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}
Cerebral ischemia–reperfusion (I/R) injury is a major consequence of ischemic stroke, leading to blood–brain barrier (BBB) disruption, neuroinflammation, and neuronal death. Recent studies suggest that tetrahydrocurcumin (THC), a natural compound, may have neuroprotective effects in ischemic stroke. However, the underlying mechanisms remain unclear. This study aims to investigate THC's neuroprotective effects in cerebral I/R injury and explore its potential mechanisms.
Methods
A middle cerebral artery occlusion (MCAO) model was used to induce ischemia–reperfusion injury in mice. Bioinformatics analysis identified key genes involved in ferroptosis. THC's effects were assessed by evaluating infarct volume, BBB permeability, and ferroptosis-related markers (GPX4, xCT, FTH1). Molecular mechanisms were explored using an Nrf2-specific inhibitor (ML385) and molecular docking analysis.
Results
THC treatment significantly reduced infarct volume, alleviated BBB disruption, and improved neurological function. It inhibited ferroptosis by upregulating the expression of GPX4, xCT, and FTH1, and by decreasing lipid peroxidation and iron accumulation. THC promoted Nrf2 nuclear translocation, which in turn activated the downstream antioxidant pathway. Molecular docking analysis revealed that THC binds to Keap1, promoting Nrf2 dissociation and nuclear translocation. ML385 reversed THC's protective effects, confirming the involvement of the Keap1/Nrf2 signaling pathway.
Conclusion
THC inhibits ferroptosis through the activation of the Keap1/Nrf2 signaling pathway, significantly improving BBB dysfunction and alleviating neurological deficits following cerebral ischemia–reperfusion. These findings suggest that THC could serve as a potential therapeutic agent for ischemic stroke, providing a novel approach for the treatment of cerebral ischemia–reperfusion injury through ferroptosis modulation.
{"title":"Tetrahydrocurcumin Ameliorates Cerebral Ischemia–Reperfusion Injury and Restores Blood–Brain Barrier Dysfunction by Inhibiting Ferroptosis","authors":"Shuang Zhang, Jizhong Han, Zhen Fan, Haoxiang Wang, Luotong Liu, Liang Liu, Liangxue Zhou, Huajiang Deng","doi":"10.1111/cns.70662","DOIUrl":"https://doi.org/10.1111/cns.70662","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cerebral ischemia–reperfusion (I/R) injury is a major consequence of ischemic stroke, leading to blood–brain barrier (BBB) disruption, neuroinflammation, and neuronal death. Recent studies suggest that tetrahydrocurcumin (THC), a natural compound, may have neuroprotective effects in ischemic stroke. However, the underlying mechanisms remain unclear. This study aims to investigate THC's neuroprotective effects in cerebral I/R injury and explore its potential mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A middle cerebral artery occlusion (MCAO) model was used to induce ischemia–reperfusion injury in mice. Bioinformatics analysis identified key genes involved in ferroptosis. THC's effects were assessed by evaluating infarct volume, BBB permeability, and ferroptosis-related markers (GPX4, xCT, FTH1). Molecular mechanisms were explored using an Nrf2-specific inhibitor (ML385) and molecular docking analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>THC treatment significantly reduced infarct volume, alleviated BBB disruption, and improved neurological function. It inhibited ferroptosis by upregulating the expression of GPX4, xCT, and FTH1, and by decreasing lipid peroxidation and iron accumulation. THC promoted Nrf2 nuclear translocation, which in turn activated the downstream antioxidant pathway. Molecular docking analysis revealed that THC binds to Keap1, promoting Nrf2 dissociation and nuclear translocation. ML385 reversed THC's protective effects, confirming the involvement of the Keap1/Nrf2 signaling pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>THC inhibits ferroptosis through the activation of the Keap1/Nrf2 signaling pathway, significantly improving BBB dysfunction and alleviating neurological deficits following cerebral ischemia–reperfusion. These findings suggest that THC could serve as a potential therapeutic agent for ischemic stroke, providing a novel approach for the treatment of cerebral ischemia–reperfusion injury through ferroptosis modulation.</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.70662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572588","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}
<p>Perioperative neurocognitive disorders (PND), encompassing postoperative delirium (POD), delayed neurocognitive recovery (dNCR), and postoperative neurocognitive disorder (PNCD), refer to neurocognitive impairments that occur during the perioperative period. They represent the most common complications of anesthesia and surgery in older patients. Currently, the most effective approaches for mitigating PND are nonpharmacological interventions, while pharmacological interventions remain limited, largely because the detailed mechanisms underlying the development of PND are still not fully understood. In a recent study published in <i>Molecular Psychiatry</i>, Dr. Lai et al. unveiled a compelling new perspective on our understanding of PND, identifying platelet factor 4 (PF4, also known as CXCL4) as a mechanistic bridge within a complement–platelet–brain signaling axis [<span>1</span>].</p><p>Β-lactam antibiotics have been recognized for their neuroprotective and anti-neuroinflammatory effects, and prior studies have shown that cefazolin can ameliorate postoperative cognitive dysfunction in young mouse models of PND. Based on this, the authors hypothesized that β-lactam antibiotics could help prevent PND in elderly patients. They recruited a clinical cohort of 40 elderly patients and conducted a randomized, double-blind clinical trial to evaluate the efficacy of perioperative β-lactam antibiotics, including cefazolin and ceftriaxone, in preventing age-related PND. Remarkably, patients in the ceftriaxone group exhibited a slower cognitive decline over time compared with those receiving cefazolin.</p><p>Neuroinflammation, characterized by glial activation and microglial accumulation in the hippocampus, is a key contributor to PND. The authors observed enhanced microglia–astrocyte cross talk mediated through the complement component 3 (C3)-C3a receptor 1 (C3aR) axis. C3, a central component of the complement cascade, is a multidomain glycoprotein essential for immune function. Elevated C3 levels have been reported in the cerebrospinal fluid of older PNCD patients, and blocking C3aR has been shown to improve cognition after surgery in young PND mouse models. In this study, serum C3 levels were measured preoperatively. Both antibiotic groups showed postoperative elevations in C3, but the cefazolin group, exhibiting a higher incidence of mild PNCD, displayed greater C3 elevations than the ceftriaxone group. Importantly, elevated serum C3 levels significantly correlated with increased incidence of mild PNCD. To further establish causality, the authors used a selective C3 inhibitor (CR2-Crry) and demonstrated that inhibition of C3 markedly reduced microglial infiltration, glial activation, and neuroinflammation after surgery. Similar protection was observed in <i>C3</i><sup><i>−/−</i></sup> mice, confirming that C3/C3aR signaling critically mediates neuronal injury and cognitive decline in age-related PND.</p><p>PF4, a cytokine released from activated pla
{"title":"PF4 at the Crossroads of Immunity and Neurodegeneration: A New Window Into Brain Aging","authors":"Zili Xie","doi":"10.1111/cns.70656","DOIUrl":"10.1111/cns.70656","url":null,"abstract":"<p>Perioperative neurocognitive disorders (PND), encompassing postoperative delirium (POD), delayed neurocognitive recovery (dNCR), and postoperative neurocognitive disorder (PNCD), refer to neurocognitive impairments that occur during the perioperative period. They represent the most common complications of anesthesia and surgery in older patients. Currently, the most effective approaches for mitigating PND are nonpharmacological interventions, while pharmacological interventions remain limited, largely because the detailed mechanisms underlying the development of PND are still not fully understood. In a recent study published in <i>Molecular Psychiatry</i>, Dr. Lai et al. unveiled a compelling new perspective on our understanding of PND, identifying platelet factor 4 (PF4, also known as CXCL4) as a mechanistic bridge within a complement–platelet–brain signaling axis [<span>1</span>].</p><p>Β-lactam antibiotics have been recognized for their neuroprotective and anti-neuroinflammatory effects, and prior studies have shown that cefazolin can ameliorate postoperative cognitive dysfunction in young mouse models of PND. Based on this, the authors hypothesized that β-lactam antibiotics could help prevent PND in elderly patients. They recruited a clinical cohort of 40 elderly patients and conducted a randomized, double-blind clinical trial to evaluate the efficacy of perioperative β-lactam antibiotics, including cefazolin and ceftriaxone, in preventing age-related PND. Remarkably, patients in the ceftriaxone group exhibited a slower cognitive decline over time compared with those receiving cefazolin.</p><p>Neuroinflammation, characterized by glial activation and microglial accumulation in the hippocampus, is a key contributor to PND. The authors observed enhanced microglia–astrocyte cross talk mediated through the complement component 3 (C3)-C3a receptor 1 (C3aR) axis. C3, a central component of the complement cascade, is a multidomain glycoprotein essential for immune function. Elevated C3 levels have been reported in the cerebrospinal fluid of older PNCD patients, and blocking C3aR has been shown to improve cognition after surgery in young PND mouse models. In this study, serum C3 levels were measured preoperatively. Both antibiotic groups showed postoperative elevations in C3, but the cefazolin group, exhibiting a higher incidence of mild PNCD, displayed greater C3 elevations than the ceftriaxone group. Importantly, elevated serum C3 levels significantly correlated with increased incidence of mild PNCD. To further establish causality, the authors used a selective C3 inhibitor (CR2-Crry) and demonstrated that inhibition of C3 markedly reduced microglial infiltration, glial activation, and neuroinflammation after surgery. Similar protection was observed in <i>C3</i><sup><i>−/−</i></sup> mice, confirming that C3/C3aR signaling critically mediates neuronal injury and cognitive decline in age-related PND.</p><p>PF4, a cytokine released from activated pla","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70656","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555936","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}
Microglia polarization and inflammatory response are closely related to cerebral ischemia–reperfusion injury (CIRI). The diterpenoid compound Jolkinolide B (JB) possesses anti-inflammatory properties, but the effects of JB and the mechanism on CIRI remain unclear.
Methods
An middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and an oxygen–glucose deprivation/reoxygenation (OGD/R)-induced HAPI cell model were used to evaluate the neuroprotective effects and mechanisms of JB. Neurological deficits and histopathological changes were assessed using Longa scoring, corner turn tests, TTC, HE, Nissl, and TUNEL staining. ELISA, flow cytometry, Western blot, and immunofluorescence were employed to analyze pro-inflammatory cytokines, JAK2/STAT3 pathway proteins, and microglial polarization. In vitro, JB's effects on cell viability and apoptosis were evaluated using CCK-8 and LDH release assays. Validation experiments were conducted using the JAK2-specific inhibitor WP1066 and activator Broussonin E.
Results
JB exhibited dose-dependent neuroprotective effects in MCAO/R rats, improving neurological function, reducing infarction area, neuronal apoptosis, cerebral edema, and neuroinflammation. JB suppressed JAK2/STAT3 signaling by downregulating p-JAK2, p-STAT3, and M1 markers (iNOS, CD16) while upregulating M2 markers (Arg-1, CD206) and reducing pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ). Both in vivo and in vitro, JB inhibited the JAK2/STAT3 signaling pathway and promoted microglial polarization from M1 to M2, alleviating CIRI. In vitro, JB enhanced HAPI cell viability, decreased apoptosis, and reduced LDH leakage.
Conclusion
The ability of JB to modulate microglial polarization through JAK2/STAT3 inhibition presents a promising pharmacological approach for cerebral ischemia–reperfusion injury management in stroke therapy.
背景：小胶质细胞极化和炎症反应与脑缺血再灌注损伤（CIRI）密切相关。二萜类化合物Jolkinolide B （JB）具有抗炎作用，但JB对CIRI的作用及其机制尚不清楚。方法：采用大脑中动脉闭塞/再灌注（MCAO/R）大鼠模型和氧糖剥夺/再氧化（OGD/R）诱导HAPI细胞模型，研究JB的神经保护作用及机制。采用Longa评分、转角试验、TTC、HE、Nissl和TUNEL染色评估神经功能缺损和组织病理学改变。采用ELISA、流式细胞术、Western blot和免疫荧光分析促炎细胞因子、JAK2/STAT3通路蛋白和小胶质细胞极化。体外，采用CCK-8和LDH释放法评估JB对细胞活力和凋亡的影响。使用jak2特异性抑制剂WP1066和激活剂Broussonin e进行验证实验。结果：JB在MCAO/R大鼠中表现出剂量依赖性的神经保护作用，改善神经功能，减少梗死面积，神经元凋亡，脑水肿和神经炎症。JB通过下调p-JAK2、p-STAT3和M1标记物（iNOS、CD16），上调M2标记物（Arg-1、CD206）和降低促炎细胞因子（IL-1β、TNF-α、IFN-γ），抑制JAK2/STAT3信号转导。在体内和体外实验中，JB抑制JAK2/STAT3信号通路，促进小胶质细胞从M1向M2极化，减轻CIRI。在体外，JB增强HAPI细胞活力，减少凋亡，减少LDH渗漏。结论：JB通过抑制JAK2/STAT3调节小胶质细胞极化的能力为脑卒中治疗中脑缺血再灌注损伤的治疗提供了一种有前景的药理学途径。
{"title":"Jolkinolide B Mitigates Cerebral Ischemia–Reperfusion Injury by Promoting Microglial M1/M2 Polarization Through the JAK2/STAT3 Signaling Pathway","authors":"Yupeng Guo, Xuanwei Dong, Min Liu, Dongsheng Liu, Jianxin Wang, Shewei Guo","doi":"10.1111/cns.70653","DOIUrl":"10.1111/cns.70653","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microglia polarization and inflammatory response are closely related to cerebral ischemia–reperfusion injury (CIRI). The diterpenoid compound Jolkinolide B (JB) possesses anti-inflammatory properties, but the effects of JB and the mechanism on CIRI remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and an oxygen–glucose deprivation/reoxygenation (OGD/R)-induced HAPI cell model were used to evaluate the neuroprotective effects and mechanisms of JB. Neurological deficits and histopathological changes were assessed using Longa scoring, corner turn tests, TTC, HE, Nissl, and TUNEL staining. ELISA, flow cytometry, Western blot, and immunofluorescence were employed to analyze pro-inflammatory cytokines, JAK2/STAT3 pathway proteins, and microglial polarization. In vitro, JB's effects on cell viability and apoptosis were evaluated using CCK-8 and LDH release assays. Validation experiments were conducted using the JAK2-specific inhibitor WP1066 and activator Broussonin E.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>JB exhibited dose-dependent neuroprotective effects in MCAO/R rats, improving neurological function, reducing infarction area, neuronal apoptosis, cerebral edema, and neuroinflammation. JB suppressed JAK2/STAT3 signaling by downregulating p-JAK2, p-STAT3, and M1 markers (iNOS, CD16) while upregulating M2 markers (Arg-1, CD206) and reducing pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ). Both in vivo and in vitro, JB inhibited the JAK2/STAT3 signaling pathway and promoted microglial polarization from M1 to M2, alleviating CIRI. In vitro, JB enhanced HAPI cell viability, decreased apoptosis, and reduced LDH leakage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The ability of JB to modulate microglial polarization through JAK2/STAT3 inhibition presents a promising pharmacological approach for cerebral ischemia–reperfusion injury management in stroke therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12627229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547335","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}
<div> <section> <h3> Background</h3> <p>High blood glucose is a well-established risk factor for poor outcomes in ischemic stroke. However, the underlying molecular mechanisms linking high blood glucose to worsened stroke outcomes remain unclear.</p> </section> <section> <h3> Objectives</h3> <p>Previous studies have implicated the NLRP3 inflammasome, a key mediator of neuroinflammation, in cerebral ischemia/reperfusion (I/R) injury. Under high blood glucose conditions, NLRP3 activation is amplified, potentially driving a vicious cycle of inflammation and neuronal death. Yet, how high blood glucose specifically modulates NLRP3 activation and its downstream pathways remains unclear. This study aimed to investigate the specific mechanisms by which high glucose enhances NLRP3 inflammasome activity and contributes to worsened brain injury following cerebral I/R.</p> </section> <section> <h3> Methods</h3> <p>We employed a combination of in vitro and in vivo experimental approaches to explore the impact of high glucose on NLRP3 inflammasome activation and its consequences on ischemic stroke outcomes. In vitro experiments were conducted by culturing various immune cells in high-glucose conditions to evaluate the activation of the NLRP3 inflammasome and the mitochondrial association of HK2. In vivo, mice with genetic knockouts of <i>Nlrp3</i>, <i>Pycard</i> (the gene encoding ASC), or microglial-specific <i>Hk2</i> were subjected to transient middle cerebral artery occlusion (tMCAO).</p> </section> <section> <h3> Results</h3> <p>Our findings revealed that the activation of the NLRP3 inflammasome was enhanced post cerebral I/R under high glucose and a N-terminal truncation of NLRP3 (miniNLRP3) was induced. Overexpression of PKA could promote the generation of miniNLRP3, while inhibition of PKA decreased the generation of miniNLRP3. In addition, treatment with pan serine protease could block PKA and LPS mediated generation of miniNLRP3. Overexpression of the N-terminal truncation of NLRP3 could potentiate the activation of the NLRP3 inflammasome under high glucose conditions by promoting the dissociation of Hexokinase 2 (HK2) from mitochondria. In addition, knockout of <i>Nlrp3</i>, <i>Pycard</i>, or microglial <i>Hk2</i>, could all attenuate cerebral I/R-induced brain injury under high blood glucose in mice.</p> </section> <section> <h3> Conclusion</h3> <p>Our study elucidates PKA-mediated generation of a 30 kD N-terminal truncation of NLRP3 (miniNLRP3) in a
{"title":"High Glucose Aggravates Cerebral Ischemia/Reperfusion via Truncated NLRP3-Mediated Hexokinase-2 Translocation","authors":"Hengchang Zhang, Ruoyi Guo, Xiang Li, Yang Zhang, Lujun Zhou, Junjie Wang, Yudi Huang, Zengqiang Yuan, Lijuan Song, Yajin Liao","doi":"10.1111/cns.70660","DOIUrl":"10.1111/cns.70660","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>High blood glucose is a well-established risk factor for poor outcomes in ischemic stroke. However, the underlying molecular mechanisms linking high blood glucose to worsened stroke outcomes remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Previous studies have implicated the NLRP3 inflammasome, a key mediator of neuroinflammation, in cerebral ischemia/reperfusion (I/R) injury. Under high blood glucose conditions, NLRP3 activation is amplified, potentially driving a vicious cycle of inflammation and neuronal death. Yet, how high blood glucose specifically modulates NLRP3 activation and its downstream pathways remains unclear. This study aimed to investigate the specific mechanisms by which high glucose enhances NLRP3 inflammasome activity and contributes to worsened brain injury following cerebral I/R.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed a combination of in vitro and in vivo experimental approaches to explore the impact of high glucose on NLRP3 inflammasome activation and its consequences on ischemic stroke outcomes. In vitro experiments were conducted by culturing various immune cells in high-glucose conditions to evaluate the activation of the NLRP3 inflammasome and the mitochondrial association of HK2. In vivo, mice with genetic knockouts of <i>Nlrp3</i>, <i>Pycard</i> (the gene encoding ASC), or microglial-specific <i>Hk2</i> were subjected to transient middle cerebral artery occlusion (tMCAO).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed that the activation of the NLRP3 inflammasome was enhanced post cerebral I/R under high glucose and a N-terminal truncation of NLRP3 (miniNLRP3) was induced. Overexpression of PKA could promote the generation of miniNLRP3, while inhibition of PKA decreased the generation of miniNLRP3. In addition, treatment with pan serine protease could block PKA and LPS mediated generation of miniNLRP3. Overexpression of the N-terminal truncation of NLRP3 could potentiate the activation of the NLRP3 inflammasome under high glucose conditions by promoting the dissociation of Hexokinase 2 (HK2) from mitochondria. In addition, knockout of <i>Nlrp3</i>, <i>Pycard</i>, or microglial <i>Hk2</i>, could all attenuate cerebral I/R-induced brain injury under high blood glucose in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study elucidates PKA-mediated generation of a 30 kD N-terminal truncation of NLRP3 (miniNLRP3) in a","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12627235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547386","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}
Mei Yang, Xin Sun, Jin Yan, Zhitong Zeng, Yuyan Tan, Shiqing Yan, Yong Wang, Linbin Wang, Chuanxin M. Niu, Dianyou Li
Background
Dysarthria in Parkinson's disease (PD) is difficult to treat, especially post–subthalamic nucleus deep brain stimulation (STN-DBS), as therapies like LSVT show variable efficacy and limited accessibility. “Yi Jin Jing, Wohu Pushi” posture-voice therapy (YJJ-WPVT), emphasizing postural coordination, offers a promising yet underexplored alternative. The objective of this study is to evaluate the effectiveness of YJJ-WPVT versus Lee Silverman Voice Treatment (LSVT) and no training for dysarthria in PD patients post-STN-DBS.
Methods
This is a prospective, parallel-assignment, unblinded, randomized controlled trial with follow-up at 6 months. The trial was conducted at the Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Patients ≥ 18 years with idiopathic PD treated with STN-DBS, native Chinese speakers, and Voice Handicap Index-10 (VHI-10) > 10. Participants were randomized 1:1:1 to YJJ-WPVT (n = 11), LSVT (n = 11), or no training (n = 12). Both intervention groups received 16 sessions over 4 weeks. LSVT included sustained phonation, pitch glides, and structured speech tasks with daily home practice. YJJ-WPVT followed a similar 4-week protocol and emphasized posture correction through lunges, clawing posture, and tiger roar vocalization. Primary outcomes were changes in Voice Handicap Index-30 (VHI-30) and sound pressure level (SPL) at 1 month.
Results
Of 68 patients screened, 34 were enrolled (mean age: YJJ-WPVT 62 [8] years; LSVT 65 [5]; untreated 60 [6]). At 1 month, YJJ-WPVT showed significantly lower VHI-30 total scores by five points (95% CI −8.7 to −1.3; p = 0.04) versus no training, with a nonsignificant SPL increase (1.8 points; 95% CI −1.3 to 4.9; p > 0.05). YJJ-WPVT improved MPT, jitter, shimmer, and HNR at 1 and 6 months, along with VHI functional subscores. Motor symptoms, swallowing function, and quality of life also improved, with YJJ-WPVT outperforming LSVT in swallowing and showing slight motor function benefits. Adverse effects (fatigue, hoarseness) were mild and transient.
Conclusions
YJJ-WPVT is a safe, effective alternative for dysarthria in PD post-STN-DBS, with added swallowing and motor benefits. Larger multicenter trials are warranted.
{"title":"“YiJinJing, Wohu Pushi” Posture-Voice Therapy for Dysarthria in Parkinson's Disease Patients Following Subthalamic Nucleus Deep Brain Stimulation: A Randomized Controlled Trial","authors":"Mei Yang, Xin Sun, Jin Yan, Zhitong Zeng, Yuyan Tan, Shiqing Yan, Yong Wang, Linbin Wang, Chuanxin M. Niu, Dianyou Li","doi":"10.1111/cns.70652","DOIUrl":"10.1111/cns.70652","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dysarthria in Parkinson's disease (PD) is difficult to treat, especially post–subthalamic nucleus deep brain stimulation (STN-DBS), as therapies like LSVT show variable efficacy and limited accessibility. “Yi Jin Jing, Wohu Pushi” posture-voice therapy (YJJ-WPVT), emphasizing postural coordination, offers a promising yet underexplored alternative. The objective of this study is to evaluate the effectiveness of YJJ-WPVT versus Lee Silverman Voice Treatment (LSVT) and no training for dysarthria in PD patients post-STN-DBS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a prospective, parallel-assignment, unblinded, randomized controlled trial with follow-up at 6 months. The trial was conducted at the Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Patients ≥ 18 years with idiopathic PD treated with STN-DBS, native Chinese speakers, and Voice Handicap Index-10 (VHI-10) > 10. Participants were randomized 1:1:1 to YJJ-WPVT (<i>n</i> = 11), LSVT (<i>n</i> = 11), or no training (<i>n</i> = 12). Both intervention groups received 16 sessions over 4 weeks. LSVT included sustained phonation, pitch glides, and structured speech tasks with daily home practice. YJJ-WPVT followed a similar 4-week protocol and emphasized posture correction through lunges, clawing posture, and tiger roar vocalization. Primary outcomes were changes in Voice Handicap Index-30 (VHI-30) and sound pressure level (SPL) at 1 month.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 68 patients screened, 34 were enrolled (mean age: YJJ-WPVT 62 [8] years; LSVT 65 [5]; untreated 60 [6]). At 1 month, YJJ-WPVT showed significantly lower VHI-30 total scores by five points (95% CI −8.7 to −1.3; <i>p</i> = 0.04) versus no training, with a nonsignificant SPL increase (1.8 points; 95% CI −1.3 to 4.9; <i>p</i> > 0.05). YJJ-WPVT improved MPT, jitter, shimmer, and HNR at 1 and 6 months, along with VHI functional subscores. Motor symptoms, swallowing function, and quality of life also improved, with YJJ-WPVT outperforming LSVT in swallowing and showing slight motor function benefits. Adverse effects (fatigue, hoarseness) were mild and transient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>YJJ-WPVT is a safe, effective alternative for dysarthria in PD post-STN-DBS, with added swallowing and motor benefits. Larger multicenter trials are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70652","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547365","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}
Lee Ya Kim, Seung Hoon Jeon, Yumin Heo, Eun Ji Kang, Dae Ki Hong, Seong Su Kang, Minwoo Lee, Eun Hee Ahn
Background
Netrin-1 is stably expressed in mature neurons, where it regulates synaptic plasticity, promotes neuronal survival, and modulates cell adhesion and migration. However, the molecular link between Netrin-1 and the pathogenesis of Parkinson's disease (PD) has not yet been clearly elucidated.
Aims
In this study, we investigated the neuroprotective effects of Netrin-1 against dopaminergic neuronal death associated with PD pathology.
Results
Here, we show that in a rotenone-induced cellular model, Netrin-1 treatment significantly reduced reactive oxygen species (ROS) production, α-synuclein phosphorylation, and subsequent apoptosis. Moreover, Netrin-1 suppressed the expression of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, and promoted the activation of dopamine D2 receptor (DRD2) signaling, which is crucial for dopaminergic neuron survival. Of note, in the Netrin-1 conditional knockout mouse model, we observed significant dopaminergic neuronal loss, accompanied by increased α-synuclein hyperphosphorylation at Ser129 and elevated levels of the truncated form of deleted in colorectal cancer (DCC) generated by activated caspase-3, a marked depletion of DRD2 expression, and hyperphosphorylation of GSK3β at Tyr216. In contrast, these pathological features were attenuated in Netrin-1 wild-type (WT) mice. Additionally, the aging process in α-synuclein (SNCA) transgenic (Tg) mice was characterized by reduced levels of Netrin-1 and DRD2, alongside increased α-synuclein accumulation, proinflammatory cytokines, and caspase-3 activation.
Conclusion
These findings suggest that Netrin-1 protects dopaminergic neurons by regulating neuroinflammation, preserving DRD2 signaling, and inhibiting phosphorylation of GSK3β at Tyr216, thereby offering potential as a therapeutic agent for dopaminergic neurodegeneration.
{"title":"Netrin-1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model","authors":"Lee Ya Kim, Seung Hoon Jeon, Yumin Heo, Eun Ji Kang, Dae Ki Hong, Seong Su Kang, Minwoo Lee, Eun Hee Ahn","doi":"10.1111/cns.70651","DOIUrl":"10.1111/cns.70651","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Netrin-1 is stably expressed in mature neurons, where it regulates synaptic plasticity, promotes neuronal survival, and modulates cell adhesion and migration. However, the molecular link between Netrin-1 and the pathogenesis of Parkinson's disease (PD) has not yet been clearly elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>In this study, we investigated the neuroprotective effects of Netrin-1 against dopaminergic neuronal death associated with PD pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we show that in a rotenone-induced cellular model, Netrin-1 treatment significantly reduced reactive oxygen species (ROS) production, α-synuclein phosphorylation, and subsequent apoptosis. Moreover, Netrin-1 suppressed the expression of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, and promoted the activation of dopamine D2 receptor (DRD2) signaling, which is crucial for dopaminergic neuron survival. Of note, in the Netrin-1 conditional knockout mouse model, we observed significant dopaminergic neuronal loss, accompanied by increased α-synuclein hyperphosphorylation at Ser129 and elevated levels of the truncated form of deleted in colorectal cancer (DCC) generated by activated caspase-3, a marked depletion of DRD2 expression, and hyperphosphorylation of GSK3β at Tyr216. In contrast, these pathological features were attenuated in Netrin-1 wild-type (WT) mice. Additionally, the aging process in α-synuclein (SNCA) transgenic (Tg) mice was characterized by reduced levels of Netrin-1 and DRD2, alongside increased α-synuclein accumulation, proinflammatory cytokines, and caspase-3 activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that Netrin-1 protects dopaminergic neurons by regulating neuroinflammation, preserving DRD2 signaling, and inhibiting phosphorylation of GSK3β at Tyr216, thereby offering potential as a therapeutic agent for dopaminergic neurodegeneration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12623146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538116","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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