed in hippocampal synaptosomal lysates from PND21 male and female mice, but recovered at PND36. VGAT density was largely conserved in PND21 and PND36 male hippocampal synaptosomal lysates when compared to adult particles, but significantly lower in PND21 female particles. Notably, these changes are consistent and support the altered vesicular storage of newly taken-up [<sup>3</sup>H]GABA detected in PND21 male and female hippocampal synaptosomes as well as the different responsiveness of GABAergic male and female synaptosomes to increasing depolarizing stimuli (12, 20 and 30 mM KCl-enriched solutions) measured as efficiency of the [<sup>3</sup>H]GABA exocytosis. Interstingly, an acute LPS treatment affects the efficiency of GABA exocytosis at PND36 in a sex-dependent manner. These results add new knowledge on the role of GABA as effector of central inhibitory plasticity at the early stage of development and its relevance in dimorphic adaptation in physio pathological conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106062"},"PeriodicalIF":4.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in Parkinson's disease models 在帕金森病模型中,TREM2缺乏通过疾病相关的小胶质细胞加重神经炎症反应和认知障碍。
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-04 DOI: 10.1016/j.neuint.2025.106068
Zhang Piao , Zhu Baoyu , Feng Jiezhu , Liang Xiaomei , Huang Peiting , He Chentao , Deng Yiyu , Lu Jiahong , Wang Lijuan , Zhang Yuhu
{"title":"TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in Parkinson's disease models","authors":"Zhang Piao ,&nbsp;Zhu Baoyu ,&nbsp;Feng Jiezhu ,&nbsp;Liang Xiaomei ,&nbsp;Huang Peiting ,&nbsp;He Chentao ,&nbsp;Deng Yiyu ,&nbsp;Lu Jiahong ,&nbsp;Wang Lijuan ,&nbsp;Zhang Yuhu","doi":"10.1016/j.neuint.2025.106068","DOIUrl":"10.1016/j.neuint.2025.106068","url":null,"abstract":"<div><div>This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106068"},"PeriodicalIF":4.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Functional effects of heavy metal exposures on N6-methyladenosine (m6A) methylation and other Epitranscriptomic modifications in the central nervous system 重金属暴露对中枢神经系统n6 -甲基腺苷(m6A)甲基化和其他表转录组修饰的功能影响
IF 4 3区 医学
Neurochemistry international Pub Date : 2025-10-02 DOI: 10.1016/j.neuint.2025.106064
Niraj Lodhi , Lauren Powell , Jay S. Schneider
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