Pub Date : 2025-12-20DOI: 10.1016/j.brainresbull.2025.111693
Shuangkai Li , Xiang Li Jr , Lu Peng , Haojie Ding , Xuan Shi , Jiale Liu , Haiying Li , Jianguo Xu , Qing Sun
Neuroinflammation mediated by microglial hyperactivation represents a pivotal pathological mechanism exacerbating neuronal damage following cerebral ischemia. Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays a crucial regulatory role in metabolic and inflammatory processes. However, its specific function in post-ischemic neuroinflammation remains incompletely understood. This study found that SCD1 was highly expressed in the penumbra region following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Then, we systematically evaluated the role of SCD1 in regulating neuroinflammation after cerebral ischemia–reperfusion and explored its underlying mechanisms through administrating SCD1-specific inhibitor CAY10566. Results showed that CAY10566 significantly reduced level of pro-inflammatory cytokines and infarct volume after cerebral ischemia–reperfusion. Furthermore,suppression of SCD1 also alleviated neuronal apoptosis and improved cognitive and motor functions after ischemic stroke Mechanistically, the modulation of the NF-κB signaling pathway by SCD1 may involve the participation of TNFR1. Collectively, these findings suggested that the SCD1 may serve as a critical checkpoint regulating NF-κB signaling in cerebral ischemia–reperfusion injury. Targeting SCD1 may represent a promising therapeutic strategy for ischemic stroke.
{"title":"Inhibition of SCD1 attenuates neuroinflammation and brain injury after cerebral ischemia-reperfusion","authors":"Shuangkai Li , Xiang Li Jr , Lu Peng , Haojie Ding , Xuan Shi , Jiale Liu , Haiying Li , Jianguo Xu , Qing Sun","doi":"10.1016/j.brainresbull.2025.111693","DOIUrl":"10.1016/j.brainresbull.2025.111693","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglial hyperactivation represents a pivotal pathological mechanism exacerbating neuronal damage following cerebral ischemia. Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays a crucial regulatory role in metabolic and inflammatory processes. However, its specific function in post-ischemic neuroinflammation remains incompletely understood. This study found that SCD1 was highly expressed in the penumbra region following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Then, we systematically evaluated the role of SCD1 in regulating neuroinflammation after cerebral ischemia–reperfusion and explored its underlying mechanisms through administrating SCD1-specific inhibitor CAY10566. Results showed that CAY10566 significantly reduced level of pro-inflammatory cytokines and infarct volume after cerebral ischemia–reperfusion. Furthermore,suppression of SCD1 also alleviated neuronal apoptosis and improved cognitive and motor functions after ischemic stroke Mechanistically, the modulation of the NF-κB signaling pathway by SCD1 may involve the participation of TNFR1. Collectively, these findings suggested that the SCD1 may serve as a critical checkpoint regulating NF-κB signaling in cerebral ischemia–reperfusion injury. Targeting SCD1 may represent a promising therapeutic strategy for ischemic stroke.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111693"},"PeriodicalIF":3.7,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.brainresbull.2025.111698
Ge Wang, Qisheng Tang, Dan Wang
Background: The gut-brain axis (GBA) has been increasingly recognized as a potential contributor to anxiety pathophysiology. Puerarin possesses anti-inflammatory, antioxidant, and neuroprotective properties, but its anxiolytic mechanism via the GBA remains unclear. The intervention of puerarin on lipopolysaccharide (LPS)-induced anxiety-like behavior (ALB) in mice was investigated based on the GBA theory.
Methods: Forty mice were allocated at random: control, LPS, LPS+PueL (low-dose puerarin), and LPS+PueH (high-dose puerarin) groups (n = 10 each). ALB was evaluated by the elevated plus maze (EPM). Inflammatory cytokines were measured by ELISA. Tight junction proteins were detected by qPCR and Western blot. Gut microbiota (GM) was analyzed by 16S rRNA sequencing.
Results: Compared with the Control, open arm entries (OAE) and open arm time (OAT) were decreased, inflammatory cytokine levels were elevated, intestinal tight junction protein expression was down-regulated, microbial diversity was reduced, and the abundance of pro-inflammatory bacterial genera was obviously increased in the LPS. In the LPS+PueH, OAE and OAT, inflammatory cytokine levels, tight junction protein expression, microbial diversity, and abundance of beneficial bacterial genera were evidently improved (P < 0.05). Correlation analysis revealed that Lactobacillus and Akkermansia were positively correlated with OAE and OAT, whereas Escherichia-Shigella was negatively correlated (P < 0.05).
Conclusion: Puerarin alleviated LPS-induced ALB in mice by suppressing neuroinflammation, restoring intestinal barrier integrity, and modulating GM balance, which was closely associated with GBA regulation.
{"title":"Exploring the Mechanism by Which Puerarin Inhibits Neuroinflammation and Alleviates Lipopolysaccharide-Induced Anxiety-Like Behavior in Mice via Modulating Gut Microbiota Based on the Brain-Gut Axis Theory.","authors":"Ge Wang, Qisheng Tang, Dan Wang","doi":"10.1016/j.brainresbull.2025.111698","DOIUrl":"https://doi.org/10.1016/j.brainresbull.2025.111698","url":null,"abstract":"<p><strong>Background: </strong>The gut-brain axis (GBA) has been increasingly recognized as a potential contributor to anxiety pathophysiology. Puerarin possesses anti-inflammatory, antioxidant, and neuroprotective properties, but its anxiolytic mechanism via the GBA remains unclear. The intervention of puerarin on lipopolysaccharide (LPS)-induced anxiety-like behavior (ALB) in mice was investigated based on the GBA theory.</p><p><strong>Methods: </strong>Forty mice were allocated at random: control, LPS, LPS+PueL (low-dose puerarin), and LPS+PueH (high-dose puerarin) groups (n = 10 each). ALB was evaluated by the elevated plus maze (EPM). Inflammatory cytokines were measured by ELISA. Tight junction proteins were detected by qPCR and Western blot. Gut microbiota (GM) was analyzed by 16S rRNA sequencing.</p><p><strong>Results: </strong>Compared with the Control, open arm entries (OAE) and open arm time (OAT) were decreased, inflammatory cytokine levels were elevated, intestinal tight junction protein expression was down-regulated, microbial diversity was reduced, and the abundance of pro-inflammatory bacterial genera was obviously increased in the LPS. In the LPS+PueH, OAE and OAT, inflammatory cytokine levels, tight junction protein expression, microbial diversity, and abundance of beneficial bacterial genera were evidently improved (P < 0.05). Correlation analysis revealed that Lactobacillus and Akkermansia were positively correlated with OAE and OAT, whereas Escherichia-Shigella was negatively correlated (P < 0.05).</p><p><strong>Conclusion: </strong>Puerarin alleviated LPS-induced ALB in mice by suppressing neuroinflammation, restoring intestinal barrier integrity, and modulating GM balance, which was closely associated with GBA regulation.</p>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":" ","pages":"111698"},"PeriodicalIF":3.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.brainresbull.2025.111696
Yajing Si , Yunmeng Bai , Bingke Liu , Jiaxin Wang , Simin Cai , Wenjing Zhong , Haiqi Zheng , Nan Zhao , Jicheng Liu , Hongxing Zhang
Schizophrenia (SZ) is a serious and disabling mental illness characterized by compromised brain network interactions. The current study investigated the potential associations between the resting-state electroencephalogram (EEG) and individual cognitive traits/clinical recordings in SZ patients. Furthermore, the positive and negative syndrome scale (PANSS) scores based on the connectivity revealed in the resting-state EEG and working memory (WM) when SZ patients participated in the visual-spatial WM task were predicted. The results demonstrated that stronger frontal-parietal linkages for the SZ group were associated with lower response accuracy compared to the HC group in the alpha and beta frequency bands during the resting-state process. There were significant relationships between PANSS scores and the resting-state network properties; increased PANSS scores were accompanied by a larger clustering coefficient, as well as global and local efficiency, and shorter characteristic path length. Moreover, based on the built multivariable linear regression model, the PANSS scores were predicted accurately, as indicated by a rather large correlation coefficient between predicted and actual PANSS scores in the SZ group. Current findings may deepen our knowledge of SZ and accelerate progress in early diagnosis and intervention approaches.
{"title":"Examining clinical symptoms in schizophrenia based on visual-spatial working memory and resting-state EEG","authors":"Yajing Si , Yunmeng Bai , Bingke Liu , Jiaxin Wang , Simin Cai , Wenjing Zhong , Haiqi Zheng , Nan Zhao , Jicheng Liu , Hongxing Zhang","doi":"10.1016/j.brainresbull.2025.111696","DOIUrl":"10.1016/j.brainresbull.2025.111696","url":null,"abstract":"<div><div>Schizophrenia (SZ) is a serious and disabling mental illness characterized by compromised brain network interactions. The current study investigated the potential associations between the resting-state electroencephalogram (EEG) and individual cognitive traits/clinical recordings in SZ patients. Furthermore, the positive and negative syndrome scale (PANSS) scores based on the connectivity revealed in the resting-state EEG and working memory (WM) when SZ patients participated in the visual-spatial WM task were predicted. The results demonstrated that stronger frontal-parietal linkages for the SZ group were associated with lower response accuracy compared to the HC group in the alpha and beta frequency bands during the resting-state process. There were significant relationships between PANSS scores and the resting-state network properties; increased PANSS scores were accompanied by a larger clustering coefficient, as well as global and local efficiency, and shorter characteristic path length. Moreover, based on the built multivariable linear regression model, the PANSS scores were predicted accurately, as indicated by a rather large correlation coefficient between predicted and actual PANSS scores in the SZ group. Current findings may deepen our knowledge of SZ and accelerate progress in early diagnosis and intervention approaches.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111696"},"PeriodicalIF":3.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145787838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.brainresbull.2025.111692
Wenxiu Li , Jianhua Jiang , Yizhen Weng , Lulu Zhang , Quanquan Zhang , Xinyi He , Xiang Li, Sr , Xiang Tang
MicroRNAs (miRNAs) are key regulators of myelination and cognitive functions, with miR-219 being particularly important for the differentiation and maturation of oligodendrocyte precursor cells (OPCs). However, its role in myelin damage and cognitive dysfunction during acute cerebral ischemia is not well understood. In this study, we used the MCAO/R rat model to investigate the mechanistic involvement of miR-219. Our results show that miR-219 alleviates cognitive dysfunction induced by MCAO/R. The agonist group showed a reduced time to locate the platform in the water maze, while the antagonist group showed an increased time compared to the solvent control. Additionally, miR-219 reduced myelin damage, as demonstrated by Luxol Fast Blue (LFB) staining, which indicated substantial hippocampal demyelination repair in the agonist group, whereas the antagonist group exhibited aggravated demyelination. Electron microscopy revealed enhanced myelin sheath regeneration and increased thickness in the agonist group, while the antagonist group displayed fewer and thinner myelin sheaths. Furthermore, miR-219 regulated OPC maturation, with more CNPase-positive cells in the agonist group and fewer in the antagonist group than the solvent control. In NG2 staining, the agonist group had fewer positive cells, while the antagonist group had more. miR-219 also decreased Lingo-1 expression, leading to reduced levels of AKT, RhoA, and mTOR in the downstream signaling pathway. These findings suggest that activating the miR-219–Lingo-1 signaling pathway during ischemia-reperfusion could offer a potential therapeutic approach for improving myelin damage and alleviating cognitive dysfunction in cerebral ischemia.
MicroRNAs （miRNAs）是髓鞘形成和认知功能的关键调节因子，其中miR-219对少突胶质前体细胞（OPCs）的分化和成熟尤为重要。然而，其在急性脑缺血时髓磷脂损伤和认知功能障碍中的作用尚不清楚。在这项研究中，我们使用MCAO/R大鼠模型来研究miR-219的机制参与。我们的研究结果表明miR-219可以缓解MCAO/R诱导的认知功能障碍。与溶剂对照组相比，激动剂组在水迷宫中定位平台的时间缩短，而拮抗剂组在水迷宫中定位平台的时间增加。此外，Luxol Fast Blue （LFB）染色显示，miR-219减少了髓鞘损伤，这表明激动剂组海马脱髓鞘修复明显，而拮抗剂组脱髓鞘恶化。电镜显示激动剂组髓鞘再生增强，厚度增加，而拮抗剂组髓鞘数量减少，厚度变薄。此外，miR-219调节OPC成熟，与溶剂对照相比，激动剂组cnpase阳性细胞较多，拮抗剂组cnpase阳性细胞较少。NG2染色中，激动剂组阳性细胞较少，而拮抗剂组阳性细胞较多。miR-219也降低了Lingo-1的表达，导致下游信号通路中AKT、RhoA和mTOR的水平降低。这些发现表明，在缺血-再灌注过程中激活miR-219-Lingo-1信号通路可能为改善脑缺血髓磷脂损伤和减轻认知功能障碍提供潜在的治疗途径。
{"title":"miR-219 ameliorates myelin impairment and cognitive function deficits in the early stage of MCAO/R rats","authors":"Wenxiu Li , Jianhua Jiang , Yizhen Weng , Lulu Zhang , Quanquan Zhang , Xinyi He , Xiang Li, Sr , Xiang Tang","doi":"10.1016/j.brainresbull.2025.111692","DOIUrl":"10.1016/j.brainresbull.2025.111692","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) are key regulators of myelination and cognitive functions, with miR-219 being particularly important for the differentiation and maturation of oligodendrocyte precursor cells (OPCs). However, its role in myelin damage and cognitive dysfunction during acute cerebral ischemia is not well understood. In this study, we used the MCAO/R rat model to investigate the mechanistic involvement of miR-219. Our results show that miR-219 alleviates cognitive dysfunction induced by MCAO/R. The agonist group showed a reduced time to locate the platform in the water maze, while the antagonist group showed an increased time compared to the solvent control. Additionally, miR-219 reduced myelin damage, as demonstrated by Luxol Fast Blue (LFB) staining, which indicated substantial hippocampal demyelination repair in the agonist group, whereas the antagonist group exhibited aggravated demyelination. Electron microscopy revealed enhanced myelin sheath regeneration and increased thickness in the agonist group, while the antagonist group displayed fewer and thinner myelin sheaths. Furthermore, miR-219 regulated OPC maturation, with more CNPase-positive cells in the agonist group and fewer in the antagonist group than the solvent control. In NG2 staining, the agonist group had fewer positive cells, while the antagonist group had more. miR-219 also decreased Lingo-1 expression, leading to reduced levels of AKT, RhoA, and mTOR in the downstream signaling pathway. These findings suggest that activating the miR-219–Lingo-1 signaling pathway during ischemia-reperfusion could offer a potential therapeutic approach for improving myelin damage and alleviating cognitive dysfunction in cerebral ischemia.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111692"},"PeriodicalIF":3.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Language impairments in post-stroke aphasia (PSA) relate to reorganizations of brain structural and functional networks. While anomalies in multiple single network parameters are increasingly reported, structural-functional (S-F) coupling has not yet been explored in PSA.
Methods
A total of 52 patients with PSA and 55 age-, sex-, and education-matched normal controls (NCs) were recruited. Firstly, structural connectivity (SC) and functional connectivity (FC) networks were constructed using diffusion kurtosis imaging (DKI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively. Subsequently, graph theoretical analysis was used to evaluate the global and nodal topological properties, followed by multiscale S-F coupling calculations.
Finally, partial correlation analysis was applied to investigate the relationships among the network topological properties, S-F coupling, and the western aphasia battery (WAB) scores in patients with PSA.
Results
Compared to NCs, PSA patients showed disrupted SC global topology: reduced global efficiency (Eglob), local efficiency (Eloc), clustering coefficient (Cp), and increased characteristic path length (Lp). No significant FC global differences emerged. Nodal SC properties were widely decreased, while FC exhibited hemispheric asymmetry with decreases in the left hemisphere and increases in the right. PSA patients had reduced whole-brain S-F coupling and decoupling in limbic (LN), default mode (DMN), somatomotor (SMN), and frontoparietal (FPN) networks. Notably, FPN S-F coupling was positively correlated with the aphasia quotient (AQ) of the WAB.
Conclusion
This study reveals asymmetric disruption of network topology properties and multiscale S-F decoupling in patients with PSA, highlighting the potential of S-F coupling in the FPN as a neuroimaging marker for predicting language recovery.
{"title":"Disrupted brain network topology and structural-functional decoupling in chronic post-stroke aphasia","authors":"Guihua Xu , Yongsheng Wu , Rui Zhu , Junyu Qu , Wenwen Xu , Jiaxiang Xin , Dawei Wang","doi":"10.1016/j.brainresbull.2025.111691","DOIUrl":"10.1016/j.brainresbull.2025.111691","url":null,"abstract":"<div><h3>Objective</h3><div>Language impairments in post-stroke aphasia (PSA) relate to reorganizations of brain structural and functional networks. While anomalies in multiple single network parameters are increasingly reported, structural-functional (S-F) coupling has not yet been explored in PSA.</div></div><div><h3>Methods</h3><div>A total of 52 patients with PSA and 55 age-, sex-, and education-matched normal controls (NCs) were recruited. Firstly, structural connectivity (SC) and functional connectivity (FC) networks were constructed using diffusion kurtosis imaging (DKI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively. Subsequently, graph theoretical analysis was used to evaluate the global and nodal topological properties, followed by multiscale S-F coupling calculations.</div><div>Finally, partial correlation analysis was applied to investigate the relationships among the network topological properties, S-F coupling, and the western aphasia battery (WAB) scores in patients with PSA.</div></div><div><h3>Results</h3><div>Compared to NCs, PSA patients showed disrupted SC global topology: reduced global efficiency (Eglob), local efficiency (Eloc), clustering coefficient (Cp), and increased characteristic path length (Lp). No significant FC global differences emerged. Nodal SC properties were widely decreased, while FC exhibited hemispheric asymmetry with decreases in the left hemisphere and increases in the right. PSA patients had reduced whole-brain S-F coupling and decoupling in limbic (LN), default mode (DMN), somatomotor (SMN), and frontoparietal (FPN) networks. Notably, FPN S-F coupling was positively correlated with the aphasia quotient (AQ) of the WAB.</div></div><div><h3>Conclusion</h3><div>This study reveals asymmetric disruption of network topology properties and multiscale S-F decoupling in patients with PSA, highlighting the potential of S-F coupling in the FPN as a neuroimaging marker for predicting language recovery.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111691"},"PeriodicalIF":3.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.brainresbull.2025.111688
Joana Garmendia , Garazi Labayru , Ainhoa Alberro , Laura Martins-Almeida , David Otaegui , Pablo Iruzubieta , Adolfo Lopez de Munain , Andone Sistiaga
Introduction
Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disease affecting the central nervous system (CNS). Blood-based biomarkers such as neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and interleukin-6 (IL-6) offer potential as non-invasive indicators of CNS dysfunction and/or inflammation. However, their longitudinal dynamics and clinical relevance in DM1 remain unclear. Additionally, sex-related differences in these biomarkers are poorly understood. This study aimed to investigate NFL, GFAP, and IL-6 serum levels in patients with DM1, examine sex-differences, track changes over four years, and explore associations with genetic, muscular, cognitive, and neuroimaging outcomes.
Method
Retrospective data from 70 DM1 patients and 54 healthy controls (HC) were analyzed. Longitudinal data were available for 68 participants (39 DM1, 29 HC). Biomarkers were measured using the ELLA immunoassay. DM1 patients had data on genetic, muscular, cognitive and structural brain outcomes. Analyses were adjusted for age.
Results
NFL and IL-6 levels were significantly higher in DM1 patients compared to HC, while GFAP levels did not differ. Male DM1 patients exhibited higher NFL and IL-6 levels compared to females. No significant longitudinal changes were observed over a four-year period. NFL and IL-6 levels correlated with larger genetic expansions and poorer cognitive performance.
Discussion
NFL and IL-6 may reflect neural damage and systemic inflammation in DM1 and could serve as biomarkers of cognitive dysfunction. However, their limited longitudinal sensitivity suggests longer follow-up is needed to evaluate their utility for disease monitoring.
{"title":"Neural damage and inflammation in myotonic dystrophy type 1: Longitudinal analysis of serum NFL, GFAP, and IL-6","authors":"Joana Garmendia , Garazi Labayru , Ainhoa Alberro , Laura Martins-Almeida , David Otaegui , Pablo Iruzubieta , Adolfo Lopez de Munain , Andone Sistiaga","doi":"10.1016/j.brainresbull.2025.111688","DOIUrl":"10.1016/j.brainresbull.2025.111688","url":null,"abstract":"<div><h3>Introduction</h3><div>Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disease affecting the central nervous system (CNS). Blood-based biomarkers such as neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and interleukin-6 (IL-6) offer potential as non-invasive indicators of CNS dysfunction and/or inflammation. However, their longitudinal dynamics and clinical relevance in DM1 remain unclear. Additionally, sex-related differences in these biomarkers are poorly understood. This study aimed to investigate NFL, GFAP, and IL-6 serum levels in patients with DM1, examine sex-differences, track changes over four years, and explore associations with genetic, muscular, cognitive, and neuroimaging outcomes.</div></div><div><h3>Method</h3><div>Retrospective data from 70 DM1 patients and 54 healthy controls (HC) were analyzed. Longitudinal data were available for 68 participants (39 DM1, 29 HC). Biomarkers were measured using the ELLA immunoassay. DM1 patients had data on genetic, muscular, cognitive and structural brain outcomes. Analyses were adjusted for age.</div></div><div><h3>Results</h3><div>NFL and IL-6 levels were significantly higher in DM1 patients compared to HC, while GFAP levels did not differ. Male DM1 patients exhibited higher NFL and IL-6 levels compared to females. No significant longitudinal changes were observed over a four-year period. NFL and IL-6 levels correlated with larger genetic expansions and poorer cognitive performance.</div></div><div><h3>Discussion</h3><div>NFL and IL-6 may reflect neural damage and systemic inflammation in DM1 and could serve as biomarkers of cognitive dysfunction. However, their limited longitudinal sensitivity suggests longer follow-up is needed to evaluate their utility for disease monitoring.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111688"},"PeriodicalIF":3.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.brainresbull.2025.111689
Su Gao , Shihui Zhu , Tianyi Qu , Jiahui Zou , Lida Yin , Xuesong Wang , Xiaokun Yin , Lin Tong , Wei Li
Objective
This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models.
Methods
In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings.
Results
In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion.
Conclusion
CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential.
{"title":"Cycloastragenol protected hippocampal CA1 neurons by regulating redox homeostasis and alleviated cognitive impairment following cerebral ischemia-reperfusion","authors":"Su Gao , Shihui Zhu , Tianyi Qu , Jiahui Zou , Lida Yin , Xuesong Wang , Xiaokun Yin , Lin Tong , Wei Li","doi":"10.1016/j.brainresbull.2025.111689","DOIUrl":"10.1016/j.brainresbull.2025.111689","url":null,"abstract":"<div><h3>Objective</h3><div>This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models.</div></div><div><h3>Methods</h3><div><em>In vivo</em>, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. <em>In vitro</em>, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm <em>in vivo</em> findings.</div></div><div><h3>Results</h3><div><em>In vivo</em>, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. <em>In vitro</em>, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion.</div></div><div><h3>Conclusion</h3><div>CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111689"},"PeriodicalIF":3.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.brainresbull.2025.111685
Zhixin Zhang , Xinmiao Xue , Dongdong He , Peng Liu , Chi Zhang , Yvke Jiang , Shuhan Lv , Li Wang , Hanwen Zhou , Weidong Shen , Shiming Yang , Fangyuan Wang
Glutamate receptors regulate neuronal excitability and drive synaptic plasticity in the auditory cortex (AC), with aberrant activation or dysfunction contributing to tinnitus pathogenesis. Photobiomodulation (PBM) exerts sustained modulatory effects on neural activity and behavioral responses across species, including humans. However, its therapeutic potential and mechanisms in noise-induced tinnitus remain unexplored. Here, we developed a noninvasive low-irradiance PBM device to target the AC of animal models, investigating near-infrared light mechanisms for reversing cortical hyperexcitability and restoring synaptic plasticity. In noise-exposed tinnitus models without significant neuronal loss, we observed abnormally elevated GluN1 activation and increased synaptic structural complexity compared to non-tinnitus or sham-exposed controls. Tinnitus models were subjected to PBM interventions with varying parameters (irradiance power: 20/40/80 mW/cm²; exposure duration: 300/600 s). Therapeutic efficacy was validated through auditory brainstem response (ABR), gap-prepulse inhibition of acoustic startle (GPIAS), and prepulse inhibition (PPI) behavioral assays. Fluorescence microscopy of brain sections quantified c-Fos/GluN1 co-localization to image activated NMDARs, while Nissl staining assessed PBM safety across parameters. Phosphoproteomic profiling explored mechanistic pathways, with neuronal morphological changes visualized via Golgi staining and transmission electron microscopy. To confirm GluN1’s pivotal role in auditory cognition, we engineered transgenic mice with GluN1 overexpression or knockdown. GluN1-overexpressing mice exhibited tinnitus-like behaviors at specific frequencies, whereas GluN1-deficient tinnitus models showed aberrant behaviors due to impaired auditory cognition. Our findings delineate noise-induced tinnitus mechanisms and PBM-mediated regulation of neuronal excitability and structural plasticity, establishing an irradiance-duration optimization framework for clinical translation.
{"title":"Reversal of auditory cortical hyperexcitability and restoration of synaptic plasticity balance by GluN1-mediated photobiomodulation in noise-induced tinnitus","authors":"Zhixin Zhang , Xinmiao Xue , Dongdong He , Peng Liu , Chi Zhang , Yvke Jiang , Shuhan Lv , Li Wang , Hanwen Zhou , Weidong Shen , Shiming Yang , Fangyuan Wang","doi":"10.1016/j.brainresbull.2025.111685","DOIUrl":"10.1016/j.brainresbull.2025.111685","url":null,"abstract":"<div><div>Glutamate receptors regulate neuronal excitability and drive synaptic plasticity in the auditory cortex (AC), with aberrant activation or dysfunction contributing to tinnitus pathogenesis. Photobiomodulation (PBM) exerts sustained modulatory effects on neural activity and behavioral responses across species, including humans. However, its therapeutic potential and mechanisms in noise-induced tinnitus remain unexplored. Here, we developed a noninvasive low-irradiance PBM device to target the AC of animal models, investigating near-infrared light mechanisms for reversing cortical hyperexcitability and restoring synaptic plasticity. In noise-exposed tinnitus models without significant neuronal loss, we observed abnormally elevated GluN1 activation and increased synaptic structural complexity compared to non-tinnitus or sham-exposed controls. Tinnitus models were subjected to PBM interventions with varying parameters (irradiance power: 20/40/80 mW/cm²; exposure duration: 300/600 s). Therapeutic efficacy was validated through auditory brainstem response (ABR), gap-prepulse inhibition of acoustic startle (GPIAS), and prepulse inhibition (PPI) behavioral assays. Fluorescence microscopy of brain sections quantified c-Fos/GluN1 co-localization to image activated NMDARs, while Nissl staining assessed PBM safety across parameters. Phosphoproteomic profiling explored mechanistic pathways, with neuronal morphological changes visualized via Golgi staining and transmission electron microscopy. To confirm GluN1’s pivotal role in auditory cognition, we engineered transgenic mice with GluN1 overexpression or knockdown. GluN1-overexpressing mice exhibited tinnitus-like behaviors at specific frequencies, whereas GluN1-deficient tinnitus models showed aberrant behaviors due to impaired auditory cognition. Our findings delineate noise-induced tinnitus mechanisms and PBM-mediated regulation of neuronal excitability and structural plasticity, establishing an irradiance-duration optimization framework for clinical translation.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111685"},"PeriodicalIF":3.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.brainresbull.2025.111686
Conelius Ngwa, Afzal Misrani, Yan Xu, Jingjing Wang, Rodney Ritzel, Fudong Liu
The immune responses to ischemic stroke are subjected to endogenous inhibitory pathways that delimitate the post-stroke inflammation. Among them, the interaction between CD200 and its receptor (CD200R) is increasingly recognized for its role in regulating neuroinflammation across various central nervous system (CNS) disorders. In the present study, we have examined the role of central (brain) vs. peripheral CD200R signaling in acute ischemic stroke using aged bone marrow chimeric (BMC) mice (16–19 months old). These chimeras were generated by transplanting bone marrow from CD200R knockout (KO), green fluorescent protein (GFP), or wild-type (WT) donor mice into irradiated recipient mice, and then subjected to a 45-min transient middle cerebral artery occlusion (MCAO). At three days post-stroke, flow cytometry, ELISA, and immunohistochemistry (IHC) were used to assess immune responses. Infarct volumes and neurobehavioral deficits were also evaluated. We found that T cell infiltration into the brain was significantly greater in KO-to-GFP (central CD200R signaling) compared to GFP-to-KO (peripheral CD200R signaling) mice. KO-to-GFP mice also exhibited significantly higher levels of pro-inflammatory cytokines IL-1β and TNF-α in the ischemic brain than GFP-to-KO chimeras. Correspondingly, KO-to-GFP mice showed significantly larger brain infarct volumes and worse neurobehavior deficits compared to GFP-to-KO chimeras. Together, these findings indicate that the peripheral (not the central) CD200R signaling plays a critical role in controlling post-stroke immune responses and delineating ischemic injury.
{"title":"Peripheral CD200R signaling: A critical regulator of post-stroke inflammation in aged mice","authors":"Conelius Ngwa, Afzal Misrani, Yan Xu, Jingjing Wang, Rodney Ritzel, Fudong Liu","doi":"10.1016/j.brainresbull.2025.111686","DOIUrl":"10.1016/j.brainresbull.2025.111686","url":null,"abstract":"<div><div>The immune responses to ischemic stroke are subjected to endogenous inhibitory pathways that delimitate the post-stroke inflammation. Among them, the interaction between CD200 and its receptor (CD200R) is increasingly recognized for its role in regulating neuroinflammation across various central nervous system (CNS) disorders. In the present study, we have examined the role of central (brain) vs. peripheral CD200R signaling in acute ischemic stroke using aged bone marrow chimeric (BMC) mice (16–19 months old). These chimeras were generated by transplanting bone marrow from CD200R knockout (KO), green fluorescent protein (GFP), or wild-type (WT) donor mice into irradiated recipient mice, and then subjected to a 45-min transient middle cerebral artery occlusion (MCAO). At three days post-stroke, flow cytometry, ELISA, and immunohistochemistry (IHC) were used to assess immune responses. Infarct volumes and neurobehavioral deficits were also evaluated. We found that T cell infiltration into the brain was significantly greater in KO-to-GFP (central CD200R signaling) compared to GFP-to-KO (peripheral CD200R signaling) mice. KO-to-GFP mice also exhibited significantly higher levels of pro-inflammatory cytokines IL-1β and TNF-α in the ischemic brain than GFP-to-KO chimeras. Correspondingly, KO-to-GFP mice showed significantly larger brain infarct volumes and worse neurobehavior deficits compared to GFP-to-KO chimeras. Together, these findings indicate that the peripheral (not the central) CD200R signaling plays a critical role in controlling post-stroke immune responses and delineating ischemic injury.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111686"},"PeriodicalIF":3.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.brainresbull.2025.111687
Qingqin Xu , Junhong Su , Qian Lei , Jinxiu Liu , Jing Wang , Mengyu Yang , Juan Song , Hemu Chen , Jianwei Lu
Background
Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive neuromodulation technique, but its mechanisms in spinal cord injury (SCI) remain unclear. This study investigated the effects and potential mechanisms of rTMS on motor recovery in SCI rats.
Methods
A rat SCI model was established using the modified Allen's method. rTMS treatment was initiated on postoperative Day 2 and administered daily for 56 days. Bioinformatics analysis was first conducted to identify SCI-related genes and signaling pathways. Western blotting, immunofluorescence staining, TUNEL assay, NeuN staining, motor evoked potential (MEP) measurement, hematoxylin-eosin staining, and Basso-Beattie-Bresnahan (BBB) score were performed to evaluate molecular and functional outcomes.
Results
Bioinformatics analysis identifies MAPK-, PI3K/AKT-, and Bcl-2-related genes as potentially involved in SCI pathology. Western blotting reveals that rTMS is associated with lower levels of p-JNK, p-p38 MAPK, Bax, and caspase-3, and with higher levels of p-ERK, p-PI3K, p-AKT, and Bcl-2 (P < 0.001). Immunofluorescence staining shows that rTMS is accompanied by reduced p-JNK and p-p38 MAPK positive cells and increased p-ERK, p-PI3K and p-AKT positive cells (P < 0.001). TUNEL and NeuN staining further suggest reduced neuronal apoptosis in the injured spinal cord. Behavioral and electrophysiological assessments show that rTMS is associated with shorter MEP latencies, higher MEP amplitudes, reduced spinal tissue damage, attenuated muscle atrophy, and improved BBB score (P < 0.001).
Conclusion
rTMS is associated with improvements in motor function and anti-apoptotic molecular changes in SCI rats, possibly via modulation of MAPK and PI3K/AKT signaling pathways, including upregulation of Bcl-2 and downregulation of Bax and caspase-3.
{"title":"Effects of repetitive transcranial magnetic stimulation on apoptosis and MAPK/PI3K-AKT signaling pathways in rats with spinal cord injury","authors":"Qingqin Xu , Junhong Su , Qian Lei , Jinxiu Liu , Jing Wang , Mengyu Yang , Juan Song , Hemu Chen , Jianwei Lu","doi":"10.1016/j.brainresbull.2025.111687","DOIUrl":"10.1016/j.brainresbull.2025.111687","url":null,"abstract":"<div><h3>Background</h3><div>Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive neuromodulation technique, but its mechanisms in spinal cord injury (SCI) remain unclear. This study investigated the effects and potential mechanisms of rTMS on motor recovery in SCI rats.</div></div><div><h3>Methods</h3><div>A rat SCI model was established using the modified Allen's method. rTMS treatment was initiated on postoperative Day 2 and administered daily for 56 days. Bioinformatics analysis was first conducted to identify SCI-related genes and signaling pathways. Western blotting, immunofluorescence staining, TUNEL assay, NeuN staining, motor evoked potential (MEP) measurement, hematoxylin-eosin staining, and Basso-Beattie-Bresnahan (BBB) score were performed to evaluate molecular and functional outcomes.</div></div><div><h3>Results</h3><div>Bioinformatics analysis identifies MAPK-, PI3K/AKT-, and Bcl-2-related genes as potentially involved in SCI pathology. Western blotting reveals that rTMS is associated with lower levels of p-JNK, p-p38 MAPK, Bax, and caspase-3, and with higher levels of p-ERK, p-PI3K, p-AKT, and Bcl-2 (<em>P</em> < 0.001). Immunofluorescence staining shows that rTMS is accompanied by reduced p-JNK and p-p38 MAPK positive cells and increased p-ERK, p-PI3K and p-AKT positive cells (<em>P</em> < 0.001). TUNEL and NeuN staining further suggest reduced neuronal apoptosis in the injured spinal cord. Behavioral and electrophysiological assessments show that rTMS is associated with shorter MEP latencies, higher MEP amplitudes, reduced spinal tissue damage, attenuated muscle atrophy, and improved BBB score (<em>P</em> < 0.001).</div></div><div><h3>Conclusion</h3><div>rTMS is associated with improvements in motor function and anti-apoptotic molecular changes in SCI rats, possibly via modulation of MAPK and PI3K/AKT signaling pathways, including upregulation of Bcl-2 and downregulation of Bax and caspase-3.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111687"},"PeriodicalIF":3.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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