ASN NEURO最新文献

{"title":"GABA Receptor Activation in Müller Glia as a Molecular Switch for Controlling VEGF-A in the Retina.","authors":"Alan E Medina-Arellano, Jesus Silvestre Albert-Garay, Karla Tovar-Hernandez, Matilde Ruiz-Cruz, Lenin Ochoa-de la Paz","doi":"10.1080/17590914.2026.2618997","DOIUrl":"10.1080/17590914.2026.2618997","url":null,"abstract":"<p><p>GABA receptors are classically known for driving neuronal hyperpolarization and modulating synaptic transmission. In glial cells, however, GABA induces depolarization and triggers calcium-dependent signaling pathways. Müller glia, the principal retinal glial population, maintain retinal homeostasis and are the major source of neuroretinal VEGF-A, a key angiogenic factor in development and disease. Although GABA receptor (GABAR) activity has been proposed to influence retinal VEGF-A, it remains unclear whether this regulation occurs through Müller glial cells (MGC) and which mechanisms are involved. Here, we investigated how GABAR activation modulates VEGF-A in primary mouse MGC cultures. Cells were exposed to GABA and selective agonists or antagonists of GABA_A (muscimol, gabazine) and GABA_B receptors (baclofen, CGP55845). VEGF-A expression and secretion were analyzed by immunofluorescence, western blot, RT-qPCR, and ELISA. To assess Ca²⁺ involvement, we used Ca²⁺-free Ringer-Krebs solution and the L-type channel blocker nimodipine, and examined MAPK signaling with the ERK1/2 inhibitor FR180204. Our findings show that GABA and muscimol increased VEGF-A fluorescence intensity after 48 hours while reducing VEGF-A secretion, without altering <i>Vegfa</i> mRNA. Both effects were abolished by extracellular Ca²⁺ removal or nimodipine, indicating a Ca²⁺-dependent mechanism. FR180204 also attenuated GABA- and GABA_A-mediated effects, implicating MAPK signaling. Short-term assays revealed that GABA rapidly elevates VEGF-A protein and secretion within ∼30 minutes. Together, these findings identify a Ca²⁺- and GABA_A-dependent pathway through which Müller glia regulate VEGF-A production and release, providing new insight into glial signaling and neurotransmitter-driven modulation of retinal angiogenic factors.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2618997"},"PeriodicalIF":3.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted Vitamin D Signaling and Metabolism in Neurodevelopmental and Neurodegenerative Disorders.","authors":"Nasim Khatibi, Jessica L MacDonald","doi":"10.1080/17590914.2026.2617453","DOIUrl":"https://doi.org/10.1080/17590914.2026.2617453","url":null,"abstract":"<p><p>Vitamin D is a secosteroid hormone with myriad physiological functions, including pleiotropic effects in the central nervous system. Vitamin D deficiency has been linked to multiple neurodevelopmental and neurodegenerative diseases, including Rett syndrome, epilepsy, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Over the past decades, vitamin D supplementation has been used as a preventative measure or a therapeutic intervention, often with inconsistent or variable responses. We discuss the known association between vitamin D deficiency and neurological disorder occurrence or progression for these disorders. Further, we assess the underlying causes for disruptions in vitamin D levels and the potential mechanisms of vitamin D-mediated improvements. We discuss disruptions in the vitamin D metabolism pathway, signaling, and/or feedback homeostasis that could underpin individual responses to vitamin D supplementation in these disorders. We further discuss the intersection between the vitamin D and cholesterol synthesis pathways and neuroinflammation, and the complex interactions that could contribute to the broad impact of vitamin D on neurological disorders.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2617453"},"PeriodicalIF":3.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-Synuclein Dynamics in Cerebral Ischemia.","authors":"Sanaz Bordbar, Sina Molavizade, Fateme Dehghani, Samin Davoody, Amir Reza Bahadori, Abbas Tafakhori","doi":"10.1080/17590914.2026.2615453","DOIUrl":"https://doi.org/10.1080/17590914.2026.2615453","url":null,"abstract":"<p><p>Cerebral ischemia is defined by insufficient blood supply to the brain and is a leading cause of mortality and neurological disability worldwide. Alpha-synuclein (α-Syn) is a protein associated with several neurodegenerative disorders, including Parkinson's disease, and has also been linked to the pathophysiology of cerebral ischemia. This narrative review provides a detailed overview of the current understanding of α-Syn in cerebral ischemia. We examine its impact on neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal cell death, as well as its potential protective roles. Additionally, we explore therapeutic strategies targeting α-Syn, including pharmacological agents, gene knockdown models, and RNA-based therapies. We also discuss α-Syn expression changes in animal and human studies and its potential as a diagnostic biomarker. By clarifying the complex interplay between α-Syn and cerebral ischemia, this review aims to deepen our understanding of ischemic brain injury mechanisms and support the development of novel treatment approaches.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2615453"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Thy1 in Cortico-Striatal Pathways Alters Response to Dopamine and Gabapentin.","authors":"Cezar Goletiani, Matthew D McEchron, Elizabeth Neely, James R Connor","doi":"10.1080/17590914.2026.2615452","DOIUrl":"10.1080/17590914.2026.2615452","url":null,"abstract":"<p><p>Thy1, a synaptic protein, may support synaptic junction adherence. Thus, we hypothesized that loss of Thy1 may alter synaptic transmission. Our focus on the Thy1 knockout (KO) mouse model stems from the loss of Thy1 expression in individuals with Restless Legs Syndrome (RLS), a neurological disorder. This investigation aimed to determine: 1) if the absence of Thy1 affects synaptic function in the striatal region, 2) if the absence of Thy1 alters the synaptic response to dopamine and gabapentin, and 3) if the Thy1 loss can alter behavior modulated by the striatum. Network-level synaptic transmission was measured in corticostriatal slices from Thy1 KO and C57BL/6 control mice. <i>In vivo</i>, acoustic startle behavioral testing was used to measure startle reaction and prepulse inhibition in both groups. Raclopride, a D₂ receptor antagonist, decreased population spike amplitude in control but not Thy1 KO slices. Quinpirole, a D₂ receptor agonist, did not change spike amplitude in any group. Gabapentin, a Ca²⁺ channel blocker, reduced population spike amplitude in Thy1 KO slices more than in controls. The behavioral acoustic startle response was diminished in Thy1 KO mice and attributed to enhanced prepulse inhibition. Loss of Thy1 alters striatal synaptic function, affecting dopaminergic modulation of corticostriatal neurotransmission and resulting in disruption of the startle response and prepulse inhibition.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2615452"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12818806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Characterization of Spinal Cord Myelin in the Mouse.","authors":"Oliver Schmitt, Hannes Kaddatz, Stefan Mikkat, Markus Kipp, Antje Schümann, Sarah Joost","doi":"10.1080/17590914.2025.2595945","DOIUrl":"10.1080/17590914.2025.2595945","url":null,"abstract":"<p><p>The myelin proteome is a critical structural and functional component of the central nervous system (CNS), undergoing dynamic remodeling throughout life. Pathological changes, such as those in multiple sclerosis, disrupt myelin integrity and lead to severe neurological deficits. Establishing a reproducible baseline of the CNS myelin proteome is therefore essential for monitoring alterations in disease models. Here, we present a comprehensive proteomic dataset of purified spinal cord myelin from healthy mice. Myelin fractions were isolated by preparative sucrose density centrifugation, followed by gel-free peptide separation and mass spectrometric analysis. Label-free quantification based on at least two tryptic peptides identified 725 proteins across six spinal cord samples. Comparison with previous large-scale datasets confirmed the robustness of our workflow. In particular, our dataset showed a 71% overlap with the 809 proteins identified by Jahn et al. using a highly similar proteomic approach. Importantly, there was near-complete agreement for canonical myelin proteins, validating both the specificity and reproducibility of our method. Beyond this shared core, our dataset contributed additional proteins, including axon- and glia-associated candidates, expanding the baseline repertoire of the spinal cord myelin proteome. In summary, this study establishes and validates a reliable workflow for spinal cord myelin proteomics and provides a reproducible reference dataset. While not yet including diseased tissue, this baseline is directly applicable to experimental models of demyelination and remyelination, offering a critical foundation for detecting and interpreting disease-related proteomic alterations in multiple sclerosis research.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2595945"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to Frontline Antiretroviral Dolutegravir Disrupts Oligodendrocyte Development Across Differentiation Stages.","authors":"Marisa A Jeffries, Raj Putatunda, Melanie Cruz-Berríos, Micah A Romer, Anushka Singhal, Kelly L Jordan-Sciutto, Judith B Grinspan","doi":"10.1080/17590914.2026.2647877","DOIUrl":"10.1080/17590914.2026.2647877","url":null,"abstract":"<p><p>The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we have limited knowledge of how ART drugs that cross the placental barrier affect fetal development, particularly in the central nervous system (CNS). During gestation, large populations of oligodendroglia are produced that are responsible for critical postnatal CNS myelination enabling appropriate neurological function. Previous studies have shown that antiretrovirals impair oligodendrocyte (OL) differentiation leading us to hypothesize that OL maturation might be inhibited by exposure to a frontline ART drug cocktail (Triumeq®) prescribed during pregnancy containing dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC). In this study, we demonstrated that exposing primary rat oligodendrocyte precursor cells (OPCs) and OLs to the Triumeq drug combination decreased OL maturation and myelin protein production in a concentration-dependent manner, and that DTG was solely responsible. Regardless of the timing of exposure during OL development, a high concentration of DTG inhibited OL maturation. Bulk RNA sequencing revealed transcriptional changes after DTG exposure related to a variety of cellular mechanisms, including cellular responses to stress pathways, amino acid starvation, and mitochondrial dysfunction. Although we found that DTG robustly activated the integrated stress response (ISR), attempted rescue experiments showed that DTG primarily inhibits OL maturation independently of the ISR. Collectively, our novel data on DTG underscore the necessity of investigating how ART drugs that are administered during pregnancy and cross the placental barrier can affect fetal CNS development.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2647877"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13034632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crocetin as a Neuroprotective Agent: Targeting Western Diet-Induced Cognitive Dysfunction Through Antioxidant, Anti-Inflammatory and Gut-Brain Axis Modulation.","authors":"Suresh Babu Kondaveeti, Vrinda Gupta, Aaqib Ahmad Dar, Junaid Ahmad Sheikh, Dinesh Kumar, Neeraj Choudhary, Rajni Tanwar, Sonia Gupta, Pooja Rani, Arunprasad Vk","doi":"10.1080/17590914.2025.2603409","DOIUrl":"10.1080/17590914.2025.2603409","url":null,"abstract":"<p><p>Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative stress, insulin resistance, gut dysbiosis, and blood-brain barrier (BBB) disruption, ultimately leading to synaptic dysfunction and cognitive decline. Crocetin, an apocarotenoid derived from saffron and <i>Gardenia jasminoides</i>, exhibits promising neuroprotective effects by scavenging reactive oxygen species, attenuating neuroinflammatory signaling, enhancing mitochondrial bioenergetics, and improving insulin sensitivity. It further upregulates brain-derived neurotrophic factor (BDNF), modulates PI3K/Akt signaling, and restores gut microbiota balance, thereby reinforcing the gut-brain axis and maintaining BBB integrity. This review further aims to critically assess these mechanistic links by distinguishing well-supported findings from speculative associations emphasizing discrepancies between preclinical and human evidence. Preclinical studies strongly support crocetin's role in ameliorating Western diet-induced neurodegeneration, while early clinical evidence highlights improvements in memory, executive function, and cerebral blood flow. However, limitations such as poor bioavailability, rapid metabolism, and limited large-scale human trials constrain its translation into clinical practice. Advanced formulations, including nanoparticles, liposomes, and prodrug derivatives, hold potential to overcome these challenges. This review critically evaluates the pathophysiological mechanisms of Western diet-induced cognitive decline, highlights the pharmacological actions of crocetin, and discusses its therapeutic prospects within the framework of personalized and precision medicine. Future directions include large-scale randomized controlled trials, pharmacokinetic optimization, and AI-driven predictive models to establish crocetin as a clinically viable neuroprotective agent.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2603409"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12721098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reboxetine Treatment Reduces Hippocampal Gliosis in the P301S Tauopathy Mouse Model.","authors":"Irene L Gutiérrez, Claudia Yanes-Castilla, Karina S MacDowell, Javier R Caso, Borja García-Bueno, Cristina Ulecia-Morón, Juan C Leza, José L M Madrigal","doi":"10.1080/17590914.2026.2630485","DOIUrl":"10.1080/17590914.2026.2630485","url":null,"abstract":"<p><p>The loss of brain noradrenergic neurons is one of the earliest alterations observed in Alzheimer's disease and other neurodegenerative pathologies. The consequent reduction of brain noradrenaline levels facilitates the progression of neuroinflammatory processes that can be fatal for neurons and other brain cells. For this reason, compensating for noradrenaline deficit through different means constitutes an interesting therapeutic strategy. Drugs that inhibit the reuptake of noradrenaline are used to elevate the extracellular concentrations of this neurotransmitter and potentiate this way its effects. These drugs are approved for the treatment of depression or attention deficit hyperactivity disorder, among other indications, but their repurposing and use in Alzheimer's disease could be of interest given the beneficial effects observed for noradrenaline in numerous studies. Based on this, we previously showed the beneficial effects of reboxetine, a noradrenaline reuptake inhibitor, on 5xFAD mice that accumulate amyloid beta in their brains and reproduce some of the typical alterations of Alzheimer's disease. In this study we have analyzed the effects of reboxetine on P301S mice, a different model of Alzheimer's disease based on the expression of mutant forms of human microtubule-associated protein tau. We observed that the administration of reboxetine with osmotic pumps for 28 days to 9-month-old mice reduced the accumulation and activation of microglia and astrocytes in different areas of the hippocampus. These findings indicate that reboxetine treatment prevents the neuroinflammatory response known to cause brain damage in Alzheimer's disease even when the treatment is initiated at an advanced stage of the disease.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2630485"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamate-Dependent Dynamic DNA Methylation Regulates Excitatory Amino Acid Transporters in Bergmann Glia Cells: Role of AMPA Receptors.","authors":"Bolaji O Oyetayo, Temitayo Subair, Natalia Morales-Ramírez, Luisa C Hernández-Kelly, Ada G Rodríguez-Campuzano, Leticia Ramírez-Martínez, Luz Nolasco-Hiniesta, Emma S Calderón, Francisco Castelán, Esther López-Bayghen, Marie-Paule Felder-Schmittbuhl, Arturo Ortega","doi":"10.1080/17590914.2025.2604823","DOIUrl":"10.1080/17590914.2025.2604823","url":null,"abstract":"<p><p>Glial glutamate uptake through sodium-dependent excitatory amino acid transporters (EAATs) is essential for synaptic homeostasis. Epigenetic modifications and neurotransmitter receptor signaling influence glial function although their interactive effects on glutamate transporter regulation remain poorly understood. To investigate how DNA methylation affects glutamate receptor-mediated regulation of its own removal, primary cultures from chick cerebellar Bergmann glial cells were used. Confluent monolayers were treated with a DNA methylation inhibitor. Glutamate transporter activity was assessed through radioactive uptake assays, while methylation levels within distinct regions of the <i>chGLAST</i> promoter were analyzed by methylated DNA immunoprecipitation (MeDIP)-PCR. The role of cytoskeletal dynamics and calcium signaling was evaluated using pharmacological modulators. DNA hypomethylation sensitizes glial cells to glutamate receptors stimulation. Kinetic analyses show a statistically significant increase in the Michaelis-Menten constant V<i>_Max</i> and a non-significant change in K<i>_M</i>, changes in <i>V_Max</i> reflect alterations in plasma membrane transporter numberinity. Pharmacological analysis revealed the involvement of the phosphatidyl inositol 3 kinase (PI3K), the Ca²⁺/calmodulin-dependent kinase II (CaMKII) and the mammalian target of rapamycin (mTOR) pathways, suggesting coordinated regulation of glutamate transport. Importantly, short-term activation of AMPA receptors induced hypomethylation of the <i>chglast</i> promoter, suggesting the engagement of active demethylation pathways that sustain transporter expression during heightened excitatory activity. Together, these findings reveal a novel mechanism in which epigenetic flexibility and synaptic receptor activity converge to enhance glutamate uptake in glial cells. This synergy between DNA methylation and AMPA receptor signaling provide new insights into the mechanisms by which glial cells dynamically adapt to excitatory stress.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2604823"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12721094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NLRP3 Inflammasome and Metabolic Dysregulation by Electroacupuncture: A Novel Therapeutic Strategy for Methamphetamine Withdrawal-Induced Depression.","authors":"Xiong Zhang, Xiao-Rui Zhao, Chun-Li You, Fang Zhang, Hong-Yi Zhu, Tian Gu, Jia Li","doi":"10.1080/17590914.2026.2624589","DOIUrl":"10.1080/17590914.2026.2624589","url":null,"abstract":"<p><p>This study demonstrates that electroacupuncture (EA) produces robust antidepressant effects in a rat model of methamphetamine (METH) withdrawal. Behavioral tests showed that EA applied at GV20, PC6, and HT7 significantly reduced immobility in the forced swim test and enhanced exploratory activity in the open field test. Mechanistically, EA repaired blood-brain barrier (BBB) disruption, as shown by reduced hippocampal water content, decreased Evans Blue leakage, and restored expression of tight-junction proteins (Occludin, Claudin-5, ZO-1). EA also inhibited neuronal apoptosis, suppressed microglial activation, and lowered pro-inflammatory cytokines IL-6 and TNF-α. Multi-omics analyses revealed that EA reversed METH-induced alterations in 32 differentially expressed genes related to the NLRP3 inflammasome pathway (Nlrp3, Pycard, Il1b) and BBB function, while metabolomic profiling identified 13 key metabolites involved in glutamate metabolism, TCA cycle, and tryptophan pathways. Crucially, the therapeutic benefits of EA were abolished by intracerebroventricular administration of the NLRP3 activator nigericin, confirming the essential role of NLRP3 inflammasome inhibition in EA's mechanism of action. In summary, EA represents a promising non-pharmacological approach for treating METH withdrawal-induced depression by coordinating BBB protection, suppression of neuroinflammation, and metabolic network regulation.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2624589"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}