Experimental Neurology最新文献

{"title":"Functional reorganization after traumatic brain injury: A group ICA-based resting-state fMRI study in a porcine model.","authors":"Ishfaque Ahmed, Morgan H LaBalle, Moira F Taber, Sydney E Sneed, Franklin D West, Erin E Kaiser, Qun Zhao","doi":"10.1016/j.expneurol.2026.116005","DOIUrl":"10.1016/j.expneurol.2026.116005","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a serious health concern in the United States and worldwide. Understanding the mechanisms underlying resting-state functional activity can play an important role in profiling induced disruptions, potentially enabling accurate and timely interventions. Due to its homology to the human brain, the porcine brain is a valuable translational model for investigating focal TBI. In this study, we used the porcine controlled cortical impact TBI model targeting the motor cortex to evaluate dynamic disruptions in functional activity in mild or severe TBI, including hemispheric imbalance, reorganization, and compensation mechanisms, using independent component analysis (ICA). Our whole-brain findings revealed that immediately after TBI, high-level resting-state networks (RSNs), including the executive control network (ECN) and cerebellar network (CN), showed significantly decreased activity, whereas the sensory motor network (SMN) displayed preserved functional activity. Further hemispheric findings demonstrated a significant decrease in ipsilateral functional activity, whereas contralateral functional activity increased in SMN. Additionally, cortical areas (CoAs) associated with the SMN demonstrated a pronounced hemispheric imbalance at the acute phase. Hemispheric and CoAs analyses revealed a restoration of functional activity over a two-month period. These alterations and lateral imbalance suggest potential lateral reorganization, compensation mechanisms, and temporal recovery processes. These findings are consistent with outcomes previously demonstrated in human TBI patients, further underscoring the importance of the porcine translational model for investigating changes in brain activity or connectivity due to TBI and future novel treatments.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116005"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the predictive value of routine electroencephalogram compared to continuous electroencephalogram in the acute phase of traumatic brain injury.","authors":"Rafael Pires de Sá Valeriano, Thiago Zaqueu Lima, Maira L Foresti, João Paulo Santiago de Oliveira, Carla Baise, Gustavo Mercenas Dos Santos, Natália Mata Longo, Renato R Viana, Joaquina C Q F Andrade, Gesael Passos Ferreira Junior, Carlos André Oshiro, Luiz Eugênio Mello, Eliana Garzon","doi":"10.1016/j.expneurol.2026.116006","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116006","url":null,"abstract":"<p><p>Early identification of epileptiform activity in patients with traumatic brain injury (TBI) remains a clinical challenge, with important implications for prognosis and treatment. The primary objective of this prospective single-center study was to determine the incremental diagnostic yield of 1 h EEG (1hEEG) and continuous EEG (cEEG; 24-h long EEG segment) compared with routine EEG (rEEG; first 30 min recording) for detecting interictal epileptiform discharges (IEDs) and electrographic seizures in adults with acute TBI and acute intracranial hemorrhage and/or brain contusion(s). A secondary exploratory objective was to assess whether clinical, neuroimaging, and EEG characteristics were associated with similarity between shorter recordings and the corresponding prolonged recording. Thirty-five adults underwent cEEG during ICU admission. Monitoring began a median of 2 days after TBI (range, 0-7 days) and lasted a median of 3 days (range, 1-9 days; mean, 3.8 days), yielding 134 analyzable segments (mean 3.8 segments per patient). For each segment, the first 30 min and first 60 min were compared with the full cEEG segment. IEDs were identified in 14/134 segments (10.4%) during the first 30 min and first hour and detection was increased to 19/134 segments (14.2%) during prolonged monitoring; thus, 5/19 IED-positive segments were detected only after the first hour. Electrographic seizures were identified during cEEG in 3/35 patients (8.6%); two had seizures within the initial 30 min, whereas one had a seizure only during prolonged monitoring. All seizures were electrographic/nonconvulsive. Prolonged EEG increased the detection of IEDs in a subset of recordings and identified an electrographic seizure that was missed by shorter recordings. Reduced level of consciousness, greater TBI severity, sedative-drug exposure, and additional trauma to other body parts were associated with a greater similarity (shorter mathematical distance) between rEEG, 1hEEG and cEEG findings (all p < 0.05). Clinical variables may help prioritize patients in whom shorter EEG recordings are more representative of prolonged EEG; however, these exploratory findings should not be used to exclude high-risk patients from cEEG.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116006"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleic acid ameliorates the disrupted blood-brain barrier and neuroinflammation following intracerebral hemorrhage in mice by regulating PPARγ.","authors":"Jingjing Li, Pingping Guo, Yang Liu, Juanfeng Qian, Qingli Wang, Bin Xia, V Wee Yong, Mengzhou Xue","doi":"10.1016/j.expneurol.2026.116002","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116002","url":null,"abstract":"<p><strong>Background: </strong>Oleic acid (OA) is demonstrated to have neuroprotective effects and may improve the therapy of neurological disorders. However, the mechanism of OA impact on blood-brain barrier (BBB) and neuroinflammation following intracerebral hemorrhage (ICH) remains indistinct. Here, we aimed to affirm the neuroprotective influence of OA in ICH and to explore the latent molecular mechanism.</p><p><strong>Methods: </strong>The male C57BL/6 mice (n = 124) was used for this study. ICH model was induced by intracerebral injection of collagenase. OA (60 mg/kg) was administrated 2 h after ICH. Neurobehavioral tests were performed to assess the neurofunctional outcome after ICH. The wet-dry method was used for quantifying brain edema at day 3 after ICH injury. The change of tight junctions (TJs) proteins (ZO-1, occludin, claudin5) and Evans Blue (EB) extravasation were used for evaluating BBB integrity. Microglial cell activation and neutrophil infiltration were evaluated by immunofluorescence staining. The levels of apoptosis-related factors and inflammatory cytokines were determined by western blot, and the apoptotic cells were tested by TUNEL assay.</p><p><strong>Results: </strong>OA treatment visibly decreased hemoglobin content and improved neurological function after ICH. OA also decreased the BBB permeability, as clarified by the declined EB extravasation and brain water content. OA remarkably reduced MMP-9 level and elevated TJs proteins (ZO-1, occludin, claudin5) levels, also reduced brain cell apoptosis. OA could markedly reduce MPO positive neutrophil infiltration and microglia activation of IBA-1⁺CD16⁺ cells, and increased microglia activation of Arg-1⁺Iba1⁺ cells. Meanwhile, OA elevated peroxisome proliferator-activated receptor-gamma (PPARγ) level and decreased the levels of inflammatory cytokines. However, GW9662 (PPARγ antagonist) abolished OA protection in brain injury of mouse ICH model.</p><p><strong>Conclusion: </strong>OA could attenuate brain injury in experimental ICH by mitigating BBB disruption and attenuating neuroinflammation associated with PPARγ, thereby, OA might act as a latent neuroprotectant for treating ICH.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116002"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive reweighting of synaptic and intrinsic excitability by deep brain stimulation in a dystonia model.","authors":"Marco Heerdegen, Denise Franz, Valentin Neubert, Fabiana Santana-Kragelund, Tina Sellmann, Christoph Werner-Schmolling, Mohd Yasser, Henning Bathel, Anika Lüttig, Jens Starke, Konstantinos Spiliotis, Franziska Richter, Angelika Richter, Rüdiger Köhling","doi":"10.1016/j.expneurol.2026.115992","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.115992","url":null,"abstract":"<p><strong>Purpose: </strong>Deep brain stimulation (DBS) is a standard treatment for movement disorders like dystonia or Parkinson's Disease. Although its clinical effectiveness is established, the mechanisms by which DBS influences neural motor networks are not fully understood. This study explores the development of adaptive network mechanisms.</p><p><strong>Methods: </strong>We compared functional impacts of short-term and long-term DBS on a. excitability of medium spiny neurons (MSNs) and b. synaptic transmission in the striatum in the dt^sz hamster model, an in vivo model exhibiting dystonic episodes, and used mathematical modelling to gauge the functional impact of these changes.</p><p><strong>Results: </strong>In this electrophysiological and modelling study, we found contrasting changes in neuronal excitability and synaptic dynamics following short-term versus long-term DBS. Short-term DBS enhanced neuronal firing responses, while long-term DBS diminished them. Both short- and long-term DBS prolonged miniature excitatory postsynaptic currents (mEPSC) intervals, but only short-term DBS reduced mean frequency. Acetylcholine application reversed this effect, restoring mEPSC frequency more efficiently in tissue subjected to short-term DBS compared to long-term DBS.</p><p><strong>Significance: </strong>These observations indicate that DBS benefits in dystonia involve immediate and adaptive mechanisms, which have implications for improving stimulation parameters and treatment protocols. The findings reveal the temporal specificity of DBS effects and highlight the importance of understanding synaptic mechanisms to enhance therapeutic outcomes for dystonia patients.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115992"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic hypothermia does not prevent dysmaturity of medial ganglionic eminence-derived interneurons in the dorsal hippocampus after neonatal hypoxia-ischemia.","authors":"Harisa Spahic, Mark St Pierre, Pritika Parmar, Daniel Severin de la Plaza, Nivriti Vanga, Alexandria Whitley, Michael Nugent, Alfredo Kirkwood, Raul Chavez-Valdez","doi":"10.1016/j.expneurol.2026.115999","DOIUrl":"10.1016/j.expneurol.2026.115999","url":null,"abstract":"<p><strong>Introduction: </strong>Neonatal hypoxic-ischemic (HI) brain injury results in a persistent deficit of hippocampal parvalbumin (PV)⁺ interneurons (INs), despite therapeutic hypothermia (TH). Since INs from the medial ganglionic eminence (MGE) begin expressing PV around time of injury, we hypothesized that HI injury would result in maturational arrest of INs persisting through adulthood and resulting in memory deficits.</p><p><strong>Methods: </strong>Following HI at P10, mice were randomized to normothermia (36 °C, NT) or hypothermia (31 °C, TH) with anesthesia-exposed littermates as shams. Hippocampus was evaluated at P11, P18, and P40 for PV, SST, SAtb1, GFAP, Kv3.1b, and Kv3.2 (IF-IHC), electrical phenotyping and mIPSC (patch clamping), and RNA (real time RT PCR) and protein (western blot). Y-maze task and open field were performed for the P40 cohort.</p><p><strong>Results: </strong>The number of SAtb1⁺ GE-derived INs was lower at P18 in injured hippocampus compared to sham. The proportion of SAtb1⁺ INs without PV or SST expression by P18 was greater in HI-injured hippocampi, regardless of TH, a difference persisting to P40. Although HI-injured PV⁺ SAtb1⁺ INs demonstrated dendritic simplification and decreased Kv3.1b levels despite TH thru P40, they still achieved mature fast-spiking electrical phenotype by P18. By P40, deficits in Kv3.2 along with in Kv3.1b were demonstrated in HI-injured PV⁺ INs and attenuated by TH. Decreased mIPSC amplitude was documented at P40. Higher proportion of SAtb1⁺ INs negative for PV or SST correlated with worse spatial memory.</p><p><strong>Conclusions: </strong>Neonatal HI brain injury leads to dysmature GE-derived INs in the hippocampus, which persists to adulthood and not prevented by TH. Surviving GE-derived SAtb1⁺ INs may serve as a target to recover GABAergic deficits after HI injury in the era of TH to treat neonatal HI brain injury.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115999"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated hyperbaric oxygen exposure increases seizure susceptibility despite GABAergic modulation and is associated with mitochondrial and transcriptional adaptations.","authors":"Elena Webber, Kris Porter, Lucas Zhong Li, Michael Aksu, Heath G Gasier","doi":"10.1016/j.expneurol.2026.116004","DOIUrl":"10.1016/j.expneurol.2026.116004","url":null,"abstract":"<p><p>GABAergic inhibition delays oxygen-induced seizures, but whether this protection is maintained during repeated hyperbaric oxygen (HBO₂) exposure is unclear. We hypothesized that tiagabine (TGB) prevents increased seizure susceptibility during repeated HBO₂ by preserving presynaptic nerve-terminal function and tested whether single and repeated HBO₂ alter mitochondrial bioenergetics, mitophagy/autophagy, and region-specific transcriptional responses. Mice were exposed to 4.5 ATA O₂ for 60 min and re-exposed after 48 h, 72 h, or 7 d intervals. Measurements included seizure latency, synaptosomal neurotransmitters and oxygen consumption, mitophagy (mito-QC reporter)/autophagy (p62 and LC3-II/LC3-I), and spatial transcriptomics with gene ontology enrichment to define region-specific responses. Repeated HBO₂ shortened seizure latency and reduced the antiseizure efficacy of TGB. Synaptosomal neurotransmitters were altered by HBO₂ but not modified by TGB. Mitophagy/autophagy showed region-specific changes, with increased LC3-II/LC3-I at 48 h and region- and time-dependent changes in p62 expression, accompanied by reduced mitolysosomal signal at 7 d in hippocampal CA3 and cerebellar granular layer, while TGB increased signal in the cerebellar molecular layer. Synaptosomal mitochondrial respiration showed time-dependent changes, with early increases in oxygen consumption followed by reduced maximal respiration and spare respiratory capacity after repeated exposure. Spatial transcriptomics revealed region-specific responses, shifting from broad activation after a single exposure to more restricted intracellular and metabolic programs after repeated exposure. These findings indicate that TGB does not preserve presynaptic neurotransmitter content or prevent increased seizure susceptibility during repeated HBO₂ exposure. Repeated HBO₂ induces mitochondrial and transcriptional adaptations associated with reduced bioenergetic reserve, with susceptibility to oxygen toxicity influenced by recovery interval.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116004"},"PeriodicalIF":4.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral and spectral electroencephalographic biomarkers of epileptogenesis, disease progression, and drug resistance in a longitudinal lithium-pilocarpine model of temporal lobe epilepsy.","authors":"Giulia Urone, Nicolò Ricciardi, Miriana Scordino, Giuseppe Giglia, Antonio Cangelosi, Heidrun Potschka, Fabrizio Di Giovanni, Mario Allegra, Pierangelo Sardo, Giuseppe Ferraro, Giuseppa Mudò, Federica Ferraguti, Giuditta Gambino, Valentina Di Liberto","doi":"10.1016/j.expneurol.2026.115993","DOIUrl":"10.1016/j.expneurol.2026.115993","url":null,"abstract":"<p><p>Temporal lobe epilepsy (TLE) is linked to progressive alterations in brain network dynamics, leading to behavioral comorbidities and emergence of drug resistance; yet the underlying mechanistic and synaptic substrates remain incompletely understood. Here, we performed longitudinal phase-specific characterization of network dysfunction in TLE employing a lithium-pilocarpine-induced model in 7-week male Wistar rats. We integrated behavioral and electroencephalographic (EEG) analyses at five timepoints: baseline, acute, latent, chronic phases, and after assessment of drug-resistant epilepsy (DRE). After the chronic phase, responsiveness to phenobarbital (PB), a standardized approach for DRE characterization, was assessed via video monitoring to identify drug-resistant (DRUG-R) and drug-sensitive (DRUG-S) subpopulations. Our data show that epileptic rats exhibited progressive and phase-dependent behavioral and EEG alterations. Behavioral profiling revealed a hypermotor phenotype, impairment in burrowing natural behavior, altered phase-specific response to anxiety and depressive-associated behavioral paradigms, and progressive memory impairment. Following PB treatment, the identified DRUG-R subpopulation displayed specific hyperactive behavioral traits compared with DRUG-S, especially in anxiety-associated and burrowing behaviors. Spectral EEG analysis revealed modulation of frequency bands across disease stages, particularly in Theta and Delta power, and descriptive analyses attempted to stratify animals based on different responsiveness to PB. Lastly, correlation analyses supported associations between EEG, frequency of seizures and behavioral measures, especially in the anxiety domain and declarative memory. This study, moving beyond a seizure-centric perspective, evidences that TLE induces progressive and phase-specific reorganization of cortical activity that relapse on distinct electrophysiological and behavioral features, offering a novel framework to identify translational stage-related signatures of epileptogenesis and DRE.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115993"},"PeriodicalIF":4.8,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multiome landscape reveals elovanoid-mediated suppression of inflammatory glial states and induction of homeostatic signaling after ischemic stroke.","authors":"Jeff X Ji, Surjyadipta Bhattacharjee, Brian L Giles, Ludmila Belayev, Nicolas G Bazan","doi":"10.1016/j.expneurol.2026.115998","DOIUrl":"10.1016/j.expneurol.2026.115998","url":null,"abstract":"<p><p>Ischemic stroke is a leading cause of death and disability. Administration of the lipid mediators elovanoids (ELVs) is protective in human neuronal-glia cultures and in experimental ischemic stroke. We now report using a single-cell multiome approach that intranasally-delivered (IN) ELV34 or its precursor reduced the loss of neuronal markers and upregulated homeostatic microglia signatures after stroke. Thus, ELV reduces disease-associated microglia (expressing Spp1, Gpnmb, Lgals3, Clec7a) and the expression of neuroinflammatory signaling genes. In astrocytes, ELV decreased reactive astrocytes (expressing Gfap, Vim, Nes, Lcn2) and upregulated genes involved in synaptic organization. Also, ELV reduced abundance of oligodendrocytes and OPCs expressing immune markers. ELV induced a phenotype shift from pro-inflammatory microglia, astrocytes, oligodendrocytes, and OPCs in response to ischemic stroke damage. ELV upregulated gene pathways promoting synaptic integrity, reducing immune cell activation and neuronal loss.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115998"},"PeriodicalIF":4.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nogo-B deletion mitigates mitochondrial dynamics imbalance in cerebral ischemia/reperfusion injury via the TLR4/ERK pathway.","authors":"Taotao Fan, Rong Xu, Zhangle Hu, Anran Guo, Qi Lou, Huiyu Jia, Min Si, Rui Li, Xiaoyu Zhu, Dongmei Yang, Shengyong Luo","doi":"10.1016/j.expneurol.2026.115988","DOIUrl":"10.1016/j.expneurol.2026.115988","url":null,"abstract":"<p><strong>Background: </strong>Our previous studies have demonstrated that the downregulation of Nogo-B expression in microglia suppresses neuroinflammatory responses by modulating microglial polarization, thereby attenuating cerebral ischemia/reperfusion (I/R) injury. However, the direct role of Nogo-B in neuronal cells remains unclear.</p><p><strong>Methods: </strong>Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation and reoxygenation (ODG/R) models were utilized to mimic ischemic stroke. Various methods, including Nogo-B shRNA transfection, balance beam and corner turn tests, immunofluorescence staining, electron microscopy, Western blot, and TUNEL, were used to investigate the effects of Nogo-B deletion on mitochondrial dynamics imbalance in neurons following cerebral I/R injury, as well as its underlying mechanisms.</p><p><strong>Results: </strong>Neuron-specific conditional knockout (cko) of Nogo-B significantly reduced cerebral infarction volume and neurological deficit scores in mice subjected to cerebral I/R. Nogo-B deletion enhanced neuronal cell viability, suppressed apoptosis, improved mitochondrial respiratory chain activity, increased mitochondrial membrane potential and ATP production, and lowered ROS levels and oxidative stress markers. Additionally, it decreased the expression of fission-related proteins (p-Drp1, Fis1) and mitochondrial fragmentation while increasing the expression of fusion-related proteins (Opa1, Mfn1, and Mfn2). Mechanistic studies show that Nogo-B knockout can significantly reduce the expression of TLR4 and p-ERK1/2 proteins. Nogo-B downregulation also resulted in a significant reduction in TLR4 and p-ERK1/2, a marked decrease in mitochondrial fission proteins, a substantial increase in fusion proteins, and concomitant improvement in mitochondrial structure, function, and cell viability. Nogo-B downregulation produced effects comparable to TAK-242. However, these protective effects were substantially attenuated by the ERK activator TPA.</p><p><strong>Conclusion: </strong>Nogo-B deletion has a direct protective effect on neurons after cerebral ischemia-reperfusion injury. The mechanism may be related to Nogo-B reducing the expression of TLR4 on the cell membrane through some indirect action, thereby inhibiting the TLR4/ERK pathway and regulating mitochondrial dynamic imbalance.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115988"},"PeriodicalIF":4.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.","authors":"Lufei Chen, Ruying Lin, Yongpei Xu, Shiqi Lin, Jinyuan Fan, Huiyao Zhang, Ying Zhou, Qinyong Ye, Zucheng Ye","doi":"10.1016/j.expneurol.2026.116000","DOIUrl":"10.1016/j.expneurol.2026.116000","url":null,"abstract":"<p><p>Glioblastoma (GBM) exhibits profound metabolic and redox adaptation that supports tumor progression and therapeutic resistance. Here, we identify the glutamate transporter EAAT1 (SLC1A3) as a critical regulator of glutamate-dependent redox homeostasis in GBM. Analysis of TCGA, GTEx, and CGGA datasets showed that EAAT1 expression is elevated in GBM and that higher EAAT1 expression is associated with poor patient survival. Using CRISPR/Cas9-mediated EAAT1 knockout together with biochemical, imaging, transcriptomic, and in vivo approaches, we found that loss of EAAT1 altered extracellular and intracellular glutamate homeostasis, reduced intracellular glutamate, glutamine, and glutathione levels, and increased reactive oxygen species (ROS) accumulation. EAAT1 deficiency also suppressed oxidative phosphorylation and ROS-related programs and attenuated the Keap1/Nrf2/HO-1 antioxidant axis, accompanied by reduced GPX4 expression and increased lipid peroxidation. Furthermore, EAAT1 ablation downregulated glutamine synthetase and glutaminase, suggesting impaired glutamine-dependent anaplerotic metabolism. Glutamate supplementation partially restored Keap1/Nrf2/HO-1 pathway protein expression in EAAT1-knockout cells. Functionally, EAAT1 loss inhibited GBM cell proliferation and migration, enhanced sensitivity to oxidative stress and temozolomide (TMZ), and reduced tumor growth in xenograft models. Collectively, our findings establish EAAT1 as a key metabolic regulator linking glutamate transport to antioxidant defense and therapeutic response in GBM. Targeting EAAT1 may therefore represent a metabolic vulnerability for overcoming metabolic and redox adaptation and improving TMZ responsiveness in GBM.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116000"},"PeriodicalIF":4.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}