Experimental Neurology最新文献

Atlas of temporal molecular pathological alterations after traumatic brain injury based on RNA-Seq

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-21 DOI: 10.1016/j.expneurol.2025.115270

Yulian Zhang , Kun He , Chuanpeng Zhang , Hanhan Dang , Junru Hei , Yunsheng Zhang , Pengyu Chen , Ze Zhang , Yanbo Yang , Zixi Wang , Xu Yang , Li Zhang , Yanbing Yu

Traumatic brain injury (TBI) involves diverse molecular pathological alterations and biological processes in a temporally dynamic manner. However, current knowledge on the various processes during the acute phase of TBI is still rather limited. RNA-seq analysis was performed on brain tissues from C57/BL6 mice at 10 time points(0 h, 1 h, 2 h, 3 h, 4 h, 6 h, 12 h, 1d, 3d, and 7d) following TBI modeling. Subsequently, a bioinformatics approach, Weighted Gene Co-expression Network Analysis (WGCNA), was employed to identify characteristic modules, which were then validated using the Mfuzz method. Pathway enrichment analysis was conducted on WGCNA module genes, and hub genes were screened using the STRING database. After exploring the various potential pathways and expression patterns (neuroinflammation, cognition, gliosis and myelin regeneration etc.), we focus on pyroptosis, a inflammatory cell death influencing immune response, for in-depth analysis. RT-qPCR, Western blot(WB) and Immunofluorescence(IF) were used to validate the hub genes and key pyroptosis-related genes(Casp1, Casp11, GSDMD). Additionally, single-cell RNA sequencing data at 7 day post injury(dpi) was also used to validate the expression of the identified hub genes. Our approach to intensive transcriptomic analysis comprehensively reveals the temporal molecular pathological alterations during TBI progression. Pyroptosis may be a key mechanism in the neuroinflammatory process. Intervention strategies targeting specific molecular pathways may offer novel approach for the treatment of TBI.

{"title":"Atlas of temporal molecular pathological alterations after traumatic brain injury based on RNA-Seq","authors":"Yulian Zhang , Kun He , Chuanpeng Zhang , Hanhan Dang , Junru Hei , Yunsheng Zhang , Pengyu Chen , Ze Zhang , Yanbo Yang , Zixi Wang , Xu Yang , Li Zhang , Yanbing Yu","doi":"10.1016/j.expneurol.2025.115270","DOIUrl":"10.1016/j.expneurol.2025.115270","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) involves diverse molecular pathological alterations and biological processes in a temporally dynamic manner. However, current knowledge on the various processes during the acute phase of TBI is still rather limited. RNA-seq analysis was performed on brain tissues from C57/BL6 mice at 10 time points(0 h, 1 h, 2 h, 3 h, 4 h, 6 h, 12 h, 1d, 3d, and 7d) following TBI modeling. Subsequently, a bioinformatics approach, Weighted Gene Co-expression Network Analysis (WGCNA), was employed to identify characteristic modules, which were then validated using the Mfuzz method. Pathway enrichment analysis was conducted on WGCNA module genes, and hub genes were screened using the STRING database. After exploring the various potential pathways and expression patterns (neuroinflammation, cognition, gliosis and myelin regeneration etc.), we focus on pyroptosis, a inflammatory cell death influencing immune response, for in-depth analysis. RT-qPCR, Western blot(WB) and Immunofluorescence(IF) were used to validate the hub genes and key pyroptosis-related genes(Casp1, Casp11, GSDMD). Additionally, single-cell RNA sequencing data at 7 day post injury(dpi) was also used to validate the expression of the identified hub genes. Our approach to intensive transcriptomic analysis comprehensively reveals the temporal molecular pathological alterations during TBI progression. Pyroptosis may be a key mechanism in the neuroinflammatory process. Intervention strategies targeting specific molecular pathways may offer novel approach for the treatment of TBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115270"},"PeriodicalIF":4.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873780","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}

引用次数: 0

Edaravone ameliorates inflammation in ischemic stroke mouse by regulating the CYP1A1 pathway through gut microbiota

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-19 DOI: 10.1016/j.expneurol.2025.115263

Yuan Zhang , Xiaojing Jiao , Xiaoying Qi , Guangtian Wang , Yabin Ma

Inflammation is one of the main contributors to post-stroke injuries, and the disorders of the gut-brain axis post-stroke can further induce inflammation. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDA) is widely utilized neuroprotective medication for ischemic stroke in Japan, China, India, and other countries. However, the effects of EDA on peripheral inflammation and gut-brain axis repair post-stroke have not been revealed yet. In this study, we employed network pharmacology to identify the potential anti-inflammatory targets and signaling pathways that EDA may influence in the treatment of ischemic stroke. Then, we used 16S rDNA sequencing and molecular docking techniques to determine whether the anti-inflammatory effects of EDA are dependent on the gut-brain axis. Using morphological and molecular biology methods, we investigate how EDA reduces inflammatory response after ischemic stroke through gut microbiota and its metabolites. We demonstrated that EDA alleviated central and peripheral inflammation and rescued gut microbiota dysbiosis post-stroke. Meanwhile, EDA also improved intestinal histological features and decreased intestinal inflammation of post-stroke. The network pharmacology, 16S rDNA sequencing, and molecular docking results revealed that EDA could bind with the ESR1 and thereby regulate the expression of CYP1A1. Furthermore, EDA regulated CYP1A1-related metabolism and decreased the level of 20-HETE post-stroke through gut microbiota. Our study confirmed that EDA alleviated central and peripheral inflammation post-stroke by inhibiting CYP1A1 and CYP1A1-related metabolic through gut microbiota. CYP1A1 was a candidate target for treating ischemic stroke.

{"title":"Edaravone ameliorates inflammation in ischemic stroke mouse by regulating the CYP1A1 pathway through gut microbiota","authors":"Yuan Zhang , Xiaojing Jiao , Xiaoying Qi , Guangtian Wang , Yabin Ma","doi":"10.1016/j.expneurol.2025.115263","DOIUrl":"10.1016/j.expneurol.2025.115263","url":null,"abstract":"<div><div>Inflammation is one of the main contributors to post-stroke injuries, and the disorders of the gut-brain axis post-stroke can further induce inflammation. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDA) is widely utilized neuroprotective medication for ischemic stroke in Japan, China, India, and other countries. However, the effects of EDA on peripheral inflammation and gut-brain axis repair post-stroke have not been revealed yet. In this study, we employed network pharmacology to identify the potential anti-inflammatory targets and signaling pathways that EDA may influence in the treatment of ischemic stroke. Then, we used 16S rDNA sequencing and molecular docking techniques to determine whether the anti-inflammatory effects of EDA are dependent on the gut-brain axis. Using morphological and molecular biology methods, we investigate how EDA reduces inflammatory response after ischemic stroke through gut microbiota and its metabolites. We demonstrated that EDA alleviated central and peripheral inflammation and rescued gut microbiota dysbiosis post-stroke. Meanwhile, EDA also improved intestinal histological features and decreased intestinal inflammation of post-stroke. The network pharmacology, 16S rDNA sequencing, and molecular docking results revealed that EDA could bind with the ESR1 and thereby regulate the expression of CYP1A1. Furthermore, EDA regulated CYP1A1-related metabolism and decreased the level of 20-HETE post-stroke through gut microbiota. Our study confirmed that EDA alleviated central and peripheral inflammation post-stroke by inhibiting CYP1A1 and CYP1A1-related metabolic through gut microbiota. CYP1A1 was a candidate target for treating ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115263"},"PeriodicalIF":4.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864356","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}

引用次数: 0

Stool-derived extracellular vesicles increase inflammasome signaling and regulate the gut-brain axis after stroke in Alzheimer's disease transgenic mice

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-18 DOI: 10.1016/j.expneurol.2025.115269

Nadine A. Kerr , Helen M. Bramlett , Juliana Sanchez-Molano , Alfredo Fernandez Higueras , Winston Walters , Juan Pablo de Rivero Vaccari , Robert W. Keane , W. Dalton Dietrich

Patients with Alzheimer's disease (AD) suffering from post-stroke gut dysfunction present with worsened neurological outcomes. This study investigated the role of stool-derived extracellular vesicle (EV)-mediated inflammasome signaling in the gut-brain axis following photothrombotic stroke (PTS) in aged 3xTg- AD and wildtype (WT) mice. Western Blot and immunohistochemical analyses evaluated inflammasome signaling proteins, Gasdermin D (GSDMD), and Aβ in intestinal and cortical tissues. Gut permeability was measured using a FITC-dextran assay 3 days post PTS. Adoptive transfer experiments assessed the impact of stool-derived EVs from PTS mice on inflammasome signaling in recipient naïve 3xTg and WT mice. At 3 days, 3xTg-PTS mice demonstrated significantly impaired sensorimotor Rotarod performance compared to WT-PTS mice. Both WT and 3xTg PTS mice had deficits compared to 3xTg and WT sham mice using the Open Field or Novel Object Recognition tests. Compared to WT- PTS mice, 3xTg-PTS mice had disrupted gut morphology at 1-month post-PTS, as well as increased gut permeability at 72 h. Immunohistochemical analysis also revealed activated microglial morphology and presence of GSDMD and Aβ in the brain and intestines post-PTS in 3xTg and WT mice. Adoptive transfer of stool-derived EVs from PTS mice to WT mice induced elevated levels of inflammasome signaling proteins in recipient cerebral cortices. These findings indicate an important role of stool-derived EV inflammasome signaling and pyroptosis in disruption of the bidirectional gut-brain axis after stroke leading to exacerbation of AD pathology in aged WT and 3xTg mice.

{"title":"Stool-derived extracellular vesicles increase inflammasome signaling and regulate the gut-brain axis after stroke in Alzheimer's disease transgenic mice","authors":"Nadine A. Kerr , Helen M. Bramlett , Juliana Sanchez-Molano , Alfredo Fernandez Higueras , Winston Walters , Juan Pablo de Rivero Vaccari , Robert W. Keane , W. Dalton Dietrich","doi":"10.1016/j.expneurol.2025.115269","DOIUrl":"10.1016/j.expneurol.2025.115269","url":null,"abstract":"<div><div>Patients with Alzheimer's disease (AD) suffering from post-stroke gut dysfunction present with worsened neurological outcomes. This study investigated the role of stool-derived extracellular vesicle (EV)-mediated inflammasome signaling in the gut-brain axis following photothrombotic stroke (PTS) in aged 3xTg- AD and wildtype (WT) mice. Western Blot and immunohistochemical analyses evaluated inflammasome signaling proteins, Gasdermin D (GSDMD), and Aβ in intestinal and cortical tissues. Gut permeability was measured using a FITC-dextran assay 3 days post PTS. Adoptive transfer experiments assessed the impact of stool-derived EVs from PTS mice on inflammasome signaling in recipient naïve 3xTg and WT mice. At 3 days, 3xTg-PTS mice demonstrated significantly impaired sensorimotor Rotarod performance compared to WT-PTS mice. Both WT and 3xTg PTS mice had deficits compared to 3xTg and WT sham mice using the Open Field or Novel Object Recognition tests. Compared to WT- PTS mice, 3xTg-PTS mice had disrupted gut morphology at 1-month post-PTS, as well as increased gut permeability at 72 h. Immunohistochemical analysis also revealed activated microglial morphology and presence of GSDMD and Aβ in the brain and intestines post-PTS in 3xTg and WT mice. Adoptive transfer of stool-derived EVs from PTS mice to WT mice induced elevated levels of inflammasome signaling proteins in recipient cerebral cortices. These findings indicate an important role of stool-derived EV inflammasome signaling and pyroptosis in disruption of the bidirectional gut-brain axis after stroke leading to exacerbation of AD pathology in aged WT and 3xTg mice.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115269"},"PeriodicalIF":4.6,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855877","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}

引用次数: 0

Lipocalin 2 mediates kidney function abnormalities induced by ischemic stroke in mice: Involvement of neural pathways

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-16 DOI: 10.1016/j.expneurol.2025.115267

Pu Hong , Dong-Xiao Yang , Ye-Hao Xu , Meng-Jiao He , Xi Chen , Fengxian Li , Shi-Yuan Xu , Hong-Fei Zhang

Background

Kidney function abnormalities is a common complication following ischemic stroke. Lipocalin 2 (LCN2) is currently a well-recognized specific biomarker of tubular injury. However, the role of LCN2 in kidney function abnormalities following stroke remains elusive. The sympathetic nervous system plays a crucial role in linking the brain and kidney. However, whether the kidney sympathetic nervous system regulates the expression of LCN2 following ischemic stroke has not been identified.

Methods

In this study, we established a middle cerebral artery occlusion (MCAO) model to induce ischemic stroke in mice. Renal function was assessed 24 h after cerebral ischemia-reperfusion injury. Transcriptomic sequencing of kidney tissue was performed to identify potential pathological mechanisms. The role of LCN2 in post-stroke renal injury was investigated using renal tubule-specific LCN2 knockout mice and a combination of qPCR, western blotting, immunofluorescence, and transmission electron microscopy. In addition, renal denervation (RDN) was used to explore the relationship between sympathetic nerves and the expression of renal LCN2.

Results

Ischemic stroke significantly exhibits renal functional impairment 24 h after reperfusion. Notably, RNA sequencing and Western blotting revealed a markedly increased expression of renal LCN2 following ischemic stroke. Renal tubular Lcn2-specific knockout significantly ameliorated the occurrence of kidney function abnormalities after stroke. Subsequently, we observed that the activation of renal sympathetic nerves upregulates LCN2 and induces kidney function abnormalities after stroke.

Conclusions

These findings reveal a neural pathway in which the sympathetic nervous system upregulates LCN2, providing potential therapeutic strategies for renal protection following ischemic stroke.

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引用次数: 0

Fasudil mitigates diabetes-associated cognitive decline and enhances neuroprotection by suppressing NLRP3/Caspase-1/GSDMD signaling in a stroke mouse model

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-16 DOI: 10.1016/j.expneurol.2025.115268

Mohd. Salman , Hiba Shahzad , Rajashekhar Gangaraju , Tauheed Ishrat

Type 2 diabetes mellitus and obesity are progressive metabolic disorders that heighten the risk of negative outcomes and cognitive decline after an ischemic stroke with limited treatment options. Previous research has shown that Fasudil, a RhoA kinase inhibitor, has therapeutic benefits in various neurological diseases; however, it is unknown if Fasudil provides neuroprotection in diabetic encephalopathy after ischemic stroke. This study aimed to explore the protective effects of Fasudil in an experimental model of diabetic encephalopathy following a photothrombotic stroke using high-fat diet-streptozotocin (HFD/STZ) mice to assess behavioral outcomes and molecular analysis. The experimental mice underwent photothrombotic stroke (pt-MCAO) surgery by retro-orbital injection of Rose Bengal (15 mg/kg), followed by 4 min exposure of the proximal-middle cerebral artery to a 532 nm laser exposure. The results indicated that Fasudil treatment provided potential neuronal protection and improved behavioral outcomes in post-stroke HFD/STZ mice. Additionally, Fasudil inhibited NOD-like receptor protein 3 (NLRP3) inflammasomes and their components, enhanced cognitive function by regulating synaptic markers, and significantly reduced neuroinflammation in post-stroke HFD/STZ mice. Fasudil also notably decreased oxidative stress and apoptosis by modulating Bax and cleaved PARP-1 protein expression and reducing the number of TUNEL-positive cells. In summary, Fasudil treatment offers neuroprotection and enhances cognitive function by preventing oxidative damage and NLRP3 inflammasome activation in post-stroke HFD/STZ mice. These results suggest that Fasudil may serve as a promising alternative therapeutic candidate for improving stroke outcomes and addressing the limitations of current treatment options.

{"title":"Fasudil mitigates diabetes-associated cognitive decline and enhances neuroprotection by suppressing NLRP3/Caspase-1/GSDMD signaling in a stroke mouse model","authors":"Mohd. Salman , Hiba Shahzad , Rajashekhar Gangaraju , Tauheed Ishrat","doi":"10.1016/j.expneurol.2025.115268","DOIUrl":"10.1016/j.expneurol.2025.115268","url":null,"abstract":"<div><div>Type 2 diabetes mellitus and obesity are progressive metabolic disorders that heighten the risk of negative outcomes and cognitive decline after an ischemic stroke with limited treatment options. Previous research has shown that Fasudil, a RhoA kinase inhibitor, has therapeutic benefits in various neurological diseases; however, it is unknown if Fasudil provides neuroprotection in diabetic encephalopathy after ischemic stroke. This study aimed to explore the protective effects of Fasudil in an experimental model of diabetic encephalopathy following a photothrombotic stroke using high-fat diet-streptozotocin (HFD/STZ) mice to assess behavioral outcomes and molecular analysis. The experimental mice underwent photothrombotic stroke (pt-MCAO) surgery by retro-orbital injection of Rose Bengal (15 mg/kg), followed by 4 min exposure of the proximal-middle cerebral artery to a 532 nm laser exposure. The results indicated that Fasudil treatment provided potential neuronal protection and improved behavioral outcomes in post-stroke HFD/STZ mice. Additionally, Fasudil inhibited NOD-like receptor protein 3 (NLRP3) inflammasomes and their components, enhanced cognitive function by regulating synaptic markers, and significantly reduced neuroinflammation in post-stroke HFD/STZ mice. Fasudil also notably decreased oxidative stress and apoptosis by modulating Bax and cleaved PARP-1 protein expression and reducing the number of TUNEL-positive cells. In summary, Fasudil treatment offers neuroprotection and enhances cognitive function by preventing oxidative damage and NLRP3 inflammasome activation in post-stroke HFD/STZ mice. These results suggest that Fasudil may serve as a promising alternative therapeutic candidate for improving stroke outcomes and addressing the limitations of current treatment options.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115268"},"PeriodicalIF":4.6,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850865","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}

引用次数: 0

4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione rescues oligodendrocytes ferroptosis leading to myelin loss and ameliorates neuronal injury facilitating memory in neonatal hypoxic-ischemic brain damage 4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮可挽救导致髓鞘脱失的少突胶质细胞铁突变，改善神经元损伤，促进新生儿缺氧缺血性脑损伤的记忆

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-15 DOI: 10.1016/j.expneurol.2025.115262

Qiyi Huang , Jiahang Tang , You Xiang , Xinying Shang , Kunlin Li , Lijia Chen , Junnan Hu , Han Li , Yanxiong Pi , Haiyan Yang , Huijia Zhang , Heng Tan , Yanbin Xiyang , Huiyan Jin , Xia Li , Manjun Chen , Rongrong Mao , Qian Wang

Neonatal brain hypoxia-ischemia (HI) is proved to cause white matter injury (WMI), which resulted in behavioral disturbance. Myelin formed by oligodendrocytes vulnerable to hypoxia-ischemia (HI), regulating motor and cognitive function, is easily damaged by HI causing myelin loss. 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) has a potential rescue role in neuronal death post HI. Studies reported that neuronal ferroptosis could be induced by HI and linked to behavioral abnormalities. However, the effect of TDZD-8 on WMI and its involvement in memory recovery remains unclear. In this study, our HIBD model showed impaired memory function caused by neuronal injury and myelin loss. TDZD-8 effectively reversed this pathology. Underlying mechanistic exploration implied that TDZD-8 ameliorating myelin loss via ferroptosis pathway was involved in the process of TDZD-8 treating neonatal HIBD. In conclusion, our data demonstrated that combined effect of white matter repairment and neuronal protection achieved the therapeutic role of TDZD-8 in neonatal HIBD, and suggested that white matter repairment also could be a considerable clinical therapy for neonatal HIBD.

{"title":"4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione rescues oligodendrocytes ferroptosis leading to myelin loss and ameliorates neuronal injury facilitating memory in neonatal hypoxic-ischemic brain damage","authors":"Qiyi Huang , Jiahang Tang , You Xiang , Xinying Shang , Kunlin Li , Lijia Chen , Junnan Hu , Han Li , Yanxiong Pi , Haiyan Yang , Huijia Zhang , Heng Tan , Yanbin Xiyang , Huiyan Jin , Xia Li , Manjun Chen , Rongrong Mao , Qian Wang","doi":"10.1016/j.expneurol.2025.115262","DOIUrl":"10.1016/j.expneurol.2025.115262","url":null,"abstract":"<div><div>Neonatal brain hypoxia-ischemia (HI) is proved to cause white matter injury (WMI), which resulted in behavioral disturbance. Myelin formed by oligodendrocytes vulnerable to hypoxia-ischemia (HI), regulating motor and cognitive function, is easily damaged by HI causing myelin loss. 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) has a potential rescue role in neuronal death post HI. Studies reported that neuronal ferroptosis could be induced by HI and linked to behavioral abnormalities. However, the effect of TDZD-8 on WMI and its involvement in memory recovery remains unclear. In this study, our HIBD model showed impaired memory function caused by neuronal injury and myelin loss. TDZD-8 effectively reversed this pathology. Underlying mechanistic exploration implied that TDZD-8 ameliorating myelin loss via ferroptosis pathway was involved in the process of TDZD-8 treating neonatal HIBD. In conclusion, our data demonstrated that combined effect of white matter repairment and neuronal protection achieved the therapeutic role of TDZD-8 in neonatal HIBD, and suggested that white matter repairment also could be a considerable clinical therapy for neonatal HIBD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115262"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855878","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}

引用次数: 0

A comparative study on the acute-phase behavioral and pathological responses of closed head injury induced by cranial vertex and temporal lobe impacts in male rats

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-15 DOI: 10.1016/j.expneurol.2025.115259

Peng Wang , Xuewei Song , Jinlong Qiu , Xiyan Zhu , Pengfei Wu , Zhikang Liao , Jingru Xie , Nan Wang , Hui Zhao

The outcomes of traumatic brain injury (TBI) are closely linked to the strength of mechanical loads applied to the head. However, the same mechanical load can lead to significant variations in injury outcomes depending on the location of impact. To compare the acute-phase behavioral and pathological effects of different impact locations on TBI outcomes, we conducted a closed head injury experimental study using male rats subjected to cranial vertex and temporal lobe impacts. The rats were injured by an impactor according to the experimental protocol established using the L₄ (2³) orthogonal table, and the behavioral and pathological outcomes were assessed. The contribution rates of impact location and strength to TBI were quantified using Analysis of Variance. The results indicated that impact strength played a dominant role in TBI and showed a positive correlation, while the role of impact location in TBI cannot be ignored. Behaviorally, cranial vertex impacts led to more severe coma, motor, memory, and anxiety deficits. Pathologically, cranial vertex impacts caused more severe diffuse axonal injury in the corpus callosum and brainstem. In the left hippocampus and amygdala, cell loss due to cranial vertex impacts was more pronounced than that caused by temporal lobe impacts, whereas the opposite was true on the right side. Notably, the pathological changes observed in the left (non-impact) hippocampus and amygdala due to temporal lobe impacts showed a stronger linear correlation with behavioral outcomes, suggesting that damage to the left side has greater predictive power for behavioral deficits. This suggests that the impact location is an important factor affecting TBI and should be considered in the study.

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引用次数: 0

Triiodothyronine ameliorates S-ketamine-induced hypomyelination via the PPARα pathway in neonatal rat

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-15 DOI: 10.1016/j.expneurol.2025.115260

Mengqin Shan , Chaoyang Tong , Xin Fu , Yuxin Zhang , Luping Feng , Liping Sun , Kan Zhang , Jijian Zheng

Growing evidence suggests that prolonged or repeated exposure to general anesthesia is associated with white matter alteration in children, which may underlie subsequent cognitive and behavioral abnormalities. Numerous infants undergo anesthesia for surgery each year, so it is imperative to identify the risk factors and find preventative treatment to prevent the effects of early anesthesia exposure. Thyroid hormones play a pivotal role in the process of myelination of white matter. Clinical studies have shown that thyroid hormone levels are decreased after infant surgery, whether thyroid hormone supplementation can prevent long-term toxicity of anesthesia remains to be elucidated. Here we used S-ketamine, an anesthetic drug commonly used in pediatric anesthesia, to investigate changes in thyroid hormones after anesthesia and their effects on myelin development. Our findings showed a significant decrease in thyroid hormones following S-ketamine anesthesia. The administration of triiodothyronine (T3) supplements ameliorated the S-ketamine-induced impairments in motor coordination and myelination. S-ketamine-induced hypothyroidism predominantly affects the differentiation of OPCs to mature oligodendrocytes. Further analysis revealed significant alterations in lipid metabolism, and we observed that S-ketamine inhibited PPARα in OPCs. Treatment with T3 effectively rescued S-ketamine-induced suppression of PPARα. The protective effects of T3 were significantly compromised by the PPARα inhibitor GW6471. The pharmacological activator of PPARα, fenofibrate, rescued the motor coordination deficits and the inhibition of OPC maturation induced by S-ketamine. In conclusion, our study demonstrates that S-ketamine anesthesia induces the decline of thyroid hormone and hypomyelination in neonatal rats. Administration of T3 ameliorates S-ketamine-induced hypomyelination through the PPARα signaling pathway.

{"title":"Triiodothyronine ameliorates S-ketamine-induced hypomyelination via the PPARα pathway in neonatal rat","authors":"Mengqin Shan , Chaoyang Tong , Xin Fu , Yuxin Zhang , Luping Feng , Liping Sun , Kan Zhang , Jijian Zheng","doi":"10.1016/j.expneurol.2025.115260","DOIUrl":"10.1016/j.expneurol.2025.115260","url":null,"abstract":"<div><div>Growing evidence suggests that prolonged or repeated exposure to general anesthesia is associated with white matter alteration in children, which may underlie subsequent cognitive and behavioral abnormalities. Numerous infants undergo anesthesia for surgery each year, so it is imperative to identify the risk factors and find preventative treatment to prevent the effects of early anesthesia exposure. Thyroid hormones play a pivotal role in the process of myelination of white matter. Clinical studies have shown that thyroid hormone levels are decreased after infant surgery, whether thyroid hormone supplementation can prevent long-term toxicity of anesthesia remains to be elucidated. Here we used S-ketamine, an anesthetic drug commonly used in pediatric anesthesia, to investigate changes in thyroid hormones after anesthesia and their effects on myelin development. Our findings showed a significant decrease in thyroid hormones following S-ketamine anesthesia. The administration of triiodothyronine (T3) supplements ameliorated the S-ketamine-induced impairments in motor coordination and myelination. S-ketamine-induced hypothyroidism predominantly affects the differentiation of OPCs to mature oligodendrocytes. Further analysis revealed significant alterations in lipid metabolism, and we observed that S-ketamine inhibited PPARα in OPCs. Treatment with T3 effectively rescued S-ketamine-induced suppression of PPARα. The protective effects of T3 were significantly compromised by the PPARα inhibitor GW6471. The pharmacological activator of PPARα, fenofibrate, rescued the motor coordination deficits and the inhibition of OPC maturation induced by S-ketamine. In conclusion, our study demonstrates that S-ketamine anesthesia induces the decline of thyroid hormone and hypomyelination in neonatal rats. Administration of T3 ameliorates S-ketamine-induced hypomyelination through the PPARα signaling pathway.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115260"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844250","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}

引用次数: 0

Differential regulation of GABAA receptor-mediated hyperexcitability at different stages of brain development in focal cortical dysplasia (FCD)

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-15 DOI: 10.1016/j.expneurol.2025.115265

Yogesh Aggarwal , Aparna Banerjee Dixit , Fouzia Siraj , Manjari Tripathi , P. Sarat Chandra , Jyotirmoy Banerjee

Focal cortical dysplasia (FCD) is a developmental abnormality of cortex commonly linked with drug-resistant seizures. Altered GABAergic activity is a key contributor to interictal discharges in FCD. In FCD, GABA_A receptor associated epileptogenicity is dependent upon the age at seizure onset, as differential epileptogenic networks are observed in early and late onset FCD patients. But the contribution of GABA_A receptor alteration to epileptogenic networks during development is unclear. We hypothesize that GABAergic signaling in FCD undergoes age-dependent molecular alterations, contributing to the development of distinct epileptogenic networks. In this study, we investigated age-dependent changes in GABA neurotransmitter levels, GABA_A receptor α subunit expression, and GABA_A receptor-mediated synaptic activity using the BCNU-rat model of FCD. GABA levels, mRNA, and protein expression of GABA_A receptor α subunits were determined by HPLC, qPCR and western blot and spontaneous GABAergic activity from pyramidal neurons was recorded using whole cell patch-clamp technique. At postnatal days (P) 12 and 21, reduced expression of α1, 2 and 4 subunits were observed in FCD rats compared to control. Consistent with this, decreased amplitude and frequency of GABAergic events were observed in FCD rats. In contrast, at P30 and P65, decreased GABA levels, without changes in receptor expression, were observed in FCD rats. Consistently, reduction in the frequency of GABAergic events was observed in FCD rats compared to the control. Furthermore, treatment with tetrodotoxin (TTX) revealed that the observed alterations in GABAergic activity were predominantly action potential (AP)-dependent. Our findings indicate that distinct epileptogenic networks exist in FCD during early and late developmental stages. These networks are driven primarily by altered GABAergic activity, with early age changes linked to aberrant GABA_A receptor configurations and late age changes associated with abnormal GABA levels.

局灶性皮质发育不良（FCD）是一种皮质发育异常，通常与耐药性癫痫发作有关。GABA能活动的改变是导致FCD发作间期放电的关键因素。在 FCD 中，与 GABAA 受体相关的致痫性取决于癫痫发作的发病年龄，因为在早期和晚期发病的 FCD 患者中观察到不同的致痫网络。但在发育过程中，GABAA 受体的改变对致痫网络的贡献尚不清楚。我们假设，FCD 中的 GABA 能信号传导会发生年龄依赖性分子改变，从而导致不同致痫网络的形成。在这项研究中，我们使用 BCNU-rat FCD 模型研究了 GABA 神经递质水平、GABAA 受体 α 亚基表达和 GABAA 受体介导的突触活动的年龄依赖性变化。通过HPLC、qPCR和Western blot测定GABA水平、mRNA和GABAA受体α亚基的蛋白表达，并使用全细胞贴片钳技术记录锥体神经元的自发GABA能活动。与对照组相比，FCD 大鼠在出生后第 12 天和第 21 天的α1、2 和 4 亚基表达量减少。与此相一致的是，在 FCD 大鼠中观察到 GABA 能事件的振幅和频率降低。相反，在 P30 和 P65，FCD 大鼠体内观察到 GABA 水平下降，但受体表达没有变化。同样，与对照组相比，FCD 大鼠的 GABA 能事件频率也有所降低。此外，用河豚毒素（TTX）处理后发现，观察到的 GABA 能活动的改变主要依赖于动作电位（AP）。我们的研究结果表明，FCD 在早期和晚期发育阶段存在不同的致痫网络。这些网络主要由改变的GABA能活动驱动，早期的年龄变化与异常的GABAA受体配置有关，晚期的年龄变化则与异常的GABA水平有关。

{"title":"Differential regulation of GABAA receptor-mediated hyperexcitability at different stages of brain development in focal cortical dysplasia (FCD)","authors":"Yogesh Aggarwal , Aparna Banerjee Dixit , Fouzia Siraj , Manjari Tripathi , P. Sarat Chandra , Jyotirmoy Banerjee","doi":"10.1016/j.expneurol.2025.115265","DOIUrl":"10.1016/j.expneurol.2025.115265","url":null,"abstract":"<div><div>Focal cortical dysplasia (FCD) is a developmental abnormality of cortex commonly linked with drug-resistant seizures. Altered GABAergic activity is a key contributor to interictal discharges in FCD. In FCD, GABA<sub>A</sub> receptor associated epileptogenicity is dependent upon the age at seizure onset, as differential epileptogenic networks are observed in early and late onset FCD patients. But the contribution of GABA<sub>A</sub> receptor alteration to epileptogenic networks during development is unclear. We hypothesize that GABAergic signaling in FCD undergoes age-dependent molecular alterations, contributing to the development of distinct epileptogenic networks. In this study, we investigated age-dependent changes in GABA neurotransmitter levels, GABA<sub>A</sub> receptor α subunit expression, and GABA<sub>A</sub> receptor-mediated synaptic activity using the BCNU-rat model of FCD. GABA levels, mRNA, and protein expression of GABA<sub>A</sub> receptor α subunits were determined by HPLC, qPCR and western blot and spontaneous GABAergic activity from pyramidal neurons was recorded using whole cell patch-clamp technique. At postnatal days (P) 12 and 21, reduced expression of α1, 2 and 4 subunits were observed in FCD rats compared to control. Consistent with this, decreased amplitude and frequency of GABAergic events were observed in FCD rats. In contrast, at P30 and P65, decreased GABA levels, without changes in receptor expression, were observed in FCD rats. Consistently, reduction in the frequency of GABAergic events was observed in FCD rats compared to the control. Furthermore, treatment with tetrodotoxin (TTX) revealed that the observed alterations in GABAergic activity were predominantly action potential (AP)-dependent. Our findings indicate that distinct epileptogenic networks exist in FCD during early and late developmental stages. These networks are driven primarily by altered GABAergic activity, with early age changes linked to aberrant GABA<sub>A</sub> receptor configurations and late age changes associated with abnormal GABA levels.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115265"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839405","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}

引用次数: 0

Dynamic changes of hippocampal dendritic spines in Alzheimer's disease mice among the different stages

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-04-15 DOI: 10.1016/j.expneurol.2025.115266

Jing Ren , Yimeng Wang , Yinuo Wang , Yiping Zhang , Mu Xing , Shouzhe Deng , Siyi Tong , Ling Wang , Chenguang Zheng , Jiajia Yang , Guangjian Ni , Dong Ming

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides and a progressive decline in cognitive function. Hippocampus as a crucial brain area for learning and memory, is also adversely affected by AD's pathology. The accumulation of Aβ is often associated with the loss of dendritic spines of the hippocampus. However, the dynamic alterations in dendritic spines throughout AD progression are not fully understood. To investigate it, we conducted in-vivo imaging in two mouse models representing the early and late stages of AD pathology: young mice injected with Aβ₁_–₄₂ oligomers and APP/PS1 transgenic mice. In the early-stage AD model, imaging was conducted at third- and fifth- weeks post-injection. In the late-stage AD model, a four-month imaging began at 14 months old. The imaging results showed spine elimination in both models. Notably, acute Aβ exposure was linked to heightened spine loss on secondary dendrites, while in the late stage the primary effect was on tertiary dendrites. Concurrently, with the metabolism of Aβ, cognition recovered to some extent by five weeks post Aβ₁_–₄₂ exposure. These findings suggested that dendritic spine plasticity was impaired during the development of AD, as evidenced by increasing spine loss at different levels. However, the cognitive recovery observed in early-stage AD model mice may indicate a compensatory structural reorganization, highlighting the potential of early intervention to mitigate disease progression. Our results provide novel insights into the neurotoxic effects of Aβ₁_–₄₂ and may contribute to the development of therapeutic strategies for AD.

{"title":"Dynamic changes of hippocampal dendritic spines in Alzheimer's disease mice among the different stages","authors":"Jing Ren , Yimeng Wang , Yinuo Wang , Yiping Zhang , Mu Xing , Shouzhe Deng , Siyi Tong , Ling Wang , Chenguang Zheng , Jiajia Yang , Guangjian Ni , Dong Ming","doi":"10.1016/j.expneurol.2025.115266","DOIUrl":"10.1016/j.expneurol.2025.115266","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides and a progressive decline in cognitive function. Hippocampus as a crucial brain area for learning and memory, is also adversely affected by AD's pathology. The accumulation of Aβ is often associated with the loss of dendritic spines of the hippocampus. However, the dynamic alterations in dendritic spines throughout AD progression are not fully understood. To investigate it, we conducted in-vivo imaging in two mouse models representing the early and late stages of AD pathology: young mice injected with Aβ<sub>1</sub><sub>–</sub><sub>42</sub> oligomers and APP/PS1 transgenic mice. In the early-stage AD model, imaging was conducted at third- and fifth- weeks post-injection. In the late-stage AD model, a four-month imaging began at 14 months old. The imaging results showed spine elimination in both models. Notably, acute Aβ exposure was linked to heightened spine loss on secondary dendrites, while in the late stage the primary effect was on tertiary dendrites. Concurrently, with the metabolism of Aβ, cognition recovered to some extent by five weeks post Aβ<sub>1</sub><sub>–</sub><sub>42</sub> exposure. These findings suggested that dendritic spine plasticity was impaired during the development of AD, as evidenced by increasing spine loss at different levels. However, the cognitive recovery observed in early-stage AD model mice may indicate a compensatory structural reorganization, highlighting the potential of early intervention to mitigate disease progression. Our results provide novel insights into the neurotoxic effects of Aβ<sub>1</sub><sub>–</sub><sub>42</sub> and may contribute to the development of therapeutic strategies for AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115266"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864355","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}

引用次数: 0