Neurochemistry international最新文献

{"title":"Investigating the role of GABAergic interneurons in the antidepressant-like mechanism of agomelatine","authors":"Suhong Ye ,&nbsp;Qiaolu Xu ,&nbsp;Nashwa Amin ,&nbsp;Ling Bao ,&nbsp;Yang Yang ,&nbsp;Irum Naz Abbasi ,&nbsp;Marong Fang","doi":"10.1016/j.neuint.2025.106101","DOIUrl":"10.1016/j.neuint.2025.106101","url":null,"abstract":"<div><div>Depression is a prevalent and debilitating mental disorder with substantial impacts on global health and socioeconomic costs. Despite various antidepressants targeting monoaminergic neurotransmission, a significant proportion of patients fail to achieve remission with existing treatments. Agomelatine (AGO), as a novel antidepressant, has shown promise in treating depression. However, the neural circuits and molecular mechanisms underlying its therapeutic effects remain largely unknown. This study aimed to investigate the role of GABAergic neural circuits on the antidepressant effects of AGO and elucidate the underlying cellular and molecular mechanisms. A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive-like behaviors. Genetic manipulation was employed to selectively ablate GABAergic neurons, and the effects of AGO treatment on behavioral performance and neuronal morphology were assessed. Additionally, the expression of synaptic and clock genes was analyzed to explore underlying molecular mechanisms. We found that AGO treatment significantly improved the behavioral performance of CUMS mice and rescued the structural integrity and quantity of central neurons. It regulated the protein expressions of VGAT, VGLUT1, and Gad65 in the brain tissues of CUMS mice. Notably, AGO altered the protein and gene expressions in GABAergic neural circuits across different brain regions. Morphological analysis revealed that AGO improved dendritic spine density and length in neurons in the selective ablation of GABAergic interneurons. The antidepressant effects of AGO involve the modulation of GABAergic neural circuits as a critical but non-exclusive target, alongside the restoration of GABAergic-glutamatergic balance, synaptic function, and clock gene expressions. These findings highlight AGO's potential in normalizing disrupted neuronal function in depression and offer insights into novel multi-target therapeutic strategies.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106101"},"PeriodicalIF":4.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734559","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}

{"title":"SPI1 suppresses YAP phosphorylation in vascular endothelial cells to prevent intracranial aneurysm progression","authors":"Yikui Liu ,&nbsp;Danyi Zheng ,&nbsp;Lanlan Zhao ,&nbsp;Bing Leng ,&nbsp;Qingfang Sun ,&nbsp;Liuguan Bian ,&nbsp;Yongtao Zheng","doi":"10.1016/j.neuint.2025.106100","DOIUrl":"10.1016/j.neuint.2025.106100","url":null,"abstract":"<div><div>This study aims to elucidate the mechanism by which YAP mediates the activity of vascular endothelial cells (ECs) in the biological process of intracranial aneurysms (IAs) and to provide a novel target for noninvasive IAs treatment. Single-nuclei RNA profiling of aneurysmal cells revealed that ECs within aneurysms exhibit an intermediate identity between arterial and venous/capillary cells, rather than clustering within the normal arterial population. These specific human ECs showed downregulated YAP expression under turbulent flow. Immunostaining of human IA tissues demonstrated reduced YAP and increased phosphorylated YAP (p-YAP) compared with superficial temporal artery walls. Using YAP-knockdown human brain microvascular endothelial cells (HBMECs), we observed elevated expression of senescence markers p21 and p16, accompanied by diminished proliferation and migration capacities. Furthermore, SPI1 (also known as PU.1) overexpression alleviated EC degeneration induced by turbulent flow through suppression of YAP phosphorylation. Collectively, our findings indicate that turbulent flow markedly reduces YAP expression while promoting its phosphorylation, thereby accelerating endothelial senescence. Importantly, SPI1 overexpression effectively mitigated turbulent-flow-induced endothelial senescence, suggesting that SPI1 may serve as a potential therapeutic target for preventing aneurysmal progression.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106100"},"PeriodicalIF":4.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734557","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}

{"title":"Transcription factor EB inhibition in response to genotoxic stress promotes apoptosis of glioblastoma cells","authors":"Seung-Ho Park ,&nbsp;Minseok Jeong ,&nbsp;Min-Jeong Kong,&nbsp;Kyung-Chul Choi","doi":"10.1016/j.neuint.2025.106087","DOIUrl":"10.1016/j.neuint.2025.106087","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB contributes to resistance to genotoxic stress and whether its inhibition promotes apoptosis of GBM cells and glioma stem cells (GSCs). Specifically, we examined whether combined treatment with etoposide and SAHA overcomes TFEB-mediated resistance and enhances apoptotic cell death. We examined the effects of etoposide, a topoisomerase II inhibitor, and SAHA, a histone deacetylase inhibitor, on TFEB expression and apoptotic signaling in human GBM cells and GSCs. To assess TFEB-mediated drug resistance, we measured cell viability, proliferation, and tumorsphere formation following single or combined treatments. Apoptotic signaling was analyzed by western blotting, MTT assays, and tumorsphere formation assays. Functional roles of TFEB were further investigated using overexpression and shRNA knockdown approaches. Treatment with etoposide induced apoptosis and reduced TFEB expression in GBM cells. Co-treatment with etoposide and SAHA synergistically increased cleaved PARP and phosphorylated H2AX levels, indicating enhanced apoptotic activity. In TFEB-overexpressing and knockdown GBM cells, apoptosis sensitivity varied according to TFEB expression levels. In GSCs, combination treatment significantly suppressed cell proliferation and tumorsphere formation, accompanied by reduced TFEB expression and oligomerization, and increased apoptosis. Our findings suggest that TFEB promotes the chemoresistance of GBM tumors and GSCs by suppressing apoptosis. Co-treatment with etoposide and SAHA inhibits TFEB activity and enhances apoptotic cell death, representing a promising therapeutic strategy for treating malignant brain tumors.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106087"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538119","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}

{"title":"A novel GSK3β inhibitor ameliorates tau aggregation and neuroinflammation in Alzheimer's disease","authors":"Xin-Yue Ning ,&nbsp;Wen-Jie Liu ,&nbsp;Li-Jun Zhou ,&nbsp;Nan Wang ,&nbsp;Xin-Zhu Li ,&nbsp;Li-Meng Wu ,&nbsp;Zhen-Shu Li ,&nbsp;Ai-Zhu Yang ,&nbsp;Si-Yuan Liu ,&nbsp;Zong-He Xu ,&nbsp;Fang-Hua Xun ,&nbsp;Zi-Hua Xu ,&nbsp;Qing-Chun Zhao","doi":"10.1016/j.neuint.2025.106090","DOIUrl":"10.1016/j.neuint.2025.106090","url":null,"abstract":"<div><div>In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, ZLWH-60, which demonstrated inhibitory activity with an IC50 of 11.5 nM. Here, we comprehensively evaluated the therapeutic potential of ZLWH-60 in suppressing tau pathology and neuroinflammation using multiple chemically-induced AD models. Our results demonstrate that ZLWH-60 could reduce the phosphorylation of multiple tau epitopes by inhibiting the activity of GSK3β, thereby ameliorating cognitive impairments in OKA-induced mouse model. In the LPS-induced mouse model, ZLWH-60 also reduced the secretion of inflammatory factors in the brain, exerting a neuroprotective effect. Our data highlight that ZLWH-60, as a GSK3β inhibitor, has a powerful ability to reduce the phosphorylation of tau protein and shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, demonstrating the potential for therapeutic use of this drug to control AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106090"},"PeriodicalIF":4.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627325","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}

{"title":"Interplay and intervention of epigenetic dysregulation in traumatic brain injury pathology","authors":"Samuel G. Faasen,&nbsp;Vijay Arruri,&nbsp;Reid S. Alisch","doi":"10.1016/j.neuint.2025.106094","DOIUrl":"10.1016/j.neuint.2025.106094","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) occurs when an external mechanical force damages brain tissue, leading to temporary or lasting disturbances in brain structure and function. The heterogeneous molecular and phenotypic nature of TBI poses a major challenge to translating basic research discoveries into clinically effective interventions. Emerging evidence indicates that epigenetic and epitranscriptomic mechanisms, including histone modifications, DNA methylation, and RNA modifications, play pivotal roles in the molecular response to TBI. In this review, we discuss post-TBI epigenomic alterations with a focus on histone modifications, DNA methylation, and RNA modifications, and we highlight preclinical interventions that modulate these alterations and improve related post-TBI behavioral outcomes.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106094"},"PeriodicalIF":4.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627306","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}

{"title":"Essential oils by name and by nature: a review of their antioxidant and neuroprotective potential in Parkinson's disease","authors":"Claudia Cannas ,&nbsp;Stefano Zoroddu ,&nbsp;Alessandra Tiziana Peana ,&nbsp;Gaia Rocchitta ,&nbsp;Luigi Bagella ,&nbsp;Rossana Migheli","doi":"10.1016/j.neuint.2025.106092","DOIUrl":"10.1016/j.neuint.2025.106092","url":null,"abstract":"<div><div>Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) and endogenous antioxidants, plays a central role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). The brain's high oxygen demand and abundance of polyunsaturated fatty acids make it particularly vulnerable to ROS-induced damage. Despite major advances in research, no disease-modifying treatments for PD are currently available. Consequently, increasing attention has been directed toward natural bioactive compounds with antioxidant and neuroprotective properties. Among these, essential oils (EOs), volatile plant-derived mixtures with documented antioxidant, anti-inflammatory, and neuroactive effects, are emerging as promising adjuvants for PD management. This review critically examines the antioxidant and neuroprotective effects of well-characterized EOs evaluated in both <em>in vitro</em> and <em>in vivo</em> models of neurodegeneration. Literature searches were conducted in PubMed and Scopus up to March 2025, identifying studies investigating EOs or their major components in PD-related experimental settings. Evidence indicates that essential oils derived from the <em>Citrus</em> and <em>Rosa</em> genus, and the <em>Lamiaceae</em> family, can reduce intracellular ROS accumulation, inhibit lipid peroxidation, enhance endogenous antioxidant enzyme activity, and modulate both apoptotic and inflammatory pathways. These multitarget actions are often attributed to synergistic interactions among EO constituents, such as limonene, linalool, thymol, and carvacrol. Owing to their low toxicity and ability to cross the blood–brain barrier, EOs represent promising natural candidates for the development of complementary therapeutic strategies in PD. Further mechanistic and translational studies are warranted to substantiate their clinical potential.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106092"},"PeriodicalIF":4.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617187","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}

{"title":"ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies","authors":"Chihiro Matsumoto ,&nbsp;Tomohiro Kabuta ,&nbsp;Terunori Sano ,&nbsp;Shigeo Murayama ,&nbsp;Yuko Saito ,&nbsp;Yuji Takahashi","doi":"10.1016/j.neuint.2025.106093","DOIUrl":"10.1016/j.neuint.2025.106093","url":null,"abstract":"<div><div>The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4—a receptor tyrosine kinase—triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with <em>MAPT</em> mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106093"},"PeriodicalIF":4.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617186","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}

{"title":"GDNF-AS1 mediated LHX2/METTL3/NCOA4 axis inhibits glioma progression via induction of ferroptosis","authors":"Yangbo zhou,&nbsp;Zhongyue Liu,&nbsp;Wenjia Ma","doi":"10.1016/j.neuint.2025.106085","DOIUrl":"10.1016/j.neuint.2025.106085","url":null,"abstract":"<div><div>Glioma, particularly glioblastoma (GBM), represents the most aggressive primary brain tumor with limited treatment options and poor prognosis. Emerging evidence highlights ferroptosis induction as a promising therapeutic strategy, while long non-coding RNAs (lncRNAs) have gained attention as potential biomarkers and regulators in glioma pathogenesis. This study aimed to investigate the molecular mechanism of lncRNA Glial Cell Line-Derived Neurotrophic Factor Antisense RNA 1 (GDNF-AS1) in glioma cell ferroptosis through the LIM Homeobox 2 (LHX2)/Methyltransferase-Like 3 (METTL3)/Nuclear Receptor Coactivator 4 (NCOA4) pathway using Normal Human Astrocytes (NHA) and glioma cell lines (U87MG, T98G, U251, and A172), along with intracranial and subcutaneous xenotransplantation models established in BALB/c nude mice. Functional experiments demonstrated that GDNF-AS1, LHX2, and NCOA4 were downregulated while METTL3 was upregulated in glioma cells. GDNF-AS1 overexpression promoted mitochondrial damage and oxidative stress by enhancing ferroptosis, ultimately impairing glioma cell biological functions. METTL3 silencing augmented GDNF-AS1's effects, further exacerbating ferroptosis and oxidative stress while inhibiting glioma progression. Mechanistically, GDNF-AS1 recruited transcription factor LHX2 to upregulate its enrichment at the METTL3 promoter, thereby suppressing METTL3 transcription, reducing N6-Methyladenosine (m6A) levels, promoting NCOA4 expression, and inducing ferroautophagy and ferroptosis in glioma cells. These findings demonstrate that GDNF-AS1 inhibits glioma development by activating ferroptosis through the LHX2/METTL3/NCOA4 axis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106085"},"PeriodicalIF":4.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585640","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}

{"title":"Therapeutic potential of KATP channels in the attenuation of Parkinson's disease pathogenesis and progression – A review","authors":"Barbara Gundi ,&nbsp;Hio Lam Ho ,&nbsp;Xinyang Zhang ,&nbsp;Amanda He ,&nbsp;Danielle Xin ,&nbsp;Ana Flávia F. Ferreira ,&nbsp;Luiz Roberto Britto ,&nbsp;Zhong-Ping Feng ,&nbsp;Hong-Shuo Sun","doi":"10.1016/j.neuint.2025.106091","DOIUrl":"10.1016/j.neuint.2025.106091","url":null,"abstract":"<div><div>Parkinson's disease (PD) is one of the most prevalent progressive neurodegenerative diseases today. However, existing treatments primarily focus on symptom management rather than attenuating disease progression and pathogenesis. ATP-sensitive potassium (K_ATP) ion channels play a significant role in motor control and coordination within the basal ganglia and have been implicated in the dopaminergic depletion mechanisms underlying PD. Recent studies have explored the potential of K_ATP channel inhibitors to slow PD pathogenesis and progression. Both pharmacological inhibition and genetic inactivation of these channels have been shown to reduce oxidative stress, dopamine (DA) depletion, and subsequent motor deficits. Contrastingly, alternative evidence suggests that K_ATP channel openers (KCOs) may elicit similar effects, highlighting the need for further exploration of K_ATP-mediated DA depletion mechanisms in PD. Future studies expanding our understanding of the mechanistic action of K_ATP in PD are essential to effectively leverage the channel's potential as a therapeutic target for combating PD pathology.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106091"},"PeriodicalIF":4.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585674","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}

{"title":"Esketamine attenuates post-traumatic stress disorder via suppressing neuroinflammation and abnormal myelination","authors":"Zhaoliang Gu ,&nbsp;Ruixue Song ,&nbsp;Guoqiang Liu ,&nbsp;Hao Yu ,&nbsp;Liangyu Ju ,&nbsp;Yu Su ,&nbsp;Jianming Bi ,&nbsp;Jianhao Qiu ,&nbsp;Yuan Dong ,&nbsp;Aijie Liu","doi":"10.1016/j.neuint.2025.106089","DOIUrl":"10.1016/j.neuint.2025.106089","url":null,"abstract":"<div><h3>Background</h3><div>Post-traumatic stress disorder (PTSD) is a chronic psychological disorder that is induced by traumatic events. The pathophysiological mechanism of PTSD involves complex neurobiological processes. However, the underlying mechanism is not clear, leading to lack of effective therapeutic interventions.</div></div><div><h3>Methods</h3><div>Mice were exposed to the electric foot shocks using the contextual fear memory paradigm. A subanesthetic dose (30 mg/kg) of esketamine or saline was administered via intraperitoneal (i.p.) injection 1 h after the electric foot shocks. Fear retrieval was tested on day 1 and day 7 after fear conditioning. Anxiety-like and depressive-like behaviors were evaluated using the open field test and elevated plus maze on day 1 and day 2, respectively, after the foot-shocks. The medial prefrontal cortex (mPFC) was freshly collected 1 h after esketamine administration following the foot-shocks for RNA sequencing. Additionally, the mPFC were collected 4 days after fear conditioning and subjected to quantitative real-time PCR (qPCR) analysis and immunofluorescence staining.</div></div><div><h3>Results</h3><div>A single subanesthetic dose of esketamine significantly alleviated PTSD-like symptoms in mice induced by electric foot-shocks. RNA sequencing revealed the involvement of neuroinflammation and aberrant myelination in the pathogenesis of PTSD. Subsequently, we observed a significant increase in the number of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells and transcriptional upregulation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), in the mPFC of mice subjected electric foot shocks, indicating elevated neuroinflammation. Subanesthetic esketamine administration significantly attenuated this neuroinflammatory response. Furthermore, electric foot shocks caused significantly increased the expression of myelin basic protein (MBP), myelin-associated glycoprotein (MAG), oligodendrocyte transcription factor 2 (Olig2) and platelet-derived growth factor receptor-α (PDGFRα), suggesting increased myelination associated with PTSD. Esketamine treatment also rescued this abnormal myelination.</div></div><div><h3>Conclusion</h3><div>Our study demonstrates the contribution of neuroinflammation and abnormal myelination are closely related to the development of PTSD. Moreover, a subanesthetic dose of esketamine alleviated the PTSD-like symptoms in mice by suppressing foot-shock-induced increases in neuroinflammation and myelination. These results highlight the therapeutic potential of subanesthetic esketamine in mitigating PTSD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106089"},"PeriodicalIF":4.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562291","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}