Neurochemical Research最新文献

{"title":"MicroRNA and Proteomic Landscape of Brain Development","authors":"Abhishek Jauhari,&nbsp;Sanjeev Kumar Yadav,&nbsp;Tanisha Singh,&nbsp;Sanjay Yadav","doi":"10.1007/s11064-026-04756-0","DOIUrl":"10.1007/s11064-026-04756-0","url":null,"abstract":"<div>\u0000 \u0000 <p>Brain development is a complex and continuous process that begins during the gestation period and peeks in adolescence. This process unfolds in multiple phases and involves cellular events like cell proliferation, migration, axonal and dendritic outgrowth, apoptosis, synapse formation, myelination, and synaptic pruning. Each of these developmental processes is tightly regulated by intricate layers of gene expression. MicroRNAs (miRNAs) play a crucial role in regulating gene expression post-transcriptionally. Due to their ability to regulate multiple genes with a single miRNA and a single gene with multiple miRNAs, miRNAs are particularly well-suited to orchestrate gene expression during brain development. In this study, we utilized rat brain samples from various developmental stages: gestation day 15 (GD15), 0-days, 1-week, 3-weeks, 6-weeks, 12-weeks, and 1-year, to investigate the dynamic changes in brain development. We analyzed the global miRNA expression and proteomic profile at each time point using rat miRNA TaqMan Low Density Arrays and LC–MS/MS, respectively. Our analysis revealed that miRNA and protein expression are tightly regulated throughout brain development from GD15 to 1 year. Interestingly, the patterns of global expression of miRNAs and proteins are dramatically different in GD15 and 0-day. Some miRNAs exhibited stage-specific expression patterns, while others were consistently expressed at higher levels across the entire developmental period. Notably, the expression levels of certain miRNAs, including the miR-29 family, miR-34 family, miR-338, and miR-219, were found to increase as brain development progressed. These miRNAs had minimal expression at GD15 and reached their highest levels at 12-weeks or 1-year. Conversely, miR-296, miR-217, miR-20b-3p, and miR-214 exhibited peak expression at GD15, with levels decreasing by 12-weeks and 1-year. In addition, we examined phase-specific protein expression profiles using mass spectrometry to further complement our findings.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728011","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":"Unpredictable Chronic Mild Stress Upregulates Dopamine Receptor Expression Independent of Fatty Acid-Binding Protein 7 Gene Deletion","authors":"Huy Lu,&nbsp;Nicole Roeder,&nbsp;Brittany Richardson,&nbsp;John Hamilton,&nbsp;George Lagamjis,&nbsp;Yuji Owada,&nbsp;Yoshiteru Kagawa,&nbsp;Abhisheak Sharma,&nbsp;Panayotis K. Thanos","doi":"10.1007/s11064-026-04753-3","DOIUrl":"10.1007/s11064-026-04753-3","url":null,"abstract":"<div><p>Fatty acid-binding protein 7 (FABP7) assists in the intracellular trafficking of endogenous cannabinoids and polyunsaturated fatty acids (PUFAs) and has been implicated for various psychiatric diseases. Rising evidence demonstrates the crosstalk between the endocannabinoid and dopaminergic systems, particularly in response to stress. The present study seeks to examine the role of FABP7 expression under chronic stress conditions and its impact on the dopaminergic system, specifically dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) levels. Adult male FABP7^+/+ and FABP7^−/− mice underwent 28-day treatment of unpredictable chronic mild stress (UCMS) procedure. After the stress paradigm, D1R and D2R levels were measured with in vitro autoradiography using [³H] SCH23390 and [³H] Spiperone, respectively. Stressed mice, regardless of genotype, exhibited an increase in D1R binding across the entire striatum (dorsal caudate putamen (CPu), dorsolateral CPu, dorsomedial CPu, ventral CPu, ventrolateral CPu, ventromedial CPu, nucleus accumbens core and shell), substantia nigra and olfactory tract. Additionally, an increase in D2R binding induced by UCMS was observed in the olfactory tract and certain regions of the striatum (dorsal CPu and ventral CPu). The UCMS paradigm upregulates D1R and D2R binding independent of FABP7 gene deletion, suggesting a compensatory role of other FABPs in the brain in maintaining dopaminergic homeostasis. This stress-induced shift in D1R: D2R ratio may underlie the pathogenesis of major depressive disorder and substance use disorder, as well as the high comorbidity among these conditions.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04753-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells","authors":"Masatoshi Nakatsuji,&nbsp;Makio Shibano,&nbsp;Ko Fujimori","doi":"10.1007/s11064-026-04759-x","DOIUrl":"10.1007/s11064-026-04759-x","url":null,"abstract":"<div>\u0000 \u0000 <p>Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of <i>Glycyrrhiza glabra</i> (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H₂O₂)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H₂O₂-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H₂O₂-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H₂O₂-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H₂O₂-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H₂O₂ treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H₂O₂-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728014","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":"Expression and Localization of Branched-Chain Ketoacid Dehydrogenase E1 Subunits and LAT1 Transporter in Rat Retinal and Ocular Tissues","authors":"Dalia I. Aldosari,&nbsp;Wedad S. Sarawi,&nbsp;Norah K. Algarzae,&nbsp;Abdullah S. Alhomida,&nbsp;Mohammad S. Ola","doi":"10.1007/s11064-026-04750-6","DOIUrl":"10.1007/s11064-026-04750-6","url":null,"abstract":"<div><p>Branched-chain amino acids (BCAAs) are essential for various metabolic and physiological functions. The enzymes responsible for breaking down and transporting them are organized in a tissue-specific manner, playing a crucial role in moving metabolites between cells but often being overlooked. This is particularly true for the rate-limiting enzyme, branched-chain keto-acid dehydrogenase (BCKD). To address this gap, our study investigated the expression and distribution of the BCKDE1 subunits and the BCAA transporter LAT1 in normal rat eye tissues, with a focus on the retina, by applying immunohistochemistry (IHC) and immunofluorescence (IF) with specific antibodies. Our findings show that BCKDE1 subunits are highly expressed in retinal neurons, specifically in the ganglion cell layer (GCL), inner and outer nuclear layers (INL/ONL), and the plexiform layers (IPL/OPL), although they are notably absent in Müller cells. Expression was also strong in the epithelial cells of the lens, iris, and ciliary body. Similarly, we observed LAT1 localized in the GCL and INL of the retina, as well as in the iris, ciliary body, and lens epithelium. These results complement our previous work, which indicated that branched-chain aminotransferase (BCAT) isozymes are widely expressed across most ocular tissues. Overall, this evidence strongly indicates that a complete BCAA metabolic pathway exists in the eye. This provides a comprehensive understanding of BCAA metabolism in eye tissues, highlighting its crucial role in maintaining amino acid balance, neurotransmitter production, and energy generation. Furthermore, this study lays a foundation for future studies on how disruptions in these enzymatic pathways might affect neurodegeneration in diabetic retinopathy and contribute to other eye conditions.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147707785","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":"Neto2 Phosphorylation Promotes Neuronal Loss in KA-Induced Epileptic Rat Hippocampus by Upregulating the Interaction with GluK2","authors":"Jiangpeng Fan,&nbsp;Yang Cao,&nbsp;Xiaohui Yin,&nbsp;Feng Lu,&nbsp;Chong Li,&nbsp;Jingzhi Yan","doi":"10.1007/s11064-026-04754-2","DOIUrl":"10.1007/s11064-026-04754-2","url":null,"abstract":"<div><p>Kainate receptor, especially containing GluK2, hyperactivation plays an important role in epileptic excitotoxicity and neuronal damage, but the function of their key regulatory protein, neuropilin and tolloid-like protein 2 (Neto2), in this process is unclear. This study aimed to elucidate the role and molecular mechanism of Neto2 in regulating GluK2-mediate hippocampal neuronal damage. Our findings indicated that in kainic acid-induced epileptic rats, the level of phosphorylation in Neto2 and GluK2 elevated, and their interaction enhanced, accompanying the loss of neurons in the hippocampal cornu ammonis 3 / dentate gyrus regions. Remarkably, the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor effectively reduced this protein phosphorylation and the interaction of the GluK2-Neto2. In addition, in HEK293T cells, the interference peptide (Tat-GluK2) targeting to the M3-S2 domain of GluK2 specifically blocked GluK2-Neto2 binding, and significantly reduced calcium influx. Importantly, CaMKII inhibitor and Tat-GluK2 both significantly improved the pathological status related to epilepsy including the abatement of hippocampal long-term potentiation, the reduced loss in hippocampal neurons, and the recovery of learning and memory. Collectively, our findings suggest that CaMKII-mediated increase in GluK2-Neto2 interaction is a primary driver of hippocampal neuronal loss in kainic acid-induced epileptic rats, targeting the GluK2-Neto2 binding domain may be a potential therapy-target for epilepsy.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147707786","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":"Resveratrol-Loaded Polymeric Nanoparticles Protect Against Rotenone-Induced Parkinsonian-Like Cellular Damage In Vitro: Association with NRF2/HMOX-1 Expression Changes","authors":"Izabell Maria Martins Teixeira,&nbsp;Bruna Ribeiro Duque,&nbsp;Mac Dionys Rodrigues da Costa,&nbsp;Mateus Edson da Silva,&nbsp;Mateus Oliveira Fernandes,&nbsp;Antônia Gabriella de Souza Freitas,&nbsp;Vitor Mendes Bezerra,&nbsp;Alice Vitória Frota Reis,&nbsp;Natasha Maria Lima Pinheiro,&nbsp;Marco Antonio de Freitas Clementino,&nbsp;Josimar Oliveira Eloy,&nbsp;Ramon Róseo Paula Pessoa Bezerra de Menenzes,&nbsp;Alice Maria Costa Martins,&nbsp;Tiago Lima Sampaio","doi":"10.1007/s11064-026-04749-z","DOIUrl":"10.1007/s11064-026-04749-z","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited treatment options. Several natural compounds have been investigated, particularly resveratrol (RSV), which exhibits antioxidant and anti-inflammatory properties. However, its unfavorable pharmacokinetic profile limits its therapeutic application, making nanoencapsulation a promising strategy. This study evaluated the protective effects of resveratrol-loaded polymeric nanoparticles (NP RSV) and the involvement of the Keap1/NRF2/ARE pathway in a rotenone (ROT)-induced PD-like model in vitro. PC12 neuronal cells and astrocytes were pretreated with NP RSV, RSV, and dopamine for 1 h, followed by ROT exposure for 24 h. Cell viability was assessed by MTT, while cell death profile, reactive oxygen species production, and mitochondrial transmembrane potential (ΔΨm) were evaluated by flow cytometry. Morphological changes were evaluated by optical microscopy. Gene expression of <i>NRF2</i> and heme oxygenase-1 (HMOX-1) was assessed by RT-qPCR. Pretreatment with NP RSV significantly protected cells by preserving viability, reducing reactive oxygen species, maintaining mitochondrial function, and decreasing apoptosis. Morphological analyses corroborated these results. Furthermore, NP RSV modulated ROT-induced <i>NRF2</i> and <i>HMOX-1</i> expression, suggesting involvement of the Keap1/NRF2/ARE pathway.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BDNF Protects Against Neuronal Damage Induced by TNF and β-Amyloid Peptides by Targeting JNK Activation","authors":"Alejandro Ramírez-Olvera,&nbsp;Jorge Luis Almazán,&nbsp;Leonor Pérez-Martínez,&nbsp;Gustavo Pedraza-Alva","doi":"10.1007/s11064-026-04740-8","DOIUrl":"10.1007/s11064-026-04740-8","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuroinflammation, driven by β-amyloid peptide accumulation, plays a critical role in the pathogenesis of Alzheimer’s disease, resulting in neurodegeneration and cognitive decline. Inflammatory cytokines, particularly tumor necrosis factor (TNF), adversely affect neuronal function and survival by counteracting the neuroprotective effects of neurotrophins. Importantly, brain-derived neurotrophic factor (BDNF) has been shown to alleviate the neurotoxic effects of pro-inflammatory cytokines. While the mechanisms through which pro-inflammatory cytokines disrupt BDNF/TrkB signaling are well understood, the specific ways in which BDNF protects neurons from inflammatory damage remain unclear. We present evidence that BDNF reduces cytotoxicity and neuritic damage in cholinergic neurons (SN56) induced by TNF and β-amyloid peptide, through the downregulation of c-Jun N-terminal kinase (JNK) activation. BDNF inhibits TNF-induced JNK activation by stimulating p38 mitogen-activated protein kinase. These findings indicate that BDNF restores neuronal functionality by modulating the signaling pathways of inflammatory cytokines, such as TNF, and highlight potential therapeutic strategies to mitigate neuroinflammation-associated neurodegeneration in Alzheimer’s disease.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04740-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147642995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson’s Disease","authors":"Yufei Liu,&nbsp;Haoran Li,&nbsp;Jie Bai","doi":"10.1007/s11064-026-04752-4","DOIUrl":"10.1007/s11064-026-04752-4","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson’s disease (PD) is a common neurodegenerative disease with multiple causes and complex mechanisms. Mitochondrial dysfunction is the main cause and central event of dopaminergic neuron degeneration in PD. Therefore, studying mitochondrial dysfunction plays an important role in understanding the pathogenesis of PD. In the future, mitochondrial dysfunction becomes an important therapeutic target for this disease. This article focuses on the mitochondrial molecular mechanism of neurodegeneration, including reactive oxygen species generation, mitochondrial autophagy, and mitochondrial dynamics, etc., and the potential targets for PD therapy. This article also discusses other potential treatment strategies, such as mitochondrial transplantation, targeted microRNA, use of stem cells and exercise, these may provide valuable insights for clinical practice. A better understanding of the role of mitochondria in the pathophysiology of PD may provide fundamental principles for designing new therapeutic interventions to combat PD.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147642993","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":"Targeting Ferroptosis and Necroptosis to Treat Stroke","authors":"Bautista-Perez Sandra Monserrat,&nbsp;Silva-Islas Carlos Alfredo,&nbsp;Sánchez-Thomas Rosina,&nbsp;Figueroa Alejandra,&nbsp;Barrera-Oviedo Diana,&nbsp;Maldonado Perla D.","doi":"10.1007/s11064-026-04751-5","DOIUrl":"10.1007/s11064-026-04751-5","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemic stroke is a leading cause of death and long-term disability worldwide. It results from cerebral blood flow obstruction (ischemia) and, in some cases, the restoration of cerebral blood flow (reperfusion), triggering a cascade of pathophysiological events collectively known as the ischemic cascade and reperfusion injury, which leads to the activation of different regulated cell death types, and this review focuses on necroptosis and ferroptosis. Both pathways are closely linked to oxidative stress and contribute significantly to neuronal death and inflammation following ischemic stroke. Dysregulation of redox homeostasis, iron dyshomeostasis, glutathione depletion, and mitochondrial dysfunction are key events in neuronal damage. Understanding the interplay between oxidative stress and these pathways is crucial for developing effective neuroprotective therapies. This review highlights recent advances in understanding necroptosis and ferroptosis in ischemic stroke, proposing redox-targeted interventions as promising strategies to mitigate brain injury and improve outcomes in patients affected by this condition.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04751-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147642992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Puerarin Alleviates Depression via Integrated Regulation of TLR4/MyD88/NF-κB Signaling and Gut Microbiota-Metabolic Axis","authors":"Xin-Yi Cao,&nbsp;Jiao-Jiao Tian,&nbsp;Wei Zhang,&nbsp;Chun-Lin Chen,&nbsp;Hao Ma","doi":"10.1007/s11064-026-04747-1","DOIUrl":"10.1007/s11064-026-04747-1","url":null,"abstract":"<div>\u0000 \u0000 <p>Depression is a highly prevalent mental disorder in which dysfunction of the gut microbiota is implicated as a significant factor in its pathogenesis. Puerarin has been suggested to alleviate depression <i>via</i> the microbe-gut-brain axis (MGBA), although the precise mechanisms remain elusive. This study aimed to elucidate the association between the antidepressant effects of puerarin and its role in regulating intestinal flora imbalance and inhibiting subsequent activation of the LPS/TLR4 inflammatory pathway from metabolomics and metagenomics perspectives. A rat model of depression was established using a 6-week chronic unpredictable mild stress (CUMS) protocol. Depressive-like behaviors were assessed through the sucrose preference test (SPT), forced swim test (FST), and open field test (OFT). Inflammatory cytokines (TNF-α, IL-1β, IL-6), LPS, corticosterone, and 5-HT were measured via ELISA. Hippocampal and colonic protein expression of TLR4, MyD88, IκBα, and NF-κB was analyzed by western blot. Colon tissue integrity was evaluated using H&amp;E staining, PAS staining, and transmission electron microscopy. Immunofluorescence was employed to detect Iba-1⁺ microglia, TLR4⁺ cells, and ZO-1 expression. Fecal metabolomics and metagenomics were conducted to identify differential metabolites and microbial composition, followed by KEGG and KO enrichment analyses to predict relevant pathways. Spearman correlation analysis was used to explore relationships among gut microbiota, metabolites, and behavioral indices. Puerarin markedly ameliorated depression-like behaviors in CUMS rats. Concurrently, puerarin inhibited the LPS/TLR4 signaling pathway and its downstream pro-inflammatory mediators in both the hippocampus and colon, resulting in a significant reduction in inflammatory responses across these regions, as well as in the serum. Metagenomic sequencing revealed that puerarin suppressed inflammation-associated bacteria, enhanced the abundance of Firmicutes, and induced alterations in the microbial community structure and composition. Metabolomic analysis demonstrated that puerarin could counteract dysregulated fecal metabolism, identifying 17 metabolites as potential key mediators in restoring metabolic homeostasis in CUMS rats. These biomarkers were implicated in several metabolic pathways, including Aminoacyl-tRNA biosynthesis, Pyrimidine metabolism, Alanine, Aspartate, and Glutamate metabolism. Puerarin may exert its antidepressant effects by modulating the gut microbial structure and metabolite profiles, thereby alleviating inflammatory stress in the colon, bloodstream, and hippocampus, potentially through inhibition of the LPS/TLR4 signaling pathway.</p>\u0000 </div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643171","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}