Brain Research最新文献

{"title":"Reduced hypothalamic [³H]PK11195 binding in Lewis rats after chronic high-intensity interval training.","authors":"Atiqur Hasany, John R Tyler, Huy Lu, Kenneth Blum, Wei Sun, Richard J Salvi, Igor Elman, Panayotis K Thanos","doi":"10.1016/j.brainres.2026.150600","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150600","url":null,"abstract":"<p><strong>Background: </strong>Exercise has emerged as a potential adjunctive intervention for mood-, trauma-, anxiety-, and addictive disorders, partly through effects on neuroimmune signaling. However, it remains unclear whether chronic high-intensity interval training (HIIT) alters translocator protein 18 kDa (TSPO)-associated neuroimmune activity across brain regions. This study examined the effects of chronic HIIT on [³H]PK11195 binding in male and female Lewis rats.</p><p><strong>Methods: </strong>Thirty-one Lewis rats were assigned to either a 6-week HIIT treadmill regimen or a sedentary control condition. Twenty-four hours after the final session, brains were collected for [³H]PK11195 autoradiography, and specific binding was quantified across multiple cortical and subcortical regions of interest. Binding in each region was analyzed using two-way ANOVA with exercise and sex as factors.</p><p><strong>Results: </strong>A significant main effect of exercise was observed in the hypothalamus, with the HIIT exercise rats showing 28% lower [³H]PK11195 binding than sedentary controls. Also, there was a significant main effect of sex in the visual cortex, with females showing higher binding than males.</p><p><strong>Conclusions: </strong>Chronic HIIT exercise was associated with a potential exercise-related modulation of TSPO-associated neuroimmune signaling in the hypothalamus reflected in region-specific reductions in [³H]PK11195 binding, an indirect index of TSPO-associated neuroimmune signaling that should not be equated with direct evidence of reduced microglial activation. Moreover, TSPO-associated neuroimmune signaling may vary by sex in a region-dependent manner. The observed hypothalamic association warrants future studies testing whether changes in TSPO-associated signaling are linked to functional outcomes in stress, reward, or neuropsychiatric models.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150600"},"PeriodicalIF":3.2,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Altered default mode network homogeneity in chronic insomnia disorder: modulation by modified suanzaoren decoction and estazolam, and machine learning classification\" [Brain Res. 1890 (2026) 150482].","authors":"Shubao Wei, Leyi Zhang, Xiuqiong Chen, Yiding Han, Dongsheng Lv, Ping Yao, Lixia Chen, Yonggui Yuan, Jingping Zhao, Yangpan Ou, Zhiguo Guo, Wenbin Guo","doi":"10.1016/j.brainres.2026.150590","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150590","url":null,"abstract":"","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150590"},"PeriodicalIF":3.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-methyl-D-aspartate receptors in the prelimbic cortex modulate chronic neuropathic pain and comorbid generalised anxiety in a rainbow boa snake threat paradigm.","authors":"Priscila Medeiros, Ana Carolina Medeiros, Ohana Turcato Macacare, Weverton Castro Coelho-Silva, Renata Moreira Acunha, Fernando René Bendaña-Córdoba, Farhad Ullah, Sérgio Henrique Ferreira, Renato Leonardo de Freitas, Norberto Cysne Coimbra","doi":"10.1016/j.brainres.2026.150598","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150598","url":null,"abstract":"<p><p>The prelimbic division (PrL) of the medial prefrontal cortex is implicated in the pathogenesis of generalised anxiety and chronic pain disorders. This study aimed to investigate the role of PrL N-methyl-D-aspartate (NMDA) receptor signalling in the comorbidity between neuropathic pain and psychiatric disorders. Male Wistar rats were exposed to the Enriched Polygonal Arena Snake-Evoked Panic Test involving confrontation by a constrictor snake. Neuropathy was induced by chronic constriction injury (CCI) of the ischiadicus nerve. Rats subjected to a sham surgical procedure were used as controls. Electrophysiological recordings were performed to assess PrL neuronal activity in CCI and sham-operated rats. Exposure to the threatening environment was conducted 21 days after surgery for 5 min following PrL cortical treatment with vehicle or LY235959 (2, 4, and 8 nmol). Neuronal activity in the PrL cortex was reduced in CCI rats. When confronted with a potential predator, threatened CCI rats exhibited increased emotional defensive responses accompanied by a decrease in mechanical paw withdrawal threshold (MWT), whereas sham-operated animals (without neuropathy) showed an increase in MWT following snake confrontation. Furthermore, NMDA receptor blockade in the PrL cortex with LY235959 reduced both defensive behaviours and mechanical allodynia in threatened animals. These findings suggest that NMDA receptor signalling in the PrL cortex plays a key role in the potentiation and maintenance of the comorbidity between anxiety/panic-like states and chronic neuropathic pain.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150598"},"PeriodicalIF":3.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin alleviates neuronal injury in MK-801-Induced Schizophrenia-Like mice by inhibiting neuronal ferroptosis.","authors":"Yanwen Lin, Gaoxia Wen, Xiaoyue Hu, Ran Hu, Yahong Duan, Na Wu, Peng Xiong, Xianlai Jin","doi":"10.1016/j.brainres.2026.150599","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150599","url":null,"abstract":"<p><strong>Background and objective: </strong>Schizophrenia (SCZ) is a severe mental disorder, and its pathological mechanism is closely associated with neuronal ferroptosis. Metformin (Met) has a well-defined anti-ferroptotic effect. Therefore, this study aimed to investigate whether Met improves neuronal injury and behavioral abnormalities in MK-801-induced SCZ-like mice by inhibiting neuronal ferroptosis.</p><p><strong>Methods: </strong>Mice received dizocilpine (MK-801) to induce a SCZ-like phenotype. The behavioral activities of mice were evaluated using the open field test, Morris water maze test, and forced swim test. Neuronal injury in the hippocampus was evaluated by Nissl staining. The mitochondrial structure in the hippocampal tissue was observed using transmission electron microscopy. Ferroptosis was assessed by measuring the levels of glutathione (GSH), malondialdehyde (MDA), and Fe²⁺; lipid peroxidation; mitochondrial membrane potential; and p53, SLC7A11, and GPX4 expression in the hippocampus.</p><p><strong>Results: </strong>Hippocampal neurons in MK-801-induced SCZ-like mice exhibited typical ferroptotic characteristics, including obvious neuronal injury; reduced mitochondrial membrane potential, GSH, SLC7A11, and GPX4 levels; and elevated lipid peroxidation, MDA, Fe²⁺, and p53 levels. Met intervention significantly reversed these ferroptosis-related indicators and inhibited hippocampal neuronal ferroptosis. Furthermore, Met alleviated MK-801-induced ferroptosis in HT22 cells. Behavioral results revealed that Met ameliorated behavioral abnormalities in the MK-801-treated mice. The ferroptosis inducer RSL3 partially reversed the behavioral improvements induced by Met. Further studies demonstrated that risperidone (RIS) or Met alone alleviated behavioral abnormalities in MK-801-induced SCZ-like mice, whereas their combined treatment produced greater improvement than either monotherapy.</p><p><strong>Conclusion: </strong>Met can alleviate neuronal damage and cognitive dysfunction in MK-801-induced SCZ-like mice, at least in part, by inhibiting neuronal ferroptosis. Moreover, combined treatment with Met and RIS is more effective.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150599"},"PeriodicalIF":3.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stage-specific exposure to an activity-permissive medium enhances neuronal activity in oligodendrocyte-enriched cortical organoids.","authors":"Clara Chung, Michelle J Kim, Grace Field, Konstantina Pilarinos, Elizabeth K Kharitonova, Natalie Baker Campbell, Marie Shi, Christopher V Gabel, Joseph L Orofino, Ella Zeldich","doi":"10.1016/j.brainres.2026.150601","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150601","url":null,"abstract":"<p><p>Oligodendrocyte-enriched cortical organoids (OCOs) are a powerful platform for modeling oligodendrogenesis in a human cellular context. However, neuronal activity is impaired in conventional culture media, limiting assessment of neuronal function in conjunction with oligodendrocyte biology. To address this, we used a modified BrainPhys medium termed neuronal activity medium (NAM) and defined the optimal developmental window for NAM exposure to generate OCOs with robust neuronal activity (NAM-OCOs). Stage-specific exposure to NAM, prior to oligodendrocyte expansion, leads to enhanced structural complexity, as evidenced by increased organoid size, heightened synaptogenesis, and upregulation of transcripts associated with neuronal morphology. Further, NAM-OCOs display increased cellular heterogeneity, with GABAergic interneurons exhibiting enhanced inhibitory synaptic features and a more advanced developmental transcriptional state, while preserving oligodendrocyte development and oligodendrocyte-axon associations. Altogether, our studies demonstrate that stage-specific exposure to an activity-permissive environment enhances neuronal activity, establishing an OCO model which integrates neuronal activity with oligodendrocyte development and differentiation.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150601"},"PeriodicalIF":3.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinctive patterns of right-hemisphere vulnerability in cerebral small vessel disease: a gray matter asymmetry study.","authors":"Jingdian Lu, Yanli Wu, Lei Gao","doi":"10.1016/j.brainres.2026.150602","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150602","url":null,"abstract":"<p><p>Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment (VCI), characteristically associated with gray matter (GM) loss. However, it remains unclear whether this GM loss exhibits regional interhemispheric asymmetry and how it relates to cognitive function. In this study, 56 CSVD patients and 56 demographically matched healthy controls were included, and structural MRI as well as cognitive and clinical data were collected. Voxel-based morphometry (VBM) and the GM Asymmetry Index (GMAI; calculated as (L-R)/(L + R), higher values indicate relatively greater left-sided GM) were performed using a study-specific symmetric template. Perivascular spaces were also estimated with a deep learning framework. Partial correlations were tested against multi-domain cognitive performance. Compared with controls, CSVD patients exhibited extensive GM reduction in the right superior and middle frontal gyri as well as in the left hippocampus and putamen. Regional GMAI analyses further suggested altered hemispheric GM loss, with leftward shifts (higher GMAI) in the middle temporal gyrus, superior frontal gyrus, and precuneus, and rightward shifts (lower GMAI) in the inferior temporal and fusiform gyri. Additionally, subcortical nuclei exhibited a corresponding leftward lateralization of perivascular space burden. Association analyses showed that right prefrontal volume was positively related to global cognitive scores, whereas left temporal asymmetry tracked cognitive decline. Of note, this right-dominant pattern in prefrontal-related regions is consistent with our activation likelihood estimation meta-analytic re-synthesis of prior VBM evidence and NeuroSynth mapping. Collectively, these findings suggest a distinct topographical vulnerability of the right hemisphere in CSVD and highlight GMAI as a neuroimaging marker for vascular cognitive decline.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150602"},"PeriodicalIF":3.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory bone-brain transcriptomic associations and an ODE-based digital-twin framework for fracture healing.","authors":"Chao Ma, Wei Lu, Ruipeng Guo","doi":"10.1016/j.brainres.2026.150597","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150597","url":null,"abstract":"<p><p>Fracture healing is generally viewed as a local tissue-regeneration process, although skeletal injury can also elicit systemic immune, vascular, and neural responses. We used a stratified analytical strategy combining reanalysis of public transcriptomic datasets, descriptive single-nucleus profiling, and an ordinary differential equation (ODE)-based simulation of fracture healing to examine possible associations between adverse bone phenotypes and Alzheimer disease. In the primary random-effects meta-analysis of three retained human bone-related binary cohorts, 72 prespecified panel genes were measured in all three cohorts; BMP10 and ANGPT1 had the smallest adjusted P values. In the separate GSE48350 whole-brain dataset, 6 of 84 mapped target genes had nominal P < 0.05. Descriptive single-nucleus RNA-sequencing analysis of GSE138852 showed within-dataset, cell-type-specific expression patterns across annotated neural cell populations. The eight-state ODE prototype, built on prespecified assumptions, generated fracture-healing trajectories and scenario-dependent model outputs. Tissue-expression and genetic analyses provided additional exploratory context for the selected genes. These analyses define a hypothesis-generating framework for studying skeletal-neural associations after fracture.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150597"},"PeriodicalIF":3.2,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing reveals vascular heterogeneity and cell–cell communication remodeling in the glioma blood–tumor barrier","authors":"Zhipeng Zhao,&nbsp;Jiachen Lang,&nbsp;Haiyan Gu,&nbsp;Luodan Wang,&nbsp;Jianchang Luo,&nbsp;Jiawang Lang,&nbsp;Qiongying Yao,&nbsp;Xinyu Qiao,&nbsp;Zida Wang,&nbsp;Ling Yin,&nbsp;Caidi He","doi":"10.1016/j.brainres.2026.150595","DOIUrl":"10.1016/j.brainres.2026.150595","url":null,"abstract":"<div><h3>Background</h3><div>The blood–brain barrier (BBB) restricts drug delivery in glioma, yet its pathologically remodeled counterpart, the blood–tumor barrier (BTB), is a promising therapeutic target. A comprehensive view of the cellular composition and transcriptional heterogeneity of the vascular compartment across the BBB-to-BTB transition is essential for improving glioma therapy.</div></div><div><h3>Methods</h3><div>We performed a secondary single-cell RNA sequencing (scRNA-seq) analysis of the public GSE242044 dataset (7 patients; 13 tumor and adjacent non-tumor surgical specimens, comprising IDH-mutant lower-grade gliomas and IDH-wild-type gliomas). After stringent quality control, doublet removal, Harmony batch correction, and annotation with SingleR plus canonical markers, we dissected vascular cell heterogeneity and performed differential expression, Gene Set Variation Analysis (GSVA), pseudotime (Monocle/Slingshot), and CellChat ligand–receptor inference, with sample-level statistical comparisons (Kruskal–Wallis and Wilcoxon rank-sum tests on per-specimen values). Findings were assessed in three independent glioma scRNA-seq cohorts (GSE162631, GSE117891, GSE174554) and in the CGGA bulk cohort.</div></div><div><h3>Results</h3><div>Vascular cell composition (relative representation among the profiled vascular-enriched cells) showed trends across conditions: endothelial cells declined from 60.6 % to 47.5 %, whereas pericytes (15.8 % to 18.0 %) and immune cells increased in IDH-wild-type tumors (macrophages 1.3 % to 7.0 %; T cells 3.0 % to 7.5 %); astrocytes increased from 1.1 % to 4.5 %; these specimen-level trends were mostly not statistically significant (Supplementary Table S1). Cell–cell communication was predicted to be rewired, shifting from pericyte–smooth muscle cell crosstalk in non-tumor and IDH-mutant tissues toward pericyte–astrocyte and predicted vascular–immune interactions in IDH-wild-type tumors. Differential expression and enrichment analyses identified an IDH-wild-type vascular program dominated by extracellular matrix remodeling (COL1A1, COL3A1, COL4A1, LAMB1, TIMP1) and angiogenic activation (ANGPT2), with loss of quiescent endothelial markers (CA4, KLF2). Candidate markers (COL1A1, COL3A1, F3, S100A4, CSPG4, ANGPT2) showed no consistent prognostic association across independent cohorts.</div></div><div><h3>Conclusions</h3><div>This secondary analysis delineates transcriptional heterogeneity of BBB/BTB vascular cells and their inferred communication remodeling in glioma. The identified subtype markers are candidate biomarkers that require independent validation; our findings provide a framework for future studies—including spatial and protein-level validation of the candidate markers, functional permeability and coculture assays of the predicted vascular–immune interactions, and preclinical testing of BTB-modulating delivery strategies such as focused-ultrasound-mediated opening in glioma models.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1894 ","pages":"Article 150595"},"PeriodicalIF":3.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147603","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":"Corrigendum to \"Mercury chloride causes cognitive impairment, oxidative stress and neuroinflammation in male Wistar rats: The potential protective effect of 6-gingerol-rich fraction of Zingiber officinale via regulation of antioxidant defence system and reversal of pro-inflammatory markers increase\" [Brain Res. 1826 (2024) 148741].","authors":"Abraham Olufemi Asuku, Maryam Tayo Ayinla, Ayodeji Johnson Ajibare, Tobiloba Samuel Olajide","doi":"10.1016/j.brainres.2026.150571","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150571","url":null,"abstract":"","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150571"},"PeriodicalIF":3.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astragaloside IV attenuates cerebral ischemia-reperfusion injury by suppressing PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress through activation of the SHH signaling pathway.","authors":"Pingbo Wei, Yangyun Han, Jun Wang, Le Luo, Jiang Meng, Bo Fan, Jiaxin Liu","doi":"10.1016/j.brainres.2026.150551","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150551","url":null,"abstract":"<p><strong>Background: </strong>Cerebral ischemia-reperfusion injury (CIRI) triggers endoplasmic reticulum stress (ERS), a key pathological driver of neuronal apoptosis and neurological impairment. While the neuroprotective effects of astragaloside IV (AS-IV) are well-documented, the precise regulatory bridge between the Sonic Hedgehog (SHH) pathway and ERS remains to be elucidated.</p><p><strong>Methods: </strong>Ischemic conditions were simulated in vitro using HT22 hippocampal neurons subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cell viability, apoptosis, and ERS/SHH-related markers were evaluated via Cell Counting Kit-8 (CCK-8), Western blotting, and immunofluorescence assays. Bidirectional rescue experiments were conducted using dithiothreitol (DTT, an ERS inducer), Cyclopamine (Cyc, an SHH inhibitor), and GLI family zinc finger 1 (Gli1) Short hairpin RNA (shRNA) (sh-Gli1). In vivo validations were performed in Middle cerebral artery occlusion/reperfusion (MCAO/R) rats pretreated with AS-IV (28 mg/kg/day, i.p. for 3 days). Neurological deficits, infarct volume, and penumbral neuronal survival were assessed alongside brain tissue immunoblotting.</p><p><strong>Results: </strong>AS-IV pretreatment rescued HT22 cells from OGD/R-induced death in a dose-dependent manner and significantly suppressed the PKR-like ER kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)-mediated ERS/apoptosis axis. Expanded analysis revealed that AS-IV also partially inhibited the Inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response (UPR) without affecting activating transcription factor 6 (ATF6). Mechanistically, AS-IV significantly elevated the expression of SHH, Patched 1 (PTCH1), and Gli1. These protective benefits were largely reversed by pharmacological SHH inhibition, ERS reactivation, or genetic silencing of Gli1, supporting a canonical Gli1-dependent transcriptional mechanism. In MCAO/R rats, AS-IV pretreatment significantly reduced infarct volumes and improved neuronal survival and functional recovery. Consistent with cellular findings, AS-IV attenuated cerebral ERS markers through SHH activation, a mechanism reversed by Cyc.</p><p><strong>Conclusion: </strong>AS-IV pretreatment protects neurons from CIRI-induced impairment by selectively suppressing the PERK and IRE1α UPR branches of the UPR through activation of the canonical SHH/Gli1 signaling pathway. These findings highlight the SHH/Gli1/ERS regulatory axis as a potential therapeutic target for ischemic stroke.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150551"},"PeriodicalIF":3.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}