Experimental Neurology最新文献

{"title":"Neuroprotective roles of SGLT2 and DPP4 inhibitors: Modulating ketone metabolism and suppressing NLRP3 inflammasome in T2D induced Alzheimer's disease","authors":"A Young Sim ,&nbsp;Jong Youl Kim ,&nbsp;Yong-ho Lee ,&nbsp;Jong Eun Lee","doi":"10.1016/j.expneurol.2025.115271","DOIUrl":"10.1016/j.expneurol.2025.115271","url":null,"abstract":"<div><div>Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) are known to ameliorate Alzheimer's disease (AD)-like pathology and cognitive decline through distinct mechanisms. In this study, we investigated how these antidiabetic drugs elevate ketone levels and subsequently reduce amyloid-β (Aβ) and tau pathology via the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in microglia, using a type 2 diabetes (T2D)-AD mouse model.</div><div>Male C57BL/6 mice were fed a high-fat diet and injected with low doses of streptozotocin to establish a T2D-AD model. The mice were then treated with either SGLT2-i or DPP4-i. Our results revealed that both the inhibitors markedly enhanced brain ketone metabolism by upregulating key metabolic enzymes and transporters. They also reduced neuroinflammation by suppressing the expression of pro-inflammatory cytokines, such as IL-1β, and increasing the expression of the anti-inflammatory cytokine IL-4. A critical mechanism for this anti-inflammatory effect involved the inhibition of the expression of the NLRP3 inflammasome, a key driver of neuroinflammation. Notably, SGLT2-i appeared to inhibit NLRP3 inflammasome expression by disrupting the pTau-CX3C1 interaction, whereas DPP4-i exerted its effects through the Aβ-TLR4-NF-κB pathway.</div><div>Moreover, our results showed that both the inhibitors promoted a shift in microglial activation from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, as indicated by the changes in CD206 and CD86 expression.</div><div>These findings suggest that SGLT2-i and DPP4-i provide neuroprotective benefits through multiple mechanisms, including enhanced ketone metabolism, reduced neuroinflammation, and modulation of microglial activity in T2D-AD mouse model. This research offers a scientific basis for considering these inhibitors as potential therapeutic agents for neurodegenerative diseases, particularly in cognitive impairment patients with metabolic dysfunction.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115271"},"PeriodicalIF":4.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900338","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":"Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques","authors":"Sarah Kaye ,&nbsp;Andrew Gold ,&nbsp;Da Lin ,&nbsp;Min Chen ,&nbsp;Jiangjiang Zhu ,&nbsp;Jie Gao","doi":"10.1016/j.expneurol.2025.115272","DOIUrl":"10.1016/j.expneurol.2025.115272","url":null,"abstract":"<div><div>Hypercholesterolemia is a recognized comorbidity of Alzheimer's disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APP^NL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APP^NL-G-F;LDLR^−/− (AL^KO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a control diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115272"},"PeriodicalIF":4.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891277","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":"Atlas of temporal molecular pathological alterations after traumatic brain injury based on RNA-Seq","authors":"Yulian Zhang ,&nbsp;Kun He ,&nbsp;Chuanpeng Zhang ,&nbsp;Hanhan Dang ,&nbsp;Junru Hei ,&nbsp;Yunsheng Zhang ,&nbsp;Pengyu Chen ,&nbsp;Ze Zhang ,&nbsp;Yanbo Yang ,&nbsp;Zixi Wang ,&nbsp;Xu Yang ,&nbsp;Li Zhang ,&nbsp;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}

{"title":"Protective effects of Salidroside against ferroptosis through PPARG-dependent mechanism in diabetes-related cognitive impairment","authors":"Shengxue Yu ,&nbsp;Wenqiang Liu","doi":"10.1016/j.expneurol.2025.115261","DOIUrl":"10.1016/j.expneurol.2025.115261","url":null,"abstract":"<div><h3>Objective</h3><div>This study focused on investigating the benefits and potential mechanism of Sal in Leptin gene knockout mice (db/db) and primary hippocampal neurons.</div></div><div><h3>Methods</h3><div>In the current investigation, male db/db mice were administered Sal via oral gavage. Cognitive functions and learning and memory capacities were assessed through the Morris Water Maze (MWM) tests, respectively. Nissl, Fluoro-Jade C (FJC) staining techniques were employed to gauge hippocampal neuronal damage. Transmission electron microscopy facilitated the observation of mitochondrial alterations within hippocampal neurons of db/db mice. We further quantified Fe²⁺ levels, oxidative stress, and lipid peroxidation both in vivo &amp; vitro. Western blotting got utilized to ascertain the relative levels of GPX4, PPARG, Nrf2 protein expressions.</div></div><div><h3>Results</h3><div>According to the study results, Sal supplement could dramatically relieve db/db mice’ cognitive impairment and protect neurons, through the inhibition of oxidative stress and the reduction of neuronal ferroptosis. According to further research, Sal could achieve a direct binding with peroxisome proliferator-activated receptor gamma (PPARG) for promoting it to be expressed. When culturing hippocampus-derived primary neurons, adding PPARG antagonist GW9662 or Nrf2 antagonist ML385 could eliminate the effect of Sal.</div></div><div><h3>Conclusion</h3><div>Taken together, the study is the first one that demonstrates the effectiveness of Sal in improving the cognitive impairment deficits of db/db mice as well as its inhibitory effect on oxidative stress and neuronal ferroptosis via PPARG-dependent mechanism.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115261"},"PeriodicalIF":4.6,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881632","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":"Edaravone ameliorates inflammation in ischemic stroke mouse by regulating the CYP1A1 pathway through gut microbiota","authors":"Yuan Zhang ,&nbsp;Xiaojing Jiao ,&nbsp;Xiaoying Qi ,&nbsp;Guangtian Wang ,&nbsp;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}

{"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 ,&nbsp;Helen M. Bramlett ,&nbsp;Juliana Sanchez-Molano ,&nbsp;Alfredo Fernandez Higueras ,&nbsp;Winston Walters ,&nbsp;Juan Pablo de Rivero Vaccari ,&nbsp;Robert W. Keane ,&nbsp;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}

{"title":"Lipocalin 2 mediates kidney function abnormalities induced by ischemic stroke in mice: Involvement of neural pathways","authors":"Pu Hong ,&nbsp;Dong-Xiao Yang ,&nbsp;Ye-Hao Xu ,&nbsp;Meng-Jiao He ,&nbsp;Xi Chen ,&nbsp;Fengxian Li ,&nbsp;Shi-Yuan Xu ,&nbsp;Hong-Fei Zhang","doi":"10.1016/j.expneurol.2025.115267","DOIUrl":"10.1016/j.expneurol.2025.115267","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 <em>Lcn2</em>-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.</div></div><div><h3>Conclusions</h3><div>These findings reveal a neural pathway in which the sympathetic nervous system upregulates LCN2, providing potential therapeutic strategies for renal protection following ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115267"},"PeriodicalIF":4.6,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844249","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":"Fasudil mitigates diabetes-associated cognitive decline and enhances neuroprotection by suppressing NLRP3/Caspase-1/GSDMD signaling in a stroke mouse model","authors":"Mohd. Salman ,&nbsp;Hiba Shahzad ,&nbsp;Rajashekhar Gangaraju ,&nbsp;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}

{"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 ,&nbsp;Jiahang Tang ,&nbsp;You Xiang ,&nbsp;Xinying Shang ,&nbsp;Kunlin Li ,&nbsp;Lijia Chen ,&nbsp;Junnan Hu ,&nbsp;Han Li ,&nbsp;Yanxiong Pi ,&nbsp;Haiyan Yang ,&nbsp;Huijia Zhang ,&nbsp;Heng Tan ,&nbsp;Yanbin Xiyang ,&nbsp;Huiyan Jin ,&nbsp;Xia Li ,&nbsp;Manjun Chen ,&nbsp;Rongrong Mao ,&nbsp;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}

{"title":"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","authors":"Peng Wang ,&nbsp;Xuewei Song ,&nbsp;Jinlong Qiu ,&nbsp;Xiyan Zhu ,&nbsp;Pengfei Wu ,&nbsp;Zhikang Liao ,&nbsp;Jingru Xie ,&nbsp;Nan Wang ,&nbsp;Hui Zhao","doi":"10.1016/j.expneurol.2025.115259","DOIUrl":"10.1016/j.expneurol.2025.115259","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"389 ","pages":"Article 115259"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844269","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}