Yulong Liu, Meiling Xia, Xinggao Zhang, Jing Luo, Tianyao Liu, Hong Gong, Jiayin Liu, Mei Chen, Lian Wang, Jinghui Zhao, Meifeng Gong, Yi Luo, Xiaotang Fan
Background
Naringin, a flavanone glycoside (naringenin 7-O-neohesperidose), exhibits a broad range of pharmacological activities, including neuroprotection. However, its effects on autistic-like behavior have not been extensively studied.
Methods
In this investigation, we utilized the autistic BTBR T + tf/J (BTBR) mice to conduct behavioral tests assessing autistic-like phenotypes. We evaluated hippocampal neurogenesis through immunofluorescence and employed molecular biological techniques, along with RNA sequencing, to elucidate the underlying molecular mechanisms.
Results
Our findings revealed that the administration of naringin alleviated autism-associated behaviors in BTBR mice. RNA sequencing analysis indicated that naringin facilitated the recovery of impaired hippocampal neurogenesis in these mice, as evidenced by an increase in doublecortin (DCX)-positive cells and neuronal progenitor cells (NPCs) in the dentate gyrus (DG). Furthermore, we confirmed that the cannabinoid receptor type-1 (CB1) plays a role in the therapeutic effects of naringin.
Conclusions
This research highlights the potential of naringin as a promising treatment option for autism spectrum disorder (ASD) and suggests that targeting hippocampal neurogenesis through the CB1 receptor may be an effective strategy.
柚皮苷是一种黄酮苷（柚皮苷7- o -新橙皮苷），具有广泛的药理活性，包括神经保护作用。然而，它对自闭症样行为的影响尚未得到广泛研究。方法采用自闭BTBR T + tf/J （BTBR）小鼠进行自闭样表型的行为测试。我们通过免疫荧光和分子生物学技术以及RNA测序来评估海马神经发生，以阐明潜在的分子机制。结果研究结果显示，柚皮苷可减轻BTBR小鼠的自闭症相关行为。RNA测序分析表明，柚皮苷促进了这些小鼠受损海马神经发生的恢复，证据是齿状回（DG）中双皮质素（DCX）阳性细胞和神经元祖细胞（npc）的增加。此外，我们证实了大麻素受体1型（CB1）在柚皮苷的治疗效果中起作用。本研究强调了柚皮苷作为自闭症谱系障碍（ASD）治疗的潜力，并表明通过CB1受体靶向海马神经发生可能是一种有效的策略。
{"title":"Naringin Alleviates Autistic-Like Behaviors in BTBR Mice Through Cannabinoid Receptor Type 1-Mediated Restoration of Hippocampal Neurogenesis","authors":"Yulong Liu, Meiling Xia, Xinggao Zhang, Jing Luo, Tianyao Liu, Hong Gong, Jiayin Liu, Mei Chen, Lian Wang, Jinghui Zhao, Meifeng Gong, Yi Luo, Xiaotang Fan","doi":"10.1111/cns.70654","DOIUrl":"https://doi.org/10.1111/cns.70654","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Naringin, a flavanone glycoside (naringenin 7-O-neohesperidose), exhibits a broad range of pharmacological activities, including neuroprotection. However, its effects on autistic-like behavior have not been extensively studied.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this investigation, we utilized the autistic BTBR T + tf/J (BTBR) mice to conduct behavioral tests assessing autistic-like phenotypes. We evaluated hippocampal neurogenesis through immunofluorescence and employed molecular biological techniques, along with RNA sequencing, to elucidate the underlying molecular mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed that the administration of naringin alleviated autism-associated behaviors in BTBR mice. RNA sequencing analysis indicated that naringin facilitated the recovery of impaired hippocampal neurogenesis in these mice, as evidenced by an increase in doublecortin (DCX)-positive cells and neuronal progenitor cells (NPCs) in the dentate gyrus (DG). Furthermore, we confirmed that the cannabinoid receptor type-1 (CB1) plays a role in the therapeutic effects of naringin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This research highlights the potential of naringin as a promising treatment option for autism spectrum disorder (ASD) and suggests that targeting hippocampal neurogenesis through the CB1 receptor may be an effective strategy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70654","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Li, Haohan Lin, Jiayu Liu, Jie Chen, Kaifeng Shen, Ningning Chen, Songyang Xiang, Duan Wang, Nong Xiao, Tingsong Li
Aims
Growing evidence implicates dysfunctional myelin in the pathogenesis of temporal lobe epilepsy (TLE). Connexin 47 (Cx47), an oligodendrocytic gap junction protein, maintains myelin integrity. This study investigates the role of Cx47 in myelin impairment and seizure progression in TLE.
Methods
Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipitation. TLE mice were treated with the CaMKII inhibitor KN93 to evaluate its effects on demyelination and seizure burden.
Results
In a experimental mouse model, phosphorylated Cx47 (p-Cx47) was significantly upregulated, recapitulating a similar trend observed in human TLE tissues. This upregulation was accompanied by marked demyelination in the TLE animals. In mice, increased levels of Cx47 and p-Cx47 were associated with elevated CaMKII and phosphorylated CaMKII (p-CaMKII). The interaction between Cx47 and CaMKII was further confirmed. Moreover, administration of KN93 suppressed the upregulation of Cx47 and p-Cx47, thereby mitigating demyelination and reducing seizure progression.
Conclusions
CaMKII-mediated Cx47 expression and phosphorylation promote demyelination and seizure progression in TLE. Targeting Cx47 phosphorylation may offer a therapeutic strategy for TLE.
{"title":"Cx47 Phosphorylation Exacerbates White Matter Damage and Kainic Acid Induced Epilepsy","authors":"Yi Li, Haohan Lin, Jiayu Liu, Jie Chen, Kaifeng Shen, Ningning Chen, Songyang Xiang, Duan Wang, Nong Xiao, Tingsong Li","doi":"10.1111/cns.70672","DOIUrl":"https://doi.org/10.1111/cns.70672","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Growing evidence implicates dysfunctional myelin in the pathogenesis of temporal lobe epilepsy (TLE). Connexin 47 (Cx47), an oligodendrocytic gap junction protein, maintains myelin integrity. This study investigates the role of Cx47 in myelin impairment and seizure progression in TLE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipitation. TLE mice were treated with the CaMKII inhibitor KN93 to evaluate its effects on demyelination and seizure burden.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In a experimental mouse model, phosphorylated Cx47 (p-Cx47) was significantly upregulated, recapitulating a similar trend observed in human TLE tissues. This upregulation was accompanied by marked demyelination in the TLE animals. In mice, increased levels of Cx47 and p-Cx47 were associated with elevated CaMKII and phosphorylated CaMKII (p-CaMKII). The interaction between Cx47 and CaMKII was further confirmed. Moreover, administration of KN93 suppressed the upregulation of Cx47 and p-Cx47, thereby mitigating demyelination and reducing seizure progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CaMKII-mediated Cx47 expression and phosphorylation promote demyelination and seizure progression in TLE. Targeting Cx47 phosphorylation may offer a therapeutic strategy for TLE.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70672","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhi Zhang, Di Du, Min Song, Jie Li, Xinning Dong, Yiwen Mei, Jinwei Zhang, Ming Zhang, Yuan Ma, Sixun Yu, Haifeng Shu, Xin Chen
Background
Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, characterized by cortical malformations and aberrant neuronal-glial interactions. Recently, the role of Liver X Receptor Beta (LXRβ) in neurodevelopment has attracted considerable attention, although its involvement in FCD pathogenesis remains unclear.
Methods
We established a freezing lesion-cortical dysplasia (FL-CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid-binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity.
Results
LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization.
Conclusion
Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL-CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug-resistant epilepsy.
{"title":"Liver X Receptor Beta Regulates Glial Dynamics and Cortical Network Remodeling in a Freezing Lesion–Cortical Dysplasia Model","authors":"Zhi Zhang, Di Du, Min Song, Jie Li, Xinning Dong, Yiwen Mei, Jinwei Zhang, Ming Zhang, Yuan Ma, Sixun Yu, Haifeng Shu, Xin Chen","doi":"10.1111/cns.70671","DOIUrl":"https://doi.org/10.1111/cns.70671","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, characterized by cortical malformations and aberrant neuronal-glial interactions. Recently, the role of Liver X Receptor Beta (LXRβ) in neurodevelopment has attracted considerable attention, although its involvement in FCD pathogenesis remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We established a freezing lesion-cortical dysplasia (FL-CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid-binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL-CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug-resistant epilepsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70671","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yulong Li, Zhen Sun, Shen Su, Jun Zhao, Yanping Sun
Objective
Compared with healthy individuals, epilepsy patients are more prone to arrhythmias, which may contribute to poor prognosis. To enable early identification of this risk, we developed a clinical prognostic prediction model to assess the risk of arrhythmia comorbidity in epilepsy patients, thereby facilitating timely clinical intervention to improve patient outcomes.
Methods
We retrospectively collected clinical data from epilepsy patients treated at the Affiliated Hospital of Qingdao University between January 2022 and February 2025, including gender, age, medical history, antiseizure medications, electrocardiograms and electroencephalograms. A total of 495 eligible patients were enrolled and randomly divided into development and validation datasets at a 7:3 ratio. Variable selection was performed using LASSO regression with a penalty term, and the selected variables were incorporated into the construction of a logistic regression model. The area under the receiver operating characteristic curve (AUC) and its 95% confidence interval were used to preliminarily evaluate the model's discriminative ability, while cross-validation and bootstrapping were employed to assess its generalizability. Calibration curves and the Brier score were utilized to evaluate the model's calibration, and decision curve analysis was plotted to analyze the net clinical benefit.
Result
The C-indices for the development and validation datasets were 0.737 (95% CI 0.675–0.799) and 0.790 (95% CI: 0.707–0.884), respectively, with an overall C-index of 0.752 (95% CI: 0.701–0.804). The corresponding sensitivity and specificity were 74.6% and 68.1%, respectively. Finally, a nomogram was constructed for the visual presentation of the predictive model.
Conclusion
Our predictive model can accurately assess the risk of arrhythmia comorbidity in epilepsy patients, assisting clinicians in early intervention to improve prognosis.
目的与正常人相比，癫痫患者更容易发生心律失常，导致预后不良。为了尽早发现这种风险，我们建立了一个临床预后预测模型来评估癫痫患者心律失常合并症的风险，从而促进及时的临床干预以改善患者的预后。方法回顾性收集青岛大学附属医院2022年1月至2025年2月收治的癫痫患者的临床资料，包括性别、年龄、病史、抗癫痫药物、心电图和脑电图。共有495名符合条件的患者入组，并按7:3的比例随机分为开发和验证数据集。使用带惩罚项的LASSO回归进行变量选择，并将选择的变量纳入逻辑回归模型的构建中。采用受试者工作特征曲线下面积（AUC）及其95%置信区间初步评价模型的判别能力，采用交叉验证法和自举法评价模型的泛化能力。采用校正曲线和Brier评分评价模型的校正效果，绘制决策曲线分析分析净临床效益。结果开发和验证数据集的c -指数分别为0.737 （95% CI 0.775 ~ 0.799）和0.790 (95% CI 0.707 ~ 0.884)，总c -指数为0.752 （95% CI 0.701 ~ 0.804）。相应的敏感性和特异性分别为74.6%和68.1%。最后，构造了一个nomogram来直观地表示预测模型。结论该预测模型能准确评估癫痫患者发生心律失常合并症的风险，有助于临床医生早期干预，改善预后。
{"title":"Development and Validation of a Model to Predict Secondary Arrhythmia in Patients With Epilepsy","authors":"Yulong Li, Zhen Sun, Shen Su, Jun Zhao, Yanping Sun","doi":"10.1111/cns.70670","DOIUrl":"https://doi.org/10.1111/cns.70670","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Compared with healthy individuals, epilepsy patients are more prone to arrhythmias, which may contribute to poor prognosis. To enable early identification of this risk, we developed a clinical prognostic prediction model to assess the risk of arrhythmia comorbidity in epilepsy patients, thereby facilitating timely clinical intervention to improve patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively collected clinical data from epilepsy patients treated at the Affiliated Hospital of Qingdao University between January 2022 and February 2025, including gender, age, medical history, antiseizure medications, electrocardiograms and electroencephalograms. A total of 495 eligible patients were enrolled and randomly divided into development and validation datasets at a 7:3 ratio. Variable selection was performed using LASSO regression with a penalty term, and the selected variables were incorporated into the construction of a logistic regression model. The area under the receiver operating characteristic curve (AUC) and its 95% confidence interval were used to preliminarily evaluate the model's discriminative ability, while cross-validation and bootstrapping were employed to assess its generalizability. Calibration curves and the Brier score were utilized to evaluate the model's calibration, and decision curve analysis was plotted to analyze the net clinical benefit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>The C-indices for the development and validation datasets were 0.737 (95% CI 0.675–0.799) and 0.790 (95% CI: 0.707–0.884), respectively, with an overall C-index of 0.752 (95% CI: 0.701–0.804). The corresponding sensitivity and specificity were 74.6% and 68.1%, respectively. Finally, a nomogram was constructed for the visual presentation of the predictive model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our predictive model can accurately assess the risk of arrhythmia comorbidity in epilepsy patients, assisting clinicians in early intervention to improve prognosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Effective remyelination in multiple sclerosis (MS) requires both the proliferation of endogenous neural stem cells (NSCs) and their lineage-specific differentiation into oligodendrocyte progenitor cells (OPCs). This study aimed to investigate whether electroacupuncture (EA) promoted NSC proliferation and OPC differentiation via β-endorphin (β-EP)–mediated opioid signaling in a murine model of MS.
Methods
Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice to model MS. EA stimulation was applied daily at the Zusanli (ST36) acupoint. NSC proliferation and OPC differentiation were assessed via immunofluorescence, flow cytometry (FCM), and RT-qPCR. β-EP expression and opioid receptor involvement were evaluated in the hypothalamus and subventricular zone (SVZ). Naloxone, a nonselective opioid receptor antagonist, was used to determine the role of opioid signaling in EA-induced effects.
Results
EA significantly enhanced NSC proliferation and increased the proportion of NSC-derived OPCs in the SVZ of EAE mice. EA treatment improved clinical score, reduced demyelination, and attenuated leukocyte infiltration of the central nervous system (CNS). Mechanistically, EA upregulated β-EP and its precursor pro-opiomelanocortin (POMC), along with opioid receptors μ-opioid receptor (MOR) and κ-opioid receptor (KOR) (encoded by Oprm1 and Oprk1, respectively). Naloxone administration abolished the beneficial effects of EA on NSC behavior and remyelination, confirming the involvement of opioid receptor-dependent β-EP signaling.
Conclusion
EA promotes remyelination in EAE mice by stimulating β-EP-mediated NSC proliferation and OPC differentiation. These findings reveal a novel neuroregenerative mechanism and support EA as a promising adjunctive strategy for demyelinating diseases such as MS.
{"title":"β-Endorphin Mediates Electroacupuncture-Induced Remyelination via Neural Stem Cell Lineage Modulation in Experimental Autoimmune Encephalomyelitis","authors":"Yanping Wang, Xiaoru Ma, Zhixin Qiao, Wei Zhuang, Xiyu Zhang, Jingyu Luo, Junfeng Wu, Anqi Li, Chao Wang, Jiayu Ji, Xin Xiu, Jing Wang, Yanting Meng, Wei Huang, Sifan Zhang, Xiujuan Lang, Xijun Liu, Bo Sun, Hulun Li, Yumei Liu","doi":"10.1111/cns.70658","DOIUrl":"10.1111/cns.70658","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Effective remyelination in multiple sclerosis (MS) requires both the proliferation of endogenous neural stem cells (NSCs) and their lineage-specific differentiation into oligodendrocyte progenitor cells (OPCs). This study aimed to investigate whether electroacupuncture (EA) promoted NSC proliferation and OPC differentiation via β-endorphin (β-EP)–mediated opioid signaling in a murine model of MS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice to model MS. EA stimulation was applied daily at the Zusanli (ST36) acupoint. NSC proliferation and OPC differentiation were assessed via immunofluorescence, flow cytometry (FCM), and RT-qPCR. β-EP expression and opioid receptor involvement were evaluated in the hypothalamus and subventricular zone (SVZ). Naloxone, a nonselective opioid receptor antagonist, was used to determine the role of opioid signaling in EA-induced effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>EA significantly enhanced NSC proliferation and increased the proportion of NSC-derived OPCs in the SVZ of EAE mice. EA treatment improved clinical score, reduced demyelination, and attenuated leukocyte infiltration of the central nervous system (CNS). Mechanistically, EA upregulated β-EP and its precursor pro-opiomelanocortin (POMC), along with opioid receptors μ-opioid receptor (MOR) and κ-opioid receptor (KOR) (encoded by <i>Oprm1</i> and <i>Oprk1</i>, respectively). Naloxone administration abolished the beneficial effects of EA on NSC behavior and remyelination, confirming the involvement of opioid receptor-dependent β-EP signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>EA promotes remyelination in EAE mice by stimulating β-EP-mediated NSC proliferation and OPC differentiation. These findings reveal a novel neuroregenerative mechanism and support EA as a promising adjunctive strategy for demyelinating diseases such as MS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder. However, its diagnosis and effective treatment present challenges. Understanding neurotransmitter impairments may offer new perspectives into the mechanisms underlying ASD and the potential therapeutic targets for this condition. This study aimed to investigate the spatial associations of ASD-related brain activity patterns and multiple specific neurotransmitter distributions to identify abnormal neurotransmitter alterations in patients with ASD, and to assess how these spatial associations relate to clinical features.
Methods
We included 44 patients with ASD and 132 typically developing controls (TDCs) and compared the regional homogeneity (ReHo) differences between the two groups. Associations between the spatial patterns of ReHo alterations and specific neurotransmitter receptor/transporter densities in patients with ASD were evaluated, and the correlations of these associations with the clinical characteristics were analyzed.
Results
In comparison with TDCs, patients with ASD exhibited specific brain activity abnormalities in the visuomotor network, cerebro-cerebellar circuits, angular gyrus, and limbic areas. These atypical brain activity patterns were significantly co-localized with the serotonergic, glutamatergic, GABAergic, dopaminergic, noradrenergic, cholinergic, and cannabinoid neurotransmitter systems in patients with ASD, and the results showed good reproducibility between different neurotransmitter maps. Additionally, the awareness score in the Social Responsiveness Scale (ρ = −0.475, p = 0.009) and the social score in the Autism Diagnostic Observation Schedule (ρ = −0.415, p = 0.049) exhibited negative correlations with the strength of ReHo co-localization of serotonin 5-hydroxytryptamine receptor subtype 2a.
Conclusions
This is the first systematic analysis of multiple neurotransmitter systems to show abnormalities in these systems in patients with ASD. These results will enhance the existing understanding of the mechanisms underlying ASD and may provide the foundation for identifying therapeutic targets.
背景：自闭症谱系障碍（ASD）是一种非常普遍的神经发育障碍。然而，其诊断和有效治疗存在挑战。了解神经递质损伤可能为ASD的潜在机制和潜在的治疗靶点提供新的视角。本研究旨在探讨ASD相关脑活动模式和多种特异性神经递质分布的空间关联，以识别ASD患者神经递质异常改变，并评估这些空间关联与临床特征的关系。方法：我们纳入了44例ASD患者和132例典型发展对照（tdc），比较两组之间的区域均匀性（ReHo）差异。评估ASD患者ReHo改变的空间模式与特定神经递质受体/转运体密度之间的关系，并分析这些关系与临床特征的相关性。结果：与TDCs相比，ASD患者在视觉运动网络、脑-小脑回路、角回和边缘区表现出特异性的脑活动异常。这些非典型脑活动模式与ASD患者的5 -羟色胺能、谷氨酸能、gaba能、多巴胺能、去甲肾上腺素能、胆碱能和大麻素神经递质系统显著共定位，并且结果在不同的神经递质图之间具有良好的再现性。社会反应量表中的意识得分（ρ = -0.475, p = 0.009）和自闭症诊断观察量表中的社会得分（ρ = -0.415, p = 0.049）与血清素5-羟色胺受体亚型2a的ReHo共定位强度呈负相关。结论：这是首次对ASD患者的多种神经递质系统进行系统分析，以显示这些系统的异常。这些结果将增强对ASD潜在机制的现有理解，并可能为确定治疗靶点提供基础。
{"title":"Mapping Resting-State Brain Functional Specialization to Neurotransmitter Profiles in Autism Spectrum Disorder","authors":"Dafa Shi, Jitian Guan, Guangsong Wang, Shuohua Wu, Caiyu Zhuang, Yumeng Mao, Yanlong Jia, Nannan Zhao, Gen Yan, Renhua Wu","doi":"10.1111/cns.70666","DOIUrl":"10.1111/cns.70666","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder. However, its diagnosis and effective treatment present challenges. Understanding neurotransmitter impairments may offer new perspectives into the mechanisms underlying ASD and the potential therapeutic targets for this condition. This study aimed to investigate the spatial associations of ASD-related brain activity patterns and multiple specific neurotransmitter distributions to identify abnormal neurotransmitter alterations in patients with ASD, and to assess how these spatial associations relate to clinical features.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 44 patients with ASD and 132 typically developing controls (TDCs) and compared the regional homogeneity (ReHo) differences between the two groups. Associations between the spatial patterns of ReHo alterations and specific neurotransmitter receptor/transporter densities in patients with ASD were evaluated, and the correlations of these associations with the clinical characteristics were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In comparison with TDCs, patients with ASD exhibited specific brain activity abnormalities in the visuomotor network, cerebro-cerebellar circuits, angular gyrus, and limbic areas. These atypical brain activity patterns were significantly co-localized with the serotonergic, glutamatergic, GABAergic, dopaminergic, noradrenergic, cholinergic, and cannabinoid neurotransmitter systems in patients with ASD, and the results showed good reproducibility between different neurotransmitter maps. Additionally, the awareness score in the Social Responsiveness Scale (<i>ρ</i> = −0.475, <i>p</i> = 0.009) and the social score in the Autism Diagnostic Observation Schedule (<i>ρ</i> = −0.415, <i>p</i> = 0.049) exhibited negative correlations with the strength of ReHo co-localization of serotonin 5-hydroxytryptamine receptor subtype 2a.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This is the first systematic analysis of multiple neurotransmitter systems to show abnormalities in these systems in patients with ASD. These results will enhance the existing understanding of the mechanisms underlying ASD and may provide the foundation for identifying therapeutic targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Boyu Zhang, Yan Han, Yajing Huo, Zidong Yang, Hongwei Li, Huihui Lv, Xiaotao Tai, He Wang
Objective
Altered cerebral perfusion has been implicated in the development of white matter hyperintensities (WMHs), yet the specific influence of hemodynamic features in proximal arteries on WMH burden remains uncertain. This study aimed to investigate the relationship between arterial flow characteristics and WMH severity.
Methods
A total of 2631 subjects (68.6 ± 11.1 years, 50.3% female) who underwent MRI (magnetic resonance imaging) and MRA (magnetic resonance angiography) scans were involved in this retrospective observational study. Using an individualized simplified hemodynamic model, we derived arterial flow rate, mean pressure, and pressure drop for each MRA-visible branch. WMHs were quantified on T2-FLAIR images and categorized into periventricular and deep subtypes. The associations between arterial features and WMH burden were examined using general linear models.
Results
Higher mean flow rate (β = 0.10, 95% CI: 0.06–0.14, p < 0.001) and mean pressure (β = 0.03, 95% CI: 0.02–0.04, p < 0.001) were associated with increased WMH volume. Adjacent-to-lesion terminal arterial branches (ALTAB), which represented arteries surrounding WMH, exhibited greater length (21.7 ± 8.21 mm vs. 13.3 ± 2.35 mm, p < 0.001), greater tortuosity (1.52 ± 0.39 vs. 1.26 ± 0.11, p < 0.001), lower mean flow rates (0.40 ± 0.09 mL/min vs. 0.90 ± 0.25 mL/min, p < 0.001) and lower pressure drops (0.42 ± 0.16 mmHg vs. 0.54 ± 0.15 mmHg, p < 0.001) compared to distant arteries. Greater WMH volume was found to be associated with an increased number of ALTAB.
Conclusion
The hemodynamic features of arteries surrounding WMH exhibited significant differences compared to those located further away. Such changes in arterial morphology and corresponding hemodynamic features might be associated with the severity of WMH.
{"title":"Distinct Hemodynamic and Morphological Characteristics of Arteries Adjacent to White Matter Hyperintensities","authors":"Boyu Zhang, Yan Han, Yajing Huo, Zidong Yang, Hongwei Li, Huihui Lv, Xiaotao Tai, He Wang","doi":"10.1111/cns.70673","DOIUrl":"10.1111/cns.70673","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Altered cerebral perfusion has been implicated in the development of white matter hyperintensities (WMHs), yet the specific influence of hemodynamic features in proximal arteries on WMH burden remains uncertain. This study aimed to investigate the relationship between arterial flow characteristics and WMH severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 2631 subjects (68.6 ± 11.1 years, 50.3% female) who underwent MRI (magnetic resonance imaging) and MRA (magnetic resonance angiography) scans were involved in this retrospective observational study. Using an individualized simplified hemodynamic model, we derived arterial flow rate, mean pressure, and pressure drop for each MRA-visible branch. WMHs were quantified on T2-FLAIR images and categorized into periventricular and deep subtypes. The associations between arterial features and WMH burden were examined using general linear models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Higher mean flow rate (<i>β</i> = 0.10, 95% CI: 0.06–0.14, <i>p</i> < 0.001) and mean pressure (<i>β</i> = 0.03, 95% CI: 0.02–0.04, <i>p</i> < 0.001) were associated with increased WMH volume. Adjacent-to-lesion terminal arterial branches (ALTAB), which represented arteries surrounding WMH, exhibited greater length (21.7 ± 8.21 mm vs. 13.3 ± 2.35 mm, <i>p</i> < 0.001), greater tortuosity (1.52 ± 0.39 vs. 1.26 ± 0.11, <i>p</i> < 0.001), lower mean flow rates (0.40 ± 0.09 mL/min vs. 0.90 ± 0.25 mL/min, <i>p</i> < 0.001) and lower pressure drops (0.42 ± 0.16 mmHg vs. 0.54 ± 0.15 mmHg, <i>p</i> < 0.001) compared to distant arteries. Greater WMH volume was found to be associated with an increased number of ALTAB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The hemodynamic features of arteries surrounding WMH exhibited significant differences compared to those located further away. Such changes in arterial morphology and corresponding hemodynamic features might be associated with the severity of WMH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liang Chen, Boli Fu, Jiaxin Liu, Cun Wang, Weijun Huang, Danhua Yuan, Chen Qing, Yao Zhang, Hao Hong
Background
The limitations of current clinical antidepressants and the slow progress in developing novel treatments highlight the need for rapid-acting, long-lasting antidepressants with minimal side effects. Nomilin, a naturally occurring limonoid compound, exhibits diverse pharmacological properties, including anti-inflammatory and anti-tumor activities. However, its potential antidepressant effects remain largely unclear.
Methods
In this study, we used lipopolysaccharide (LPS)-induced and chronic restraint stress (CRS)-induced depression mouse models to verify the antidepressant effects of nomilin. The brain regions with altered activity after nomilin administration were identified using c-fos immunofluorescence staining. Then chemogenetics, viral tracing, fiber photometry and pharmacological strategies were conducted to further investigate the neural circuit mechanisms of nomilin's antidepressant effects.
Results
This study demonstrated that nomilin significantly alleviated depressive-like behaviors and increased the excitability of GABAergic neurons in the ventral part of the lateral septal nucleus (LSv), a region exhibiting diminished activity in depressive states. Chemogenetic activation of LSv GABAergic neurons ameliorated LPS-induced depressive-like behaviors, whereas their inhibition attenuated the antidepressant effects of nomilin. Nomilin exerted its antidepressant effects via LSv to bed nucleus of the stria terminalis (BNST) GABAergic projections, with downstream GABAA receptors playing a crucial role in regulating the LSvGABA → BNST neural circuit.
Conclusion
Collectively, these findings identify nomilin as a potential candidate for depression and provide novel insights into the development of antidepressant drugs.
{"title":"Nomilin Regulates Depressive-Like Behaviors in Mice via the Ventral Part of the Lateral Septum to Bed Nucleus of the Stria Terminalis Circuit","authors":"Liang Chen, Boli Fu, Jiaxin Liu, Cun Wang, Weijun Huang, Danhua Yuan, Chen Qing, Yao Zhang, Hao Hong","doi":"10.1111/cns.70647","DOIUrl":"10.1111/cns.70647","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The limitations of current clinical antidepressants and the slow progress in developing novel treatments highlight the need for rapid-acting, long-lasting antidepressants with minimal side effects. Nomilin, a naturally occurring limonoid compound, exhibits diverse pharmacological properties, including anti-inflammatory and anti-tumor activities. However, its potential antidepressant effects remain largely unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we used lipopolysaccharide (LPS)-induced and chronic restraint stress (CRS)-induced depression mouse models to verify the antidepressant effects of nomilin. The brain regions with altered activity after nomilin administration were identified using c-fos immunofluorescence staining. Then chemogenetics, viral tracing, fiber photometry and pharmacological strategies were conducted to further investigate the neural circuit mechanisms of nomilin's antidepressant effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This study demonstrated that nomilin significantly alleviated depressive-like behaviors and increased the excitability of GABAergic neurons in the ventral part of the lateral septal nucleus (LSv), a region exhibiting diminished activity in depressive states. Chemogenetic activation of LSv GABAergic neurons ameliorated LPS-induced depressive-like behaviors, whereas their inhibition attenuated the antidepressant effects of nomilin. Nomilin exerted its antidepressant effects via LSv to bed nucleus of the stria terminalis (BNST) GABAergic projections, with downstream GABA<sub>A</sub> receptors playing a crucial role in regulating the LSv<sup>GABA</sup> → BNST neural circuit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, these findings identify nomilin as a potential candidate for depression and provide novel insights into the development of antidepressant drugs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70647","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xue Zhao, Luo Shi, Yongqiang Chen, Hongxiao Yu, Xiaoyi Wang, Xinyi Jing, Tianjiao Deng, Ke Zhao, Xiang Zhang, Yixian Liu, Fang Yuan, Sheng Wang
Objective
Astrocytes within the preBötzinger complex (preBötC) critically regulate respiratory rhythmogenesis and pattern formation. However, the molecular mechanisms underlying their contributions remain poorly understood. This study aims to investigate whether connexin 43 (Cx43) channels, a prominent subtype of connexin proteins expressed in preBötC astrocytes, are essential for stabilizing breathing patterns.
Methods
We employed a multidisciplinary approach, integrating whole-body plethysmography, in vivo fiber photometry, phrenic nerve discharge (PND) recordings, photostimulation, RNAscope fluorescence in situ hybridization, and RNA sequencing to elucidate the functional role of Cx43 channels in respiratory regulation.
Results
Elevated activation levels of preBötC astrocytes were synchronized with specific respiratory events, including sighs and transiently augmented breathing. RNA-sequencing analysis demonstrated that Gja1 (encoding Cx43) was identified as the predominant connexin transcript in preBötC astrocytes. Photostimulation of preBötC astrocytes significantly increased PND frequency in anesthetized mice, an effect replicated by pharmacological blockade of Cx43 hemichannels. Conditional knockdown of astrocytic Gja1 in the preBötC considerably increased resting breathing frequency and minute ventilation. Blockade of Cx43 hemichannels enhanced astrocytic activation and induced ATP accumulation around somatostatin-expressing preBötC neurons (preBötCSST). Furthermore, Cx43 hemichannel blockade activated preBötCSST neurons, an effect mediated by P2Y1 but not P2X receptors.
Conclusion
We identify an astrocyte-to-neuron signaling cascade involving Cx43 hemichannel-dependent ATP release, P2Y1 receptor activation on preBötCSST neurons, and subsequent modulation of respiratory motor output. These findings establish Cx43 hemichannels as critical molecular determinants for stabilizing breathing patterns.
{"title":"Astrocytic Connexin43 Channels Are Essential for Breathing Pattern Stabilization in the preBötzinger Complex","authors":"Xue Zhao, Luo Shi, Yongqiang Chen, Hongxiao Yu, Xiaoyi Wang, Xinyi Jing, Tianjiao Deng, Ke Zhao, Xiang Zhang, Yixian Liu, Fang Yuan, Sheng Wang","doi":"10.1111/cns.70668","DOIUrl":"10.1111/cns.70668","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Astrocytes within the preBötzinger complex (preBötC) critically regulate respiratory rhythmogenesis and pattern formation. However, the molecular mechanisms underlying their contributions remain poorly understood. This study aims to investigate whether connexin 43 (Cx43) channels, a prominent subtype of connexin proteins expressed in preBötC astrocytes, are essential for stabilizing breathing patterns.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed a multidisciplinary approach, integrating whole-body plethysmography, in vivo fiber photometry, phrenic nerve discharge (PND) recordings, photostimulation, RNAscope fluorescence in situ hybridization, and RNA sequencing to elucidate the functional role of Cx43 channels in respiratory regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated activation levels of preBötC astrocytes were synchronized with specific respiratory events, including sighs and transiently augmented breathing. RNA-sequencing analysis demonstrated that <i>Gja1</i> (encoding Cx43) was identified as the predominant connexin transcript in preBötC astrocytes. Photostimulation of preBötC astrocytes significantly increased PND frequency in anesthetized mice, an effect replicated by pharmacological blockade of Cx43 hemichannels. Conditional knockdown of astrocytic <i>Gja1</i> in the preBötC considerably increased resting breathing frequency and minute ventilation. Blockade of Cx43 hemichannels enhanced astrocytic activation and induced ATP accumulation around somatostatin-expressing preBötC neurons (preBötC<sup>SST</sup>). Furthermore, Cx43 hemichannel blockade activated preBötC<sup>SST</sup> neurons, an effect mediated by P2Y1 but not P2X receptors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identify an astrocyte-to-neuron signaling cascade involving Cx43 hemichannel-dependent ATP release, P2Y1 receptor activation on preBötC<sup>SST</sup> neurons, and subsequent modulation of respiratory motor output. These findings establish Cx43 hemichannels as critical molecular determinants for stabilizing breathing patterns.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12641571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target.
Methods
We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms—including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease—to dissect its tissue-specific pathophysiological impacts.
Results
The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling.
Conclusions
The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies—including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)—offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.
{"title":"AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy","authors":"Junyang Chen, Boya Liu, Xinlei Yao, Xiaoming Yang, Jiacheng Sun, Jia Yi, Fei Xue, Jitai Zhang, Yuntian Shen, Bingqian Chen, Hualin Sun","doi":"10.1111/cns.70657","DOIUrl":"10.1111/cns.70657","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms—including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease—to dissect its tissue-specific pathophysiological impacts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies—including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)—offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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