CNS Neuroscience & Therapeutics最新文献_第9页

Tetrahydrocurcumin Ameliorates Cerebral Ischemia–Reperfusion Injury and Restores Blood–Brain Barrier Dysfunction by Inhibiting Ferroptosis 四氢姜黄素通过抑制铁下垂改善脑缺血再灌注损伤和恢复血脑屏障功能障碍

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-21 DOI: 10.1111/cns.70662

Shuang Zhang, Jizhong Han, Zhen Fan, Haoxiang Wang, Luotong Liu, Liang Liu, Liangxue Zhou, Huajiang Deng

Background

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.

脑缺血再灌注（I/R）损伤是缺血性脑卒中的主要后果，可导致血脑屏障（BBB）破坏、神经炎症和神经元死亡。最近的研究表明，四氢姜黄素（THC）是一种天然化合物，可能对缺血性中风有神经保护作用。然而，潜在的机制仍不清楚。本研究旨在探讨四氢大麻酚在脑I/R损伤中的神经保护作用，并探讨其可能的机制。方法采用大脑中动脉闭塞（MCAO）模型诱导小鼠脑缺血再灌注损伤。生物信息学分析确定了铁下垂的关键基因。通过评估梗死面积、血脑屏障通透性和凋亡相关标志物（GPX4、xCT、FTH1）来评估THC的作用。利用nrf2特异性抑制剂ML385和分子对接分析探讨了分子机制。结果四氢大麻酚治疗可显著减少梗死面积，减轻血脑屏障破坏，改善神经功能。它通过上调GPX4、xCT和FTH1的表达，并通过减少脂质过氧化和铁积累来抑制铁下垂。THC促进Nrf2核易位，进而激活下游抗氧化途径。分子对接分析显示THC与Keap1结合，促进Nrf2解离和核易位。ML385逆转了THC的保护作用，证实了Keap1/Nrf2信号通路的参与。结论四氢大麻酚通过激活Keap1/Nrf2信号通路抑制铁下沉，显著改善血脑屏障功能障碍，减轻脑缺血再灌注后神经功能缺损。以上结果提示，四氢大麻酚可作为缺血性脑卒中的潜在治疗剂，为通过调节铁下垂治疗脑缺血再灌注损伤提供了新的途径。

{"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}

引用次数: 0

PF4 at the Crossroads of Immunity and Neurodegeneration: A New Window Into Brain Aging PF4在免疫和神经退行性变的十字路口：研究大脑衰老的新窗口。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-19 DOI: 10.1111/cns.70656

Zili Xie

<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

围手术期神经认知障碍（PND）是指围手术期发生的神经认知障碍，包括术后谵妄（POD）、延迟神经认知恢复（dNCR）和术后神经认知障碍（PNCD）。它们是老年患者麻醉和手术最常见的并发症。目前，缓解PND最有效的方法是非药物干预，而药物干预仍然有限，主要是因为PND发展的详细机制仍未完全了解。在最近发表在《分子精神病学》上的一项研究中，Lai博士等人揭示了我们对PND的理解的一个令人信服的新视角，确定血小板因子4 （PF4，也称为CXCL4）是补体-血小板-脑信号轴[1]中的一个机制桥梁。Β-lactam抗生素已被公认具有神经保护和抗神经炎症作用，先前的研究表明头孢唑林可以改善PND年轻小鼠模型术后的认知功能障碍。基于此，作者推测β-内酰胺类抗生素可能有助于预防老年患者的PND。他们招募了40名老年患者的临床队列，进行了一项随机双盲临床试验，以评估围手术期β-内酰胺类抗生素（包括头孢唑林和头孢曲松）预防年龄相关性PND的疗效。值得注意的是，与接受头孢唑林的患者相比，头孢曲松组的患者随着时间的推移表现出较慢的认知衰退。以神经胶质细胞激活和海马小胶质细胞积聚为特征的神经炎症是PND的关键因素。作者观察到通过补体成分3 (C3)-C3a受体1 （C3aR）轴介导的小胶质细胞-星形胶质细胞串音增强。C3是补体级联的核心成分，是免疫功能所必需的多结构域糖蛋白。据报道，老年PNCD患者脑脊液中C3水平升高，阻断C3aR已被证明可改善年轻PND小鼠模型手术后的认知。在本研究中，术前测定血清C3水平。两种抗生素组术后C3均升高，但头孢唑林组由于轻度PNCD发生率较高，C3升高高于头孢曲松组。重要的是，血清C3水平升高与轻度PNCD发病率增加显著相关。为了进一步确定因果关系，作者使用了一种选择性C3抑制剂（CR2-Crry），并证明C3的抑制显著减少了手术后的小胶质细胞浸润、胶质细胞激活和神经炎症。在C3 - / -小鼠中观察到类似的保护作用，证实C3/C3aR信号在年龄相关性PND中介导神经元损伤和认知能力下降。PF4是一种在凝血过程中被激活的血小板释放的细胞因子，它与肝素相互作用形成抗原复合物，在肝素诱导的血小板减少症中触发igg介导的免疫反应。它也与疫苗诱导的免疫性血栓性血小板减少症有关[2,3]。除血液学外，PF4最近在神经科学和衰老研究中得到了关注。在《自然》杂志上发表的一项具有里程碑意义的研究中，Villeda及其同事证明，PF4抑制小胶质细胞的激活和促炎介质的释放，从而减轻神经炎症，提高老年小鼠b[4]的学习和记忆能力。这些发现表明，PF4可能赋予神经保护和恢复老化大脑的认知功能。在本研究中，头孢曲松组血清PF4水平明显高于头孢唑林组。相关分析进一步显示，较高的PF4水平与较好的认知表现呈正相关。为了验证PF4的机制作用，作者利用老年PND小鼠模型，证明即使在C3aR持续激活的情况下，外源性PF4也能拯救认知缺陷。这些发现强调了PF4作为免疫调节剂和神经保护剂的潜力。然而，PF4进入中枢神经系统（CNS）的机制及其与小胶质细胞或神经元的直接相互作用尚不清楚。阐明这些通路对于理解外周PF4如何发挥中枢神经保护作用至关重要。这项研究描述了一种新的PND分子通路，并提供了补体信号、血小板生物学和神经免疫调节之间的桥梁概念。如果PF4被证明是多种与衰老相关的脑部疾病的共同特征，它可能不仅代表了一个有希望的治疗靶点，而且代表了抗神经变性的弹性的分子特征。此外，这项工作挑战了传统的以神经元或神经胶质为中心的CNS疾病观点，表明免疫功能障碍可能是认知能力下降的关键驱动因素。这一发现不仅加强了PF4的治疗潜力，而且提出了关于其在神经退行性和神经炎症性疾病中的广泛相关性的重要问题。作者声明无利益冲突。数据共享不适用于本文，因为在本研究中没有生成或分析数据集。

{"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}

引用次数: 0

Jolkinolide B Mitigates Cerebral Ischemia–Reperfusion Injury by Promoting Microglial M1/M2 Polarization Through the JAK2/STAT3 Signaling Pathway Jolkinolide B通过JAK2/STAT3信号通路促进小胶质细胞M1/M2极化减轻脑缺血再灌注损伤

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-18 DOI: 10.1111/cns.70653

Yupeng Guo, Xuanwei Dong, Min Liu, Dongsheng Liu, Jianxin Wang, Shewei Guo

Background

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}

引用次数: 0

High Glucose Aggravates Cerebral Ischemia/Reperfusion via Truncated NLRP3-Mediated Hexokinase-2 Translocation 高糖通过截断nlrp3介导的己糖激酶-2易位加重脑缺血/再灌注

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-18 DOI: 10.1111/cns.70660

Hengchang Zhang, Ruoyi Guo, Xiang Li, Yang Zhang, Lujun Zhou, Junjie Wang, Yudi Huang, Zengqiang Yuan, Lijuan Song, Yajin Liao

<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

背景：高血糖是缺血性卒中预后不良的一个公认的危险因素。然而，高血糖与卒中预后恶化之间的潜在分子机制尚不清楚。目的：先前的研究表明NLRP3炎症小体是脑缺血/再灌注（I/R）损伤中神经炎症的关键介质。在高血糖条件下，NLRP3的激活被放大，可能导致炎症和神经元死亡的恶性循环。然而，高血糖如何特异性调节NLRP3的激活及其下游途径仍不清楚。本研究旨在探讨高糖增强NLRP3炎性体活性并导致脑I/R后脑损伤加重的具体机制。方法：采用体外和体内相结合的实验方法，探讨高糖对NLRP3炎性体活化的影响及其对缺血性卒中预后的影响。体外实验通过在高糖条件下培养多种免疫细胞来评估NLRP3炎性体的激活和HK2的线粒体关联。在体内，基因敲除Nlrp3、Pycard（编码ASC的基因）或小胶质细胞特异性Hk2的小鼠遭受短暂性大脑中动脉闭塞（tMCAO）。结果：我们的研究结果显示，高糖脑I/R后NLRP3炎症小体的激活增强，NLRP3的n端截断（miniNLRP3）被诱导。过表达PKA可促进miniNLRP3的生成，抑制PKA可降低miniNLRP3的生成。此外，用泛丝氨酸蛋白酶处理可以阻断PKA和LPS介导的miniNLRP3的生成。NLRP3 n端截断的过表达可以通过促进线粒体中己糖激酶2 （HK2）的解离来增强高糖条件下NLRP3炎性体的激活。此外，敲除Nlrp3、Pycard或小胶质细胞Hk2均可减轻小鼠高血糖下脑I/ r诱导的脑损伤。结论：我们的研究阐明了pka以丝氨酸蛋白酶依赖的方式介导NLRP3 （miniNLRP3）的30 kD n端截断，这可能通过促进HK2与线粒体的解离来增强高糖条件下NLRP3炎性体的激活。这些发现为我们了解NLRP3在脑卒中损伤中的调控提供了新的视角，并表明PKA-miniNLRP3-HK2-NLRP3通路是一种有希望改善血糖升高患者脑卒中预后的治疗策略。

{"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}

引用次数: 0

“YiJinJing, Wohu Pushi” Posture-Voice Therapy for Dysarthria in Parkinson's Disease Patients Following Subthalamic Nucleus Deep Brain Stimulation: A Randomized Controlled Trial 《易金静，我虎普氏》：一项随机对照试验：姿态-声音疗法治疗丘脑下核深部脑刺激后帕金森病患者构音障碍。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-18 DOI: 10.1111/cns.70652

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.

背景：帕金森病（PD）的构音障碍很难治疗，尤其是丘脑下核深部脑刺激（STN-DBS）后，因为LSVT等治疗效果不一，可及性有限。“易进经，我呼普适”姿势-声音疗法（YJJ-WPVT）强调姿势协调，提供了一个有希望但尚未被充分开发的替代方案。本研究的目的是评估YJJ-WPVT与Lee Silverman语音治疗（LSVT）和不训练对stn - dbs后PD患者构音障碍的有效性。方法：这是一项前瞻性、平行分配、非盲、随机对照试验，随访6个月。试验在中国上海交通大学医学院瑞金医院功能神经外科神经外科进行。≥18岁特发性PD患者，接受STN-DBS治疗，母语为汉语，语音障碍指数-10 (VHI-10) bbb10。参与者以1:1:1的比例随机分配到YJJ-WPVT （n = 11）、LSVT （n = 11）或无训练（n = 12）。两个干预组在4周内接受了16次治疗。LSVT包括持续发声，音高滑动，以及每天在家练习的结构化语音任务。YJJ-WPVT遵循类似的4周方案，并强调通过弓步，抓爪姿势和虎吼发声来纠正姿势。主要观察指标为1个月时语音障碍指数-30 （VHI-30）和声压级（SPL）的变化。结果：在筛选的68例患者中，34例入组（平均年龄：yj - wpvt 62亿2岁；LSVT 65亿2岁；未治疗60亿1岁）。1个月时，与未训练相比，YJJ-WPVT的VHI-30总分显著降低5分（95% CI -8.7至-1.3;p = 0.04）， SPL无显著升高（1.8分；95% CI -1.3至4.9;p = 0.05）。YJJ-WPVT改善了1个月和6个月时的MPT、抖动、闪烁和HNR，以及VHI功能评分。运动症状、吞咽功能和生活质量也得到改善，YJJ-WPVT在吞咽方面优于LSVT，并显示出轻微的运动功能改善。不良反应（疲劳、声音嘶哑）轻微且短暂。结论：YJJ-WPVT是一种安全、有效的替代stn - dbs后PD构音障碍的方法，具有额外的吞咽和运动益处。更大规模的多中心试验是必要的。

{"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}

引用次数: 0

Netrin-1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model Netrin-1通过调节DRD2/GSK3β信号和抑制ROS抑制帕金森病模型中的神经炎症

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-17 DOI: 10.1111/cns.70651

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.

背景：Netrin-1在成熟神经元中稳定表达，调节突触可塑性，促进神经元存活，调节细胞粘附和迁移。然而，Netrin-1与帕金森病（PD）发病机制之间的分子联系尚未清楚阐明。目的：在本研究中，我们研究了Netrin-1对PD病理相关多巴胺能神经元死亡的神经保护作用。结果：在鱼藤酮诱导的细胞模型中，Netrin-1处理显著减少活性氧（ROS）的产生、α-突触核蛋白磷酸化和随后的细胞凋亡。此外，Netrin-1抑制IL-6、TNF-α和IL-1β等促炎细胞因子的表达，并促进多巴胺D2受体（DRD2）信号的激活，这对多巴胺能神经元的存活至关重要。值得注意的是，在Netrin-1条件敲除小鼠模型中，我们观察到明显的多巴胺能神经元丢失，伴随着α-突触核蛋白Ser129位点的过度磷酸化增加，以及由激活的caspase-3产生的结肠直肠癌（DCC）中缺失的截断形式的水平升高，DRD2表达的明显缺失，以及GSK3β Tyr216位点的过度磷酸化。相比之下，这些病理特征在Netrin-1野生型（WT）小鼠中减弱。此外，α-突触核蛋白（SNCA）转基因（Tg）小鼠衰老过程的特征是Netrin-1和DRD2水平降低，α-突触核蛋白积累、促炎细胞因子和caspase-3激活增加。结论：这些发现表明Netrin-1通过调节神经炎症、保留DRD2信号、抑制GSK3β Tyr216位点磷酸化来保护多巴胺能神经元，从而有可能成为多巴胺能神经变性的治疗药物。

{"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}

引用次数: 0

Aerobic Exercise Training Exerts Neuroprotective Effects in Alzheimer's Disease Mice by Regulating Endoplasmic Reticulum Stress-Autophagy Pathway-Mediated Pyroptosis 有氧运动训练通过调节内质网应激自噬途径介导的焦亡对阿尔茨海默病小鼠的神经保护作用。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-17 DOI: 10.1111/cns.70620

Yunliang Wang, Xiangyun Sun, Biao He, Shaowen Yu, Yiyou Yu

Objective

This study probed into the neuroprotective effects of aerobic exercise training (AET) on Alzheimer's disease (AD) mice and further explored the molecular mechanisms through which AET regulates the endoplasmic reticulum stress (ERS)–autophagy pathway to mediate pyroptosis.

Methods

APP/PS1 mice (AD model) underwent 8 weeks of treadmill-based AET. In addition to the exercise regimen, mice were treated with intraperitoneal injections of an NLRP3 inflammasome activator, an autophagy inhibitor, an ERS inducer, and a PERK activator for assessing cognitive function and neuronal damage in the hippocampal CA1 region through cognitive assessments, histological analyses, and biochemical assays. BrdU/EdU labeling combined with NeuN and doublecortin immunostaining was used to evaluate AET-stimulated neuronal proliferation and differentiation in the hippocampus.

Results

AET improved cognitive function in AD mice. Following AET, neuronal damage in the hippocampal CA1 region was reduced, the number of Nissl bodies increased, and Aβ_1-42 and p-Tau protein levels decreased. Mechanistically, AET alleviated NLRP3 inflammasome-mediated pyroptosis and cognitive dysfunction in AD mice by inhibiting ERS and promoting autophagy in the hippocampal CA1 region. Activation of the NLRP3 inflammasome or inhibition of autophagy partially reversed the beneficial effects of AET on pyroptosis and cognitive dysfunction in AD mice. Moreover, AET reduced ERS by inhibiting the PERK-eIF2α pathway, thereby enhancing autophagy, reducing pyroptosis, and improving cognitive dysfunction.

Conclusion

AET reduces NLRP3 inflammasome-mediated pyroptosis and neuronal damage in the hippocampal CA1 region of AD mice by regulating the ERS-autophagy pathway through the inhibition of the PERK-eIF2α pathway, thereby improving cognitive function in AD mice.

目的：探讨有氧运动训练（AET）对阿尔茨海默病（AD）小鼠的神经保护作用，并进一步探讨AET通过调节内质网应激(ERS)-自噬通路介导焦亡的分子机制。方法：APP/PS1小鼠（AD模型）进行8周的跑步机AET。除了运动方案外，小鼠还通过腹腔注射NLRP3炎性体激活剂、自噬抑制剂、ERS诱导剂和PERK激活剂，通过认知评估、组织学分析和生化分析评估海马CA1区的认知功能和神经元损伤。采用BrdU/EdU标记联合NeuN和双皮质素免疫染色评价aet刺激海马神经元的增殖和分化。结果：AET改善了AD小鼠的认知功能。AET后海马CA1区神经元损伤减轻，Nissl小体数量增加，Aβ1-42和p-Tau蛋白水平降低。机制上，AET通过抑制ERS和促进海马CA1区的自噬，减轻了NLRP3炎症小体介导的AD小鼠焦亡和认知功能障碍。激活NLRP3炎性小体或抑制自噬部分逆转了AET对AD小鼠焦亡和认知功能障碍的有益作用。此外，AET通过抑制PERK-eIF2α途径降低ERS，从而增强自噬，减少焦亡，改善认知功能障碍。结论：AET通过抑制PERK-eIF2α通路调节ers自噬通路，减轻AD小鼠NLRP3炎性体介导的焦亡和海马CA1区神经元损伤，从而改善AD小鼠的认知功能。

{"title":"Aerobic Exercise Training Exerts Neuroprotective Effects in Alzheimer's Disease Mice by Regulating Endoplasmic Reticulum Stress-Autophagy Pathway-Mediated Pyroptosis","authors":"Yunliang Wang, Xiangyun Sun, Biao He, Shaowen Yu, Yiyou Yu","doi":"10.1111/cns.70620","DOIUrl":"10.1111/cns.70620","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study probed into the neuroprotective effects of aerobic exercise training (AET) on Alzheimer's disease (AD) mice and further explored the molecular mechanisms through which AET regulates the endoplasmic reticulum stress (ERS)–autophagy pathway to mediate pyroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>APP/PS1 mice (AD model) underwent 8 weeks of treadmill-based AET. In addition to the exercise regimen, mice were treated with intraperitoneal injections of an NLRP3 inflammasome activator, an autophagy inhibitor, an ERS inducer, and a PERK activator for assessing cognitive function and neuronal damage in the hippocampal CA1 region through cognitive assessments, histological analyses, and biochemical assays. BrdU/EdU labeling combined with NeuN and doublecortin immunostaining was used to evaluate AET-stimulated neuronal proliferation and differentiation in the hippocampus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AET improved cognitive function in AD mice. Following AET, neuronal damage in the hippocampal CA1 region was reduced, the number of Nissl bodies increased, and Aβ<sub>1-42</sub> and p-Tau protein levels decreased. Mechanistically, AET alleviated NLRP3 inflammasome-mediated pyroptosis and cognitive dysfunction in AD mice by inhibiting ERS and promoting autophagy in the hippocampal CA1 region. Activation of the NLRP3 inflammasome or inhibition of autophagy partially reversed the beneficial effects of AET on pyroptosis and cognitive dysfunction in AD mice. Moreover, AET reduced ERS by inhibiting the PERK-eIF2α pathway, thereby enhancing autophagy, reducing pyroptosis, and improving cognitive dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>AET reduces NLRP3 inflammasome-mediated pyroptosis and neuronal damage in the hippocampal CA1 region of AD mice by regulating the ERS-autophagy pathway through the inhibition of the PERK-eIF2α pathway, thereby improving cognitive function in AD mice.</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://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70620","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538148","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}

引用次数: 0

CXCL10 Involvement in Vestibular Migraine via the PI3K/AKT Signaling Pathway CXCL10通过PI3K/AKT信号通路参与前庭偏头痛。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-17 DOI: 10.1111/cns.70655

Mao-mei Song, Ting-yan Chen, Shi-na Song, Ying-jie Gao, Chang-xin Li, Sui-yi Xu

Aims

C-X-C motif chemokine ligand 10 (CXCL10) is a member of the CXC chemokine family, known as a classical pain-related chemokine. While CXCL10 is implicated in neuropathic pain, its role in vestibular migraine (VM) remains unclear.

Methods

Serum CXCL10 levels correlated with dizziness and headache severity in VM patients. In the rat VM model, CXCL10, C-X-C motif chemokine receptor 3 (CXCR3), and phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway expression were evaluated to explore the potential mechanisms of CXCL10 in VM.

Results

Serum CXCL10 levels in VM patients were significantly elevated and positively correlated with headache and dizziness severity. In the rat VM model, CXCL10 and CXCR3 expression in the trigeminal nucleus caudalis and vestibular nuclei were significantly increased. Additionally, molecules related to the PI3K/AKT signaling pathway and downstream inflammatory factors showed significantly elevated expression.

Conclusion

CXCL10 activates the PI3K/AKT signaling pathway, promoting the release of inflammatory factors, including interleukin-1β, interleukin-6, and tumor necrosis factor-α, and is thus involved in the pathogenesis of VM.

目的：C-X-C基序趋化因子配体10 （CXCL10）是CXC趋化因子家族的成员，被称为经典的疼痛相关趋化因子。虽然CXCL10与神经性疼痛有关，但其在前庭偏头痛（VM）中的作用尚不清楚。方法：VM患者血清CXCL10水平与头晕、头痛严重程度相关。在大鼠VM模型中，通过CXCL10、C-X-C基元趋化因子受体3 （CXCR3）和磷脂酰肌醇4,5-二磷酸3激酶(PI3K)/蛋白激酶B （AKT）信号通路的表达，探讨CXCL10在VM中的潜在机制。结果：VM患者血清CXCL10水平显著升高，且与头痛、头晕严重程度呈正相关。在大鼠VM模型中，CXCL10和CXCR3在三叉神经尾核和前庭核中的表达显著升高。此外，PI3K/AKT信号通路相关分子及下游炎症因子表达显著升高。结论：CXCL10激活PI3K/AKT信号通路，促进白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α等炎症因子的释放，参与VM的发病过程。

{"title":"CXCL10 Involvement in Vestibular Migraine via the PI3K/AKT Signaling Pathway","authors":"Mao-mei Song, Ting-yan Chen, Shi-na Song, Ying-jie Gao, Chang-xin Li, Sui-yi Xu","doi":"10.1111/cns.70655","DOIUrl":"10.1111/cns.70655","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>C-X-C motif chemokine ligand 10 (CXCL10) is a member of the CXC chemokine family, known as a classical pain-related chemokine. While CXCL10 is implicated in neuropathic pain, its role in vestibular migraine (VM) remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Serum CXCL10 levels correlated with dizziness and headache severity in VM patients. In the rat VM model, CXCL10, C-X-C motif chemokine receptor 3 (CXCR3), and phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway expression were evaluated to explore the potential mechanisms of CXCL10 in VM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Serum CXCL10 levels in VM patients were significantly elevated and positively correlated with headache and dizziness severity. In the rat VM model, CXCL10 and CXCR3 expression in the trigeminal nucleus caudalis and vestibular nuclei were significantly increased. Additionally, molecules related to the PI3K/AKT signaling pathway and downstream inflammatory factors showed significantly elevated expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CXCL10 activates the PI3K/AKT signaling pathway, promoting the release of inflammatory factors, including interleukin-1β, interleukin-6, and tumor necrosis factor-α, and is thus involved in the pathogenesis of VM.</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://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70655","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538134","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}

引用次数: 0

Dialogue Between the Clock Gene Bmal1 and Retinopathy: What Is the Exact Relationship? 时钟基因Bmal1与视网膜病变之间的对话：确切的关系是什么？

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-17 DOI: 10.1111/cns.70490

Yongheng Cui, Haoyan Li, Wenhui Fan, Hao Wu, Jiale Wang, Chengkang Qu, Ning Pu, Ye Tao

Background

Circadian clock coordinates the physiologic and behavioral activities with a 24-hour solar rhythm to maintain the temporal homeostasis of the body. In the mammalian retina, the circadian system regulates the physiological function of this organ. The realm of ocular circadian rhythm has earned kinds of research interest as the circadian rhythms dysfunction will disrupt the retinal homeostasis. Bmal1 functions as a major transcriptional regulator of the circadian clock.

Results

In the retina, Bmal1 mediates the processing of light information, sustains photoreceptor viability and governs neurotransmitter release. Moreover, Bmal1 gene is believed to be a pathologic cofactor of the diabetic retinopathy (DR), age-related macular degeneration (AMD), premature aging and refractive myopia. To date, the precise mechanisms underlying the pathological effects mediated by Bmal1 remain incompletely elucidated.

Conclusions

This review presents recent findings and evidence regarding the contributory role of Bmal1 in retinal degeneration and its deficits, while exploring its therapeutic potential. And th review provides a comprehensive analysis of the underlying mechanisms of the clock gene Bmal1 in other diseases, with the aim of offering insights into innovative therapeutic strategies for retinopathy.

背景：昼夜节律钟以24小时的太阳节律来协调生理和行为活动，以维持身体的时间内稳态。在哺乳动物的视网膜上，昼夜节律系统调节着这个器官的生理功能。由于昼夜节律紊乱会破坏视网膜内平衡，因此眼内昼夜节律领域引起了各种研究兴趣。Bmal1是生物钟的主要转录调节因子。结果：在视网膜中，Bmal1介导光信息的处理，维持光感受器的活力，并控制神经递质释放。此外，Bmal1基因被认为是糖尿病视网膜病变（DR）、年龄相关性黄斑变性（AMD）、早衰和屈光性近视的病理辅助因子。迄今为止，Bmal1介导的病理作用的确切机制尚未完全阐明。结论：本文综述了Bmal1在视网膜变性及其缺陷中的作用的最新发现和证据，同时探讨了其治疗潜力。此外，本综述还对时钟基因Bmal1在其他疾病中的潜在机制进行了全面分析，旨在为视网膜病变的创新治疗策略提供见解。

{"title":"Dialogue Between the Clock Gene Bmal1 and Retinopathy: What Is the Exact Relationship?","authors":"Yongheng Cui, Haoyan Li, Wenhui Fan, Hao Wu, Jiale Wang, Chengkang Qu, Ning Pu, Ye Tao","doi":"10.1111/cns.70490","DOIUrl":"10.1111/cns.70490","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Circadian clock coordinates the physiologic and behavioral activities with a 24-hour solar rhythm to maintain the temporal homeostasis of the body. In the mammalian retina, the circadian system regulates the physiological function of this organ. The realm of ocular circadian rhythm has earned kinds of research interest as the circadian rhythms dysfunction will disrupt the retinal homeostasis. <i>Bmal1</i> functions as a major transcriptional regulator of the circadian clock.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the retina, <i>Bmal1</i> mediates the processing of light information, sustains photoreceptor viability and governs neurotransmitter release. Moreover, <i>Bmal1</i> gene is believed to be a pathologic cofactor of the diabetic retinopathy (DR), age-related macular degeneration (AMD), premature aging and refractive myopia. To date, the precise mechanisms underlying the pathological effects mediated by <i>Bmal1</i> remain incompletely elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This review presents recent findings and evidence regarding the contributory role of <i>Bmal1</i> in retinal degeneration and its deficits, while exploring its therapeutic potential. And th review provides a comprehensive analysis of the underlying mechanisms of the clock gene <i>Bmal1</i> in other diseases, with the aim of offering insights into innovative therapeutic strategies for retinopathy.</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://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70490","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533964","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}

引用次数: 0

Automated MRI-Based Classification of Parkinsonism: A Deep Learning Approach to Distinguish PD From PSP 基于mri的帕金森病自动分类：一种区分PD和PSP的深度学习方法。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2025-11-12 DOI: 10.1111/cns.70645

Xiaofei Hu, Zehong Cao, Tianbin Song, Ying Zhou, Weizhao Lu, Yingjie Zhu, Rui Hua, Dawei Peng, Feng Shi, Jie Lu

Objective

Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) is crucial for appropriate treatment, as each disease has distinct therapeutic requirements. The Magnetic Resonance Parkinsonism Index (MRPI) has shown promise as a diagnostic biomarker, yet manual methods introduce variability and limit its applicability. In this study, we aim to develop a fully automated algorithm for MRPI 1.0 and 2.0 calculation, and assess its ability to distinguish PD from PSP in two cohorts from different regions of China.

Methods

A total of 75 PD patients and 29 PSP patients from two hospitals were enrolled. All participants underwent neurological examinations, including the MDS-UPDRS-III and H-Y scale, as well as brain MRI scans. Additionally, tissue-intensity images derived from 3D isotropic T1WI images from 2D thick slices using a deep learning (DL)-based super-resolution (SR) technique were aligned to a standard template followed by corresponding structural mask parcellation for measurement of MRPI 1.0 and MRPI 2.0. Subsequently, a logistic regression model was constructed to identify PD patients from PSP based on these indexes.

Results

MRPI 2.0 demonstrated higher diagnostic accuracy than MRPI 1.0, with an AUC of 0.78. Additionally, the automated method showed strong linear correlations with manual assessments from an experienced radiologist, validating its reliability, and identification of PSP from PD with the average AUC of 0.85.

Conclusion

The automated MRPI method improves diagnostic accuracy for differentiating PD from PSP, providing a reliable and clinically applicable tool. The integration of a super-resolution technique to convert 2D MRI data into high-resolution images expands the potential of MRPI as a neuroimaging biomarker.

目的：区分帕金森病（PD）和进行性核上性麻痹（PSP）对于适当的治疗至关重要，因为每种疾病都有不同的治疗要求。磁共振帕金森氏症指数（MRPI）已显示出作为诊断生物标志物的希望，但手工方法引入了可变性并限制了其适用性。在本研究中，我们旨在开发一种全自动的MRPI 1.0和2.0计算算法，并评估其在中国不同地区的两个队列中区分PD和PSP的能力。方法：选取两所医院PD患者75例，PSP患者29例。所有参与者都接受了神经学检查，包括MDS-UPDRS-III和H-Y量表，以及脑部MRI扫描。此外，使用基于深度学习（DL）的超分辨率（SR）技术，从2D厚切片的3D各向同性T1WI图像中获得的组织强度图像与标准模板对齐，然后进行相应的结构掩膜分割，以测量MRPI 1.0和MRPI 2.0。随后，根据这些指标构建逻辑回归模型，从PSP中识别PD患者。结果：MRPI 2.0的诊断准确率高于MRPI 1.0， AUC为0.78。此外，自动化方法与经验丰富的放射科医生的人工评估显示出很强的线性相关性，验证了其可靠性，并且PD中PSP的识别平均AUC为0.85。结论：自动化MRPI方法提高了PD与PSP的诊断准确性，是一种可靠的临床应用工具。整合超分辨率技术将2D MRI数据转换为高分辨率图像，扩大了MRPI作为神经成像生物标志物的潜力。

{"title":"Automated MRI-Based Classification of Parkinsonism: A Deep Learning Approach to Distinguish PD From PSP","authors":"Xiaofei Hu, Zehong Cao, Tianbin Song, Ying Zhou, Weizhao Lu, Yingjie Zhu, Rui Hua, Dawei Peng, Feng Shi, Jie Lu","doi":"10.1111/cns.70645","DOIUrl":"10.1111/cns.70645","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) is crucial for appropriate treatment, as each disease has distinct therapeutic requirements. The Magnetic Resonance Parkinsonism Index (MRPI) has shown promise as a diagnostic biomarker, yet manual methods introduce variability and limit its applicability. In this study, we aim to develop a fully automated algorithm for MRPI 1.0 and 2.0 calculation, and assess its ability to distinguish PD from PSP in two cohorts from different regions of China.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 75 PD patients and 29 PSP patients from two hospitals were enrolled. All participants underwent neurological examinations, including the MDS-UPDRS-III and H-Y scale, as well as brain MRI scans. Additionally, tissue-intensity images derived from 3D isotropic T1WI images from 2D thick slices using a deep learning (DL)-based super-resolution (SR) technique were aligned to a standard template followed by corresponding structural mask parcellation for measurement of MRPI 1.0 and MRPI 2.0. Subsequently, a logistic regression model was constructed to identify PD patients from PSP based on these indexes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MRPI 2.0 demonstrated higher diagnostic accuracy than MRPI 1.0, with an AUC of 0.78. Additionally, the automated method showed strong linear correlations with manual assessments from an experienced radiologist, validating its reliability, and identification of PSP from PD with the average AUC of 0.85.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The automated MRPI method improves diagnostic accuracy for differentiating PD from PSP, providing a reliable and clinically applicable tool. The integration of a super-resolution technique to convert 2D MRI data into high-resolution images expands the potential of MRPI as a neuroimaging biomarker.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 11","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501192","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}

引用次数: 0