Neurochemistry international最新文献

{"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":"2025-12-01","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}

{"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":"2025-12-01","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}

{"title":"Transgenerational non-genomic transmission of acquired nervous system Phenotypes: Narrative review and epigenetic insights","authors":"Anas Abou Merhi ,&nbsp;Vivek Sivan ,&nbsp;Joyce Koueik ,&nbsp;Alexandra Walsh ,&nbsp;Ligia A. Papale ,&nbsp;Reid S. Alisch ,&nbsp;Kirk Hogan ,&nbsp;Bermans J. Iskandar","doi":"10.1016/j.neuint.2025.106088","DOIUrl":"10.1016/j.neuint.2025.106088","url":null,"abstract":"<div><div>Transgenerational epigenetic inheritance (TEI) refers to the transmission of phenotypic traits across multiple generations independent of changes in DNA sequence that are mediated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin morphology, and non-coding RNAs. This review focuses on manuscripts that report epigenetic mechanisms in the transgenerational inheritance of nervous system phenotypes in both mammalian and non-mammalian experimental models. Non-mammalian organisms such as <em>C. elegans</em> and <em>Drosophila</em> have been instrumental in disclosing TEI pathways comprising small RNA networks, histone-based modifications, and N6-methyladenine modifications that balance limited cytosine methylation. Authenticating TEI in mammals is complex due to extensive elimination of epigenetic factors and pathways essential for mitosis that do not participate in meiosis, germline development, and early embryogenesis, termed epigenetic “erasure” or “reprogramming”. Specific epigenetic pathways that guide neural development, including DNA methylation at metastable epialleles and gamete-derived small RNAs, escape erasure, and have been linked to altered neurodevelopment and behavior in offspring. Together, these data indicate a role for epigenetic regulation in tuning neural circuits during neurodevelopment with enduring impacts on brain organization and behavior. This perspective situates neural TEI within a mechanistic framework that links early environmental exposures to long-lived neuronal circuit properties and behavioral outcomes. Accordingly, elucidating neural-specific TEI mechanisms alone and in combination will enhance our understanding of how ancestral environmental exposures shape neurological structures, functions, behaviors, and susceptibilities to disease across generations. The present review synthesizes current evidence, identifies key interpretative challenges, and details directions for future research in neural TEI.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106088"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562285","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":"Functional impact of CYFIP2 RNA editing on actin regulation, axon growth, and spinogenesis","authors":"Luca La Via ,&nbsp;Elona Ndoj ,&nbsp;Matteo Bertoli ,&nbsp;Veronica Mutti ,&nbsp;Giulia Carini ,&nbsp;Alice Filippini ,&nbsp;Federica Bono ,&nbsp;Chiara Fiorentini ,&nbsp;Giovanni Ribaudo ,&nbsp;Alessandra Gianoncelli ,&nbsp;Giuseppe Borsani ,&nbsp;Isabella Russo ,&nbsp;Alessandro Barbon","doi":"10.1016/j.neuint.2025.106084","DOIUrl":"10.1016/j.neuint.2025.106084","url":null,"abstract":"<div><div>Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a component of the wave regulatory complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, the CYFIP2 transcript undergoes RNA editing, an epitranscriptomic modification catalyzed by ADAR enzymes, which leads to adenosine (A) to inosine (I) deamination. <em>CYFIP2</em> editing in the coding sequence results in a K/E substitution at amino acid 320. The functional meaning of this regulation is still unknown. In this study, we aimed to investigate the potential implications of CYFIP2 RNA editing related to actin dynamics during cell differentiation, axon development and synaptogenesis in neural cells. We generated SH-SY5Y neuroblastoma cell lines in which the <em>CYFIP2</em> gene has been functionally inactivated via CRISPR-Cas9 technology. <em>CYFIP2</em> KO cells exhibited profound actin filament disorganization and loss of the ability to differentiate into a neuron-like phenotype. The overexpression of both the unedited (K) and edited (E) CYFIP2 isoforms restored normal abilities. Finally, we used primary neuronal cultures in which endogenous CYFIP2 was knocked down via short hairpin RNA (shRNA) technology and <em>CYFIP2</em> editing variants were overexpressed.</div><div>While CYFIP2-KD cells presented a decrease in axon development and spine frequency, CYFIP2-E variants increased the number of axon branches, total axon length and dendritic spine frequency compared with both CYFIP2-KD cells and CYFIP-K variants. Overall, our work reveals for the first time the functional significance of the CYFIP2 K/E RNA editing process in regulating the spread of neuronal axons during the initial stages of in vitro development and spinogenesis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106084"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470512","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":"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":"2025-12-01","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}

{"title":"Toxic Tango in Parkinson's Disease: A dance between αSyn and iron import, export and speciation","authors":"Tasha Cosson ,&nbsp;Peter Faller ,&nbsp;Dean L. Pountney","doi":"10.1016/j.neuint.2025.106053","DOIUrl":"10.1016/j.neuint.2025.106053","url":null,"abstract":"<div><div>The intricate interplay between brain iron homeostasis and pathological α-Synuclein (αSyn) in Parkinson's Disease (PD) is still unclear. αSyn is the primary protein involved in disease progression and promotes cytotoxicity by impairing dopamine synthesis, mitochondrial dysfunction and disrupts brain iron homeostasis. Iron has further revealed to induce αSyn aggregation however, the exact mechanism of interaction between iron and αSyn is uncertain. Many studies have demonstrated an imbalance of iron homeostasis in PD pathogenesis, including macroautophagy related to αSyn aggregate and accumulated ferritin degradation. Inducible ferritinophagy has been suggested as a possible therapeutic to combat raised ferritin levels and reinstate iron homeostasis however this may lead to increased ferroptosis. Despite limited knowledge of ferritinophagy induced ferroptosis in PD there is a possible link to neurodegeneration. This review aims to summarise the current understanding of the chemical interactions between iron and αSyn and possible binding affinities in biologically relevant models, while further highlighting αSyn's pathological role in neurodegeneration and aberrant iron homeostasis. Developing knowledge surrounding the complex interactions between αSyn and iron in PD will aid in possible therapeutic strategies to combat PD disease progression.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106053"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084821","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":"Decoding the role of m6A RNA methylation regulators in psychiatric and substance use disorders","authors":"Ji Sun Koo ,&nbsp;Huiping Zhang","doi":"10.1016/j.neuint.2025.106035","DOIUrl":"10.1016/j.neuint.2025.106035","url":null,"abstract":"<div><div>N6-methyladenosine (m⁶A) is the most prevalent internal modification of eukaryotic mRNA and plays a crucial role in regulating gene expression. This dynamic and reversible epitranscriptomic mark responses to both environmental and internal cues and influences RNA stability, splicing, translation, and localization. In the central nervous system, m⁶A modifications are tightly regulated and critically involved in neural development, synaptic plasticity, learning, memory, and stress responses. These modifications are governed by a complex and responsive network of regulatory proteins, including writers (methyltransferases), erasers (demethylases), and readers (RNA-binding proteins). Emerging evidence indicates that dysregulation of m⁶A regulators contributes to the pathophysiology of various psychiatric disorders. Altered expression or function of m⁶A-related genes has been associated with neuroadaptive changes underlying conditions such as schizophrenia, depression, bipolar disorder, and substance use disorder. This review provides an overview of the molecular mechanisms of m⁶A modification, highlights the roles of m⁶A regulators in psychiatric disorders, summarizes recent findings, and discusses potential therapeutic strategies targeting m6A pathways. A better understanding of m⁶A-mediated mechanisms may advance the diagnosis and treatment of neuropsychiatric conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106035"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924972","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":"Spinal p38 MAPK/PGC-1α/SIRT3 signaling pathway mediates remifentanil-induced hyperalgesia in rats via ROS release and NR2B activation","authors":"Guoyan Feng ,&nbsp;Fengxiang Song ,&nbsp;Aiqi Wang ,&nbsp;Lu Wang ,&nbsp;Haotian Zhang ,&nbsp;Shun Wang ,&nbsp;Haitao Hou ,&nbsp;Lianxiang Zhang ,&nbsp;Liqin Deng","doi":"10.1016/j.neuint.2025.106061","DOIUrl":"10.1016/j.neuint.2025.106061","url":null,"abstract":"<div><div>Remifentanil-induced hyperalgesia (RIH) poses a significant clinical challenge. Our research group has previously confirmed that abnormal activation of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal dorsal horn contributes to RIH, but the specific regulatory pathway remains unclear. It is known that p38 MAPK can regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and the PGC-1α/Sirtuin 3 (SIRT3) pathway plays an important role in various pain models. However, whether this pathway is involved in RIH remains to be elucidated. In this study, an RIH model was established using male Sprague-Dawley (SD) rats, and significant hyperalgesia was observed in the RIH group. Intrathecal injection of the p38 MAPK inhibitor SB203580 or the PGC-1α agonist ZLN005 significantly alleviated this hyperalgesic response.</div><div>Mechanistic analysis further revealed that in the RIH model group, activation of p38 MAPK was increased in spinal dorsal horn microglia, while the expression of PGC-1α and SIRT3 were decreased. In neurons, reactive oxygen species (ROS) levels were increased, accompanied by increased expression of the N-methyl-<span>d</span>-aspartate receptor (NMDAR) subunit NR2B, synaptic structural remodeling, and an increase in the amplitude and frequency of NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs). All these pathological changes could be reversed by intervention with either SB203580 or ZLN005. In conclusion, this study demonstrates that remifentanil activates p38 MAPK in spinal dorsal horn microglia, inhibits the PGC-1α/SIRT3 signaling pathway, promotes ROS release, subsequently activates the neuronal NR2B subunit, and ultimately induces RIH. This mechanism provides a new potential target for the treatment of RIH.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106061"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184516","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":"Opioids induce constipation by prompting alpha-Synuclein hyperphosphorylation in the colonic myenteric plexus","authors":"Binghan Jia ,&nbsp;Yuqiong Zhao ,&nbsp;Xiaojie Ren ,&nbsp;Dandan Zhang ,&nbsp;Hua Jia ,&nbsp;Dengke Wang ,&nbsp;Lixin Wang ,&nbsp;Junping Li","doi":"10.1016/j.neuint.2025.106036","DOIUrl":"10.1016/j.neuint.2025.106036","url":null,"abstract":"<div><div>Opioid-induced constipation (OIC) is the most common gastrointestinal disorder associated with opioid use. It is linked to impaired neurotransmitter release. Alpha-Synuclein (α-Syn) plays a crucial role in maintaining neurotransmitter homeostasis and regulating synaptic plasticity in the nervous system. However, its role in the disease progression remains unclear. In the present study, we investigated the impact of α-Syn hyperphosphorylation on colonic dysmotility and constipation symptoms using a Sprague-Dawley rat model of OIC. Our results suggest that α-Syn expression at the Ser129 phosphorylation site (pS129-α-Syn) is significantly increased in the colonic myenteric layer of OIC rats. Conversely, inhibiting pS129-α-Syn reversed the colonic dysmotility and increased the expression of synaptic functional proteins, such as Synapsin-1, Synaptotagmin-1, vesicle-associated membrane protein 2 (VAMP-2), and Syntaxin-1, as well as enteric neurotransmitter synthases, including neuronal nitric oxide synthase (nNOS) and adenosine triphosphate synthase (ATPB). Additionally, we found that opioids downregulate GSK3β protein expression at the Ser9 site by activating the μ-opioid receptors (MOR). This increases GSK3β kinase activity, ultimately inducing pS129-α-Syn overexpression. In summary, the development of OIC correlates with α-Syn hyperphosphorylation in myenteric plexus neurons in the colon. Opioids can inhibit synaptic vesicle trafficking and enteric neurotransmitter release via the GSK3β/α-Syn hyperphosphorylation signaling axis, ultimately leading to colonic dysmotility and constipation.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106036"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889131","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":"Transcranial direct current stimulation attenuates cerebral ischemia-reperfusion injury by inhibiting neuronal pyroptosis via Netrin-1","authors":"Ying Wang ,&nbsp;Hao Liu ,&nbsp;Ping Li ,&nbsp;Zhuohang Zhang ,&nbsp;Yingxi He ,&nbsp;Yu Chen ,&nbsp;Yan Peng ,&nbsp;Bo Wang ,&nbsp;Linlin Jiang ,&nbsp;Changhong Li ,&nbsp;Qiyan Zhu ,&nbsp;Lingchuan Niu","doi":"10.1016/j.neuint.2025.106041","DOIUrl":"10.1016/j.neuint.2025.106041","url":null,"abstract":"<div><div>The significant role of pyroptosis in the early pathogenesis of ischemic stroke underscores the urgent need for effective management strategies. Transcranial direct current stimulation (tDCS), a noninvasive modality for modulating brain activity, has been shown to confer neuroprotection by inhibiting neuroinflammation during the acute phase of stroke. However, the specific mechanisms underlying the effect of tDCS on neuronal pyroptosis remain largely unexplored. We established brain I/R injury in adult male Sprague Dawley rats through a middle artery occlusion (MCAO) model. tDCS treatment began 24 h after MCAO and lasts for 6 consecutive days. Evaluate neurobehavioral deficits through an improved Neurological Severity Score (mNSS), Western blot, immunofluorescence staining, TUNEL staining, transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the expression of pyroptosis related proteins, cell morphology, and levels of inflammatory factors. The results showed that tDCS markedly reduced the levels of NLRP3 inflammasome-dependent pyroptosis proteins (NLRP3, ASC, cleaved-Caspase-1, and GSDMD-N), accompanied by a reduction in the number of cell membrane perforation and cell death related to pyroptosis. Moreover, tDCS increased the expression of NTN-1, which inhibited the activation of NLRP3 inflammasome through the peroxisome proliferator-activated receptor gamma (PPAR-γ)/nuclear factor kappa-B (NF-κB) signaling pathway. Knockdown of NTN-1 reversed the anti-pyroptosis and neuroprotective effect of tDCS. In conclusion, tDCS exerted neuroprotection by curbing neuronal pyroptosis through the NTN-1-mediated PPAR-γ/NF- κB pathway, and could be a useful strategy for ischemic stroke recovery.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106041"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923014","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}