CNS Neuroscience & Therapeutics最新文献_第8页

Activation of Piezo1 by intracranial hypertension induced neuronal apoptosis via activating hippo pathway 颅内高压激活 Piezo1，通过激活 hippo 通路诱导神经细胞凋亡

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-27 DOI: 10.1111/cns.14872

Jia Zeng, Zhen Fang, Jiajia Duan, Zichen Zhang, Yunzhi Wang, Yiping Wang, Lei Chen, Jikai Wang, Fei Liu

Aim

Most of the subarachnoid hemorrhage (SAH) patients experienced the symptom of severe headache caused by intracranial hypertension. Piezo1 is a mechanosensitive ion channel protein. This study aimed to investigate the effect of Piezo1 on neurons in response to intracranial hypertension.

Methods

The SAH rat model was performed by the modified endovascular perforation method. Piezo1 inhibitor GsMTx4 was administered intraperitoneally after SAH induction. To investigate the underlying mechanism, the selective Piezo1 agonist Yoda1, Piezo1 shRNA, and MY-875 were administered via intracerebroventricular injection before SAH induction. In vitro, we designed a pressurizing device to exclusively explore the effect of Piezo1 activation on primary neurons. Neurons were pretreated with Piezo1 inhibition followed by intracranial hypertension treatment, and then apoptosis-related proteins were detected.

Results

Piezo1 inhibition significantly attenuated neuronal apoptosis and improved the outcome of neurological deficits in rats after SAH. The Hippo pathway agonist MY-875 reversed the anti-apoptotic effects of Piezo1 knockdown. In vitro, intracranial hypertension mimicked by the pressurizing device induced Piezo1 expression, resulting in Hippo pathway activation and neuronal apoptosis. The Hippo pathway inhibitor Xmu-mp-1 attenuated Yoda1-induced neuronal apoptosis. In addition, the combination of hypertension and oxyhemoglobin treatment exacerbated neuronal apoptosis.

Conclusions

Intracranial hypertension induced Piezo1 expression, neuronal apoptosis, and the Hippo pathway activation; the Hippo signaling pathway is involved in Piezo1 activation-induced neuronal apoptosis in respond to intracranial hypertension. Primary neurons treated with intracranial hypertension and oxyhemoglobin together can better characterize the circumstance of SAH in vivo, which is contributed to construct an ideal in vitro SAH model.

目的大多数蛛网膜下腔出血（SAH）患者都有颅内高压引起的剧烈头痛症状。Piezo1 是一种机械敏感性离子通道蛋白。本研究旨在探讨 Piezo1 在颅内高压反应中对神经元的影响。方法 SAH 大鼠模型采用改良血管内穿孔法。诱导 SAH 后腹腔注射 Piezo1 抑制剂 GsMTx4。为了研究其潜在机制，我们在诱导 SAH 之前通过脑室内注射选择性 Piezo1 激动剂 Yoda1、Piezo1 shRNA 和 MY-875。在体外，我们设计了一个加压装置，专门探讨 Piezo1 激活对初级神经元的影响。先对神经元进行 Piezo1 抑制预处理，然后进行颅内高压处理，最后检测凋亡相关蛋白。结果 Piezo1 抑制剂能明显减轻 SAH 后大鼠神经元凋亡，改善神经功能缺损的预后。Hippo 通路激动剂 MY-875 逆转了 Piezo1 敲除的抗凋亡作用。在体外，加压装置模拟的颅内高压诱导了Piezo1的表达，导致Hippo通路激活和神经元凋亡。Hippo通路抑制剂Xmu-mp-1可减轻Yoda1诱导的神经细胞凋亡。此外，高血压和氧合血红蛋白联合治疗会加剧神经元凋亡。结论颅内高血压诱导 Piezo1 表达、神经元凋亡和 Hippo 通路激活；Hippo 信号通路参与了 Piezo1 激活诱导神经元凋亡对颅内高血压的反应。用颅内高压和氧合血红蛋白处理原代神经元能更好地描述 SAH 在体内的情况，有助于构建理想的体外 SAH 模型。

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引用次数: 0

Additional Cover 附加封面

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-26 DOI: 10.1111/cns.70074

The cover image is based on the article Transcranial direct current stimulation enhances the protective effect of isoflurane preconditioning on cerebral ischemia/reperfusion injury: A new mechanism associated with the nuclear protein Akirin2 by Xiangyi Kong et al., https://doi.org/10.1111/cns.70033.

封面图片来源于文章《经颅直流电刺激可增强异氟醚预处理对脑缺血再灌注损伤的保护作用》，作者：Xiangyi Kong 等（）：一种与核蛋白Akirin2相关的新机制》，作者：Xiangyi Kong等，https://doi.org/10.1111/cns.70033.

引用次数: 0

Decreased cold-inducible RNA-binding protein (CIRP) binding to GluRl on neuronal membranes mediates memory impairment resulting from prolonged hypobaric hypoxia exposure 冷诱导 RNA 结合蛋白（CIRP）与神经元膜上的 GluRl 结合减少介导了长时间低压氧暴露导致的记忆损伤。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-24 DOI: 10.1111/cns.70059

Hui Jiang, Chenyan Lu, Haoyang Wu, Jie Ding, Jiayan Li, Jianfeng Ding, Yuqi Gao, Guohua Wang, Qianqian Luo

Aim

To investigate the molecular mechanisms underlying memory impairment induced by high-altitude (HA) hypoxia, specifically focusing on the role of cold-inducible RNA-binding protein (CIRP) in regulating the AMPA receptor subunit GluR1 and its potential as a therapeutic target.

Methods

A mouse model was exposed to 14 days of hypobaric hypoxia (HH), simulating conditions at an altitude of 6000 m. Behavioral tests were conducted to evaluate memory function. The expression, distribution, and interaction of CIRP with GluR1 in neuronal cells were analyzed. The binding of CIRP to GluR1 mRNA and its impact on GluR1 protein expression were examined. Additionally, the role of CIRP in GluR1 regulation was assessed using Cirp knockout mice. The efficacy of the Tat-C16 peptide, which consists of the Tat sequence combined with the CIRP 110-125 amino acid sequence, was also tested for its ability to mitigate HH-induced memory decline.

Results

CIRP was primarily localized in neurons, with its expression significantly reduced following HH exposure. This reduction was associated with decreased GluR1 protein expression on the cell membrane and increased localization in the cytoplasm. The interaction between CIRP and GluR1 was diminished under HH conditions, leading to reduced GluR1 stability on the cell membrane and increased cytoplasmic relocation. These changes resulted in a decreased number of synapses and dendritic spines, impairing learning and memory functions. Administration of the Tat-C16 peptide effectively ameliorated these impairments by modulating GluR1 expression and distribution in HH-exposed mice.

Conclusion

CIRP plays a critical role in maintaining synaptic integrity under hypoxic conditions by regulating GluR1 expression and distribution. The Tat-C16 peptide shows promise as a therapeutic strategy for alleviating cognitive decline associated with HA hypoxia.

目的：研究高海拔缺氧诱导记忆损伤的分子机制，特别关注冷诱导RNA结合蛋白（CIRP）在调节AMPA受体亚基GluR1中的作用及其作为治疗靶点的潜力：方法：模拟海拔 6000 米的环境，对小鼠模型进行为期 14 天的低压缺氧（HH）。进行行为测试以评估记忆功能。分析了神经元细胞中 CIRP 的表达、分布以及与 GluR1 的相互作用。研究了 CIRP 与 GluR1 mRNA 的结合及其对 GluR1 蛋白表达的影响。此外，还利用 Cirp 基因敲除小鼠评估了 CIRP 在 GluR1 调节中的作用。此外，还测试了由 Tat 序列和 CIRP 110-125 氨基酸序列组成的 Tat-C16 肽对缓解 HH 诱导的记忆衰退的功效：结果：CIRP主要定位于神经元，其表达在暴露于HH后显著减少。这种减少与细胞膜上 GluR1 蛋白表达的减少和细胞质中定位的增加有关。在 HH 条件下，CIRP 与 GluR1 之间的相互作用减弱，导致 GluR1 在细胞膜上的稳定性降低，而在细胞质中的定位增加。这些变化导致突触和树突棘数量减少，从而损害了学习和记忆功能。通过调节 GluR1 在暴露于 HH 的小鼠中的表达和分布，服用 Tat-C16 肽可有效改善这些损伤：结论：CIRP 通过调节 GluR1 的表达和分布，在缺氧条件下维持突触完整性方面发挥着关键作用。Tat-C16肽有望成为缓解与HA缺氧相关的认知能力下降的治疗策略。

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引用次数: 0

Expression of microRNA induced by postoperative delirium-like behavior is associated with long-term default mode network disruption: Sequencing and a secondary analysis of resting-state fMRI data 术后谵妄样行为诱导的微RNA表达与长期默认模式网络中断有关：静息态 fMRI 数据的测序和二次分析

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-24 DOI: 10.1111/cns.70038

Yang Liu, Huiru Feng, Huiqun Fu, Binbin Nie, Tianlong Wang

Aims

Resting state functional magnetic resonance imaging (rs-fMRI) has been widely used in studying default mode network (DMN) changes in postoperative delirium (POD). Reproducibility and interpretability of the analyzing results remain insufficiently studied.

Methods

Delirium-like behavior was induced by tibial fixation surgery under isoflurane anesthesia. Firstly, we evaluated delirium-like behavior and inflammatory responses in hippocampus and systemic level. Then the expressions of microRNA (miRNA) and target gene were sequenced and validated. Afterwards the functional connectivity (FC) in DMN was analyzed. Finally, results were correlated with DMN changes.

Results

POD-like behavior caused significant changes of miR-34b-5p, miR-328-5p, and miR-3505 in miRNA level and Nos1, Tubb3, and Gys1 in the gene level. The FC in left and right hippocampus (L-Hip and R-Hip) and right auditory cortex (R-AC) was found significantly changed. Significant correlations were found in FC_L-Hip/R-AC and FC_R-Hip/R-AC for miR-34b-5p and miR-3505, as well as Nos1 and Tubb3. For miR-328-5p, no significant correlations were found.

Conclusion

Our study demonstrates that POD-like behavior induced significant miRNA and gene expression changes were associated with hippocampus related long-term FC disruption in DMN. The results increased reproducibility and interpretability for standardized rs-fMRI data analysis, as well as providing potential targets for postoperative delirium treatment.

目的静息状态功能磁共振成像（rs-fMRI）已被广泛用于研究术后谵妄（POD）中默认模式网络（DMN）的变化。但对分析结果的可重复性和可解释性的研究仍然不足。方法在异氟烷麻醉下进行胫骨固定手术，诱发谵妄样行为。首先，我们评估了谵妄样行为和海马及全身的炎症反应。然后对微小RNA（miRNA）和靶基因的表达进行测序和验证。然后分析了DMN的功能连接（FC）。最后，将结果与 DMN 变化相关联。结果 POD-like 行为导致 miRNA 水平上的 miR-34b-5p、miR-328-5p 和 miR-3505 以及基因水平上的 Nos1、Tubb3 和 Gys1 发生了显著变化。研究发现，左右海马（L-Hip 和 R-Hip）和右听觉皮层（R-AC）的 FC 发生了显著变化。在 FCL-Hip/R-AC 和 FCR-Hip/R-AC 中，miR-34b-5p、miR-3505 以及 Nos1 和 Tubb3 均有显著相关性。至于 miR-328-5p，则没有发现明显的相关性。结论我们的研究表明，POD 类行为诱导的显著 miRNA 和基因表达变化与 DMN 中与海马相关的长期 FC 干扰有关。研究结果提高了标准化 rs-fMRI 数据分析的可重复性和可解释性，并为术后谵妄治疗提供了潜在靶点。

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引用次数: 0

A hypothalamus-lateral periaqueductal gray GABAergic neural projection facilitates arousal following sevoflurane anesthesia in mice 下丘脑-外侧uctal gray GABA 能神经投射有助于小鼠在七氟醚麻醉后觉醒

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-24 DOI: 10.1111/cns.70047

Dan Wang, Chang Bao, Huimin Wu, Jiannan Li, Xinxin Zhang, Sa Wang, Fang Zhou, Huiming Li, Hailong Dong

Background

The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHA^GABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHA^GABA neurons play either an inhibitory or a facilitatory role in sevoflurane-induced anesthetic arousal regulation.

Methods

We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto-/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion.

Results

c-Fos staining showed that LHA^GABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHA^GABA neurons project to multiple arousal-associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHA^GABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHA^GABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness.

Conclusions

In summary, we show that an inhibitory projection from LHA^GABA to LPAG^GABA neurons promotes arousal from sevoflurane-induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long-range connections.

背景外侧下丘脑（LHA）是一个进化保守的结构，调节生物体的基本功能，尤其是觉醒。阐明LHAGABA神经元及其投射对全身麻醉的调节功能，对于理解麻醉剂对大脑的兴奋和抑制作用至关重要。本研究旨在探讨 LHAGABA 神经元在七氟醚诱导的麻醉唤醒调节中是起抑制作用还是起促进作用。方法我们使用纤维光度法和免疫荧光染色法监测七氟醚麻醉过程中神经元活动的变化。采用光/化学调制来研究麻醉过程中神经回路调制的影响。通过前向追踪来确定从 LHA 到uctal gray（PAG）亚区的 GABA 能投射。结果 c-Fos染色显示，七氟醚麻醉诱导抑制了LHAGABA活性。逆行追踪发现，LHAGABA神经元投射到多个与唤醒相关的脑区，外侧下凹灰质（LPAG）是密集投射区之一。光遗传学实验表明，激活LHAGABA神经元及其下游靶点LPAG可降低连续七氟醚麻醉时的爆发抑制比（BSR）。化学遗传实验表明，激活 LHAGABA 及其向 LPAG 神经元的投射可延长麻醉诱导时间并促进清醒。结论综上所述，我们发现从 LHAGABA 到 LPAGGABA 神经元的抑制性投射可促进从七氟烷诱导的意识丧失中唤醒，这表明通过长程连接之间的密切互动可对觉醒进行复杂的控制。

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引用次数: 0

Early screening of post-stroke fall risk: A simultaneous multimodal fNIRs-EMG study 中风后跌倒风险的早期筛查：同步多模态 fNIRs-EMG 研究。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-24 DOI: 10.1111/cns.70041

Zheng Yang, Liu Ye, Lining Yang, Qiuyi Lu, Anqi Yu, Dingqun Bai

Background

Stroke is the third-leading cause of death and disability, and poststroke falls (PSF) are common at all stages after stroke and could even lead to injuries or death. Brain information from functional near-infrared spectroscopy (fNIRs) may precede conventional imaging and clinical symptoms but has not been systematically considered in PSF risk prediction. This study investigated the difference in brain activation between stroke patients and healthy subjects, and this study was aimed to explore fNIRs biomarkers for early screening of PSF risk by comparing the brain activation in patients at and not at PSF risk.

Methods

In this study, we explored the differences in brain activation and connectivity between stroke and healthy subjects by synchronizing the detection of fNIRs and EMG tests during simple (usual sit-to-stand) and difficult tasks (sit-to-stand based on EMG feedback). Thereby further screened for neuroimaging biomarkers for early prediction of PSF risk by comparing brain activation variability in poststroke patients at and not at fall risk during simple and difficult tasks. The area under the ROC curve (AUROC), sensitivity, and specificity were used to compare the diagnostic effect.

Results

A total of 40 patients (22 not at and 18 at PSF risk) and 38 healthy subjects were enrolled. As the difficulty of standing task increased, stroke patients compared with healthy subjects further increased the activation of the unaffected side of supplementary motor area (H-SMA) and dorsolateral prefrontal cortex-Brodmann area 46 (H-DLFC-BA46) but were unable to increase functional connectivity (Group*Task: p < 0.05). More importantly, the novel finding showed that hyperactivation of the H-SMA during a simple standing task was a valid fNIRs predictor of PSF risk [AUROC 0.74, p = 0.010, sensitivity 77.8%, specificity 63.6%].

Conclusions

This study provided novel evidence that fNIR-derived biomarkers could early predict PSF risk that can facilitate the widespread use of real-time assessment tools in early screening and rehabilitation. Meanwhile, this study demonstrated that the higher brain activation and inability to increase the brain functional connectivity in stroke patients during difficult task indicated the inefficient use of brain resources.

背景：中风是导致死亡和残疾的第三大原因，中风后跌倒（PSF）在中风后的各个阶段都很常见，甚至可能导致受伤或死亡。来自功能性近红外光谱（fNIRs）的脑信息可能先于常规成像和临床症状，但在 PSF 风险预测中尚未得到系统考虑。本研究调查了脑卒中患者与健康受试者脑激活的差异，旨在通过比较有和无 PSF 风险患者的脑激活，探索用于早期筛查 PSF 风险的 fNIRs 生物标志物：在这项研究中，我们通过在简单任务（通常的坐立）和困难任务（基于肌电图反馈的坐立）中同步检测 fNIRs 和肌电图测试，探索了脑卒中和健康受试者之间大脑激活和连接的差异。通过比较有和没有跌倒风险的脑卒中后患者在简单和困难任务中的脑激活变异性，进一步筛选用于早期预测 PSF 风险的神经影像生物标志物。研究使用 ROC 曲线下面积（AUROC）、灵敏度和特异性来比较诊断效果：共纳入了 40 名患者（22 名无 PSF 风险和 18 名有 PSF 风险）和 38 名健康受试者。随着站立任务难度的增加，与健康受试者相比，脑卒中患者未受影响一侧的辅助运动区（H-SMA）和背外侧前额叶皮层-布罗德曼区 46（H-DLFC-BA46）的激活进一步增加，但功能连通性却未能增加（组*任务：p 结论：该研究提供了一个新的证据，表明脑卒中患者和健康受试者之间的功能连通性存在差异：本研究提供了新的证据，证明 fNIR 衍生的生物标志物可以早期预测 PSF 风险，从而促进实时评估工具在早期筛查和康复中的广泛应用。同时，本研究还表明，脑卒中患者在完成高难度任务时脑激活程度较高，且无法提高脑功能连通性，这表明脑资源的利用效率较低。

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引用次数: 0

A novel strategy for spinal cord reconstruction via vascularized allogeneic spinal cord transplantation combine spinal cord fusion 通过血管化异体脊髓移植联合脊髓融合进行脊髓重建的新策略。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-23 DOI: 10.1111/cns.70020

Weihua Zhang, Rongyu Lan, Tingting Shen, Jie Qin, Zhihui Wang, Jiayang Chen, Jiaxing Wang, Zhuotan Wu, Yudong Xu, Yangyang Shen, Qikai Lin, Yuan Chen, Yi Wei, Yiwen Liu, Yuance Ning, Yiyan Zhou, Liji Deng, Linxuan Han, Xiaofei Wu, Haixuan Deng, Zhenbin Cao, Xianping Yao, Xiaoping Ren

Aims

Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects.

Materials and Methods

In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up.

Results

The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs.

Conclusion

In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI.

目的：脊髓损伤（SCI）会造成二次损伤，给临床实践带来持续挑战。借鉴脊髓融合术（SCF）的经验，我们提出血管化异体脊髓移植（vASCT）作为治疗SCI的新方法，就像器官移植彻底改变了器官衰竭的治疗，血管化复合组织异体移植解决了肢体缺损问题一样：在这项研究中，24 只狗配对接受了 vASCT，供体脊髓移植物和聚乙二醇（PEG）应用于 SCF。实验组（n = 8）接受他克莫司和甲基强的松龙治疗，对照组（n = 4）仅接受甲基强的松龙治疗。通过电生理学、影像学和 6 个月的随访评估了 vASCT 的安全性和有效性：结果：实验组后肢运动功能显著恢复。成像显示脊髓移植物存活率高，脊髓连续性得到恢复。相比之下，对照组后肢仍然瘫痪，影像学证实脊髓移植物坏死和广泛缺损。在电生理学上，实验组与对照组不同，术后运动诱发电位信号传导得到恢复。值得注意的是，在 vASCT 期间应用 PEG 可使所有犬的术中脊髓诱发电位检查信号传导恢复：结论：在 vASCT 手术模型中，PEG 与他克莫司的联合应用已证明能够重建小猎犬脊髓的连续性并恢复其后肢运动功能。值得注意的是，小剂量他克莫司也表现出了极佳的抗免疫排斥效果。这些研究结果突显了 vASCT 作为一种治疗策略在解决不可逆 SCI 方面的潜在前景。

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引用次数: 0

KA-mediated excitotoxicity induces neuronal ferroptosis through activation of ferritinophagy KA 介导的兴奋性毒性通过激活噬铁蛋白诱导神经元铁变态反应。

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-22 DOI: 10.1111/cns.70054

Yi-Yue Jiang, Wei-Long Wu, Jia-Ni Huang, Na Liu, Jing Wang, Xiao-Rui Wan, Zheng-Hong Qin, Yan Wang

Objectives

This study aims to elucidate the role of Fe²⁺ overload in kainic acid (KA)-induced excitotoxicity, investigate the involvement of ferritinophagy selective cargo receptor NCOA4 in the pathogenesis of excitotoxicity.

Methods

Western blotting was used to detect the expression of FTH1, NCOA4, Lamp2, TfR, FPN, and DMT1 after KA stereotaxic injection into the unilateral striatum of mice. Colocalization of Fe²⁺ with lysosomes in KA-treated primary cortical neurons was observed by using confocal microscopy. Desferrioxamine (DFO) was added to chelate free iron, a CCK8 kit was used to measure cell viability, and the Fe²⁺ levels were detected by FerroOrange. BODIPY C11 was used to determine intracellular lipid reactive oxygen species (ROS) levels, and the mRNA levels of PTGS2, a biomarker of ferroptosis, were measured by fluorescent quantitative PCR. 3-Methyladenine (3-MA) was employed to inhibit KA-induced activation of autophagy, and changes in ferritinophagy-related protein expression and the indicated biomarkers of ferroptosis were detected. Endogenous NCOA4 was knocked down by lentivirus transfection, and cell viability and intracellular Fe²⁺ levels were observed after KA treatment.

Results

Western blot results showed that the expression of NCOA4, DMT1, and Lamp2 was significantly upregulated, while FTH1 was downregulated, but there were no significant changes in TfR and FPN. The fluorescence results indicated that KA enhanced the colocalization of free Fe²⁺ with lysosomes in neurons. DFO intervention could effectively rescue cell damage, reduce intracellular lipid peroxidation, and decrease the increased transcript levels of PTGS2 caused by KA. Pretreatment with 3-MA effectively reversed KA-induced ferritinophagy and ferroptosis. Endogenous interference with NCOA4 significantly improved cell viability and reduced intracellular free Fe²⁺ levels in KA-treated cells.

Conclusion

KA-induced excitotoxicity activates ferritinophagy, and targeting ferritinophagy effectively inhibits downstream ferroptosis. Interference with NCOA4 effectively attenuates KA-induced neuronal damage. This study provides a potential therapeutic target for excitotoxicity related disease conditions.

研究目的本研究旨在阐明Fe2+超载在凯尼酸（KA）诱导的兴奋性中毒中的作用，探讨噬铁选择性货物受体NCOA4参与兴奋性中毒的发病机制：方法：小鼠单侧纹状体注射 KA 后，采用 Western 印迹法检测 FTH1、NCOA4、Lamp2、TfR、FPN 和 DMT1 的表达。利用共聚焦显微镜观察了经 KA 处理的初级皮质神经元中 Fe2+ 与溶酶体的共定位。加入去铁胺（DFO）以螯合游离铁，使用 CCK8 试剂盒测量细胞活力，并用 FerroOrange 检测 Fe2+ 水平。用 BODIPY C11 测定细胞内脂质活性氧（ROS）水平，用荧光定量 PCR 检测铁变态反应生物标志物 PTGS2 的 mRNA 水平。采用 3-甲基腺嘌呤（3-MA）抑制 KA 诱导的自噬活化，并检测了嗜铁蛋白相关蛋白表达的变化和铁变态反应的指示生物标志物。通过慢病毒转染敲除内源性 NCOA4，观察 KA 处理后的细胞活力和细胞内 Fe2+ 水平：Western印迹结果显示，NCOA4、DMT1和Lamp2的表达明显上调，而FTH1的表达下调，但TfR和FPN的表达无明显变化。荧光结果表明，KA增强了游离Fe2+与神经元溶酶体的共定位。DFO干预能有效挽救细胞损伤，减少细胞内脂质过氧化，并降低KA引起的PTGS2转录水平的升高。3-MA预处理能有效逆转KA诱导的铁蛋白吞噬和铁突变。内源性干扰 NCOA4 能显著提高 KA 处理细胞的存活率并降低细胞内游离 Fe2+ 的水平：结论：KA诱导的兴奋性毒性激活了噬铁蛋白，针对噬铁蛋白能有效抑制下游的铁突变。干扰 NCOA4 能有效减轻 KA 诱导的神经元损伤。这项研究为兴奋毒性相关疾病提供了一个潜在的治疗靶点。

{"title":"KA-mediated excitotoxicity induces neuronal ferroptosis through activation of ferritinophagy","authors":"Yi-Yue Jiang, Wei-Long Wu, Jia-Ni Huang, Na Liu, Jing Wang, Xiao-Rui Wan, Zheng-Hong Qin, Yan Wang","doi":"10.1111/cns.70054","DOIUrl":"10.1111/cns.70054","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aims to elucidate the role of Fe<sup>2+</sup> overload in kainic acid (KA)-induced excitotoxicity, investigate the involvement of ferritinophagy selective cargo receptor NCOA4 in the pathogenesis of excitotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Western blotting was used to detect the expression of FTH1, NCOA4, Lamp2, TfR, FPN, and DMT1 after KA stereotaxic injection into the unilateral striatum of mice. Colocalization of Fe<sup>2+</sup> with lysosomes in KA-treated primary cortical neurons was observed by using confocal microscopy. Desferrioxamine (DFO) was added to chelate free iron, a CCK8 kit was used to measure cell viability, and the Fe<sup>2+</sup> levels were detected by FerroOrange. BODIPY C11 was used to determine intracellular lipid reactive oxygen species (ROS) levels, and the mRNA levels of PTGS2, a biomarker of ferroptosis, were measured by fluorescent quantitative PCR. 3-Methyladenine (3-MA) was employed to inhibit KA-induced activation of autophagy, and changes in ferritinophagy-related protein expression and the indicated biomarkers of ferroptosis were detected. Endogenous NCOA4 was knocked down by lentivirus transfection, and cell viability and intracellular Fe<sup>2+</sup> levels were observed after KA treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Western blot results showed that the expression of NCOA4, DMT1, and Lamp2 was significantly upregulated, while FTH1 was downregulated, but there were no significant changes in TfR and FPN. The fluorescence results indicated that KA enhanced the colocalization of free Fe<sup>2+</sup> with lysosomes in neurons. DFO intervention could effectively rescue cell damage, reduce intracellular lipid peroxidation, and decrease the increased transcript levels of PTGS2 caused by KA. Pretreatment with 3-MA effectively reversed KA-induced ferritinophagy and ferroptosis. Endogenous interference with NCOA4 significantly improved cell viability and reduced intracellular free Fe<sup>2+</sup> levels in KA-treated cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>KA-induced excitotoxicity activates ferritinophagy, and targeting ferritinophagy effectively inhibits downstream ferroptosis. Interference with NCOA4 effectively attenuates KA-induced neuronal damage. This study provides a potential therapeutic target for excitotoxicity related disease conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11416743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277589","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

Effects of β-sitosterol on anxiety in migraine-induced rats: The role of oxidative/nitrosative stress and mitochondrial function β-谷甾醇对偏头痛诱发大鼠焦虑的影响：氧化/亚硝基应激和线粒体功能的作用

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-20 DOI: 10.1111/cns.14892

Ali Vafaei, Ahmad Vafaeian, Arad Iranmehr, Ehsan Nassireslami, Behnam Hasannezhad, Yasaman Hosseini

Aims

Anxiety often coexists with migraine, and both conditions share a commonality in oxidative/nitrosative stress and mitochondrial dysfunction contributing to their pathogenesis. β-Sitosterol, a plant sterol, has shown promise in mitigating oxidative/nitrosative stress, enhancing mitochondrial function, and exerting neuroprotective effects. In this study, we investigated the impact of β-sitosterol on migraine-associated anxiety and whether this effect was associated with alleviation of oxidative/nitrosative stress and improvement in mitochondrial function.

Methods

Nitroglycerin was used to induce migraine in adult male Wistar rats. β-Sitosterol treatment consisted of daily intraperitoneal injections (10 mg/kg) for 10 days following migraine induction. Anxiety levels were evaluated using open-field test (OFT) and hole-board test (HBT). Frontal cortex samples were analyzed for malondialdehyde (MDA), glutathione (GSH), reactive oxygen/nitrogen species, nitric oxide (NO) (markers of oxidative/nitrosative stress), and ATP (indicator of mitochondrial function).

Results

Migraine induction led to impaired performance in both the OFT and the HBT. Concurrently, it elevated MDA, reactive oxygen/nitrogen species, and NO levels while diminishing GSH levels in the frontal cortex, signifying heightened oxidative/nitrosative stress. Moreover, ATP levels decreased, indicating mitochondrial dysfunction. Treatment with β-sitosterol significantly restored performance in both behavioral assays and normalized the levels of MDA, GSH, reactive oxygen/nitrogen species, NO, and ATP.

Conclusion

β-Sitosterol exerted anxiolytic effects in migraine, which can be attributed to its ability to ameliorate oxidative/nitrosative stress and enhance mitochondrial function.

目的焦虑症常常与偏头痛并存，这两种疾病的共同点是氧化/亚硝基应激和线粒体功能障碍都是导致其发病的原因。β-谷甾醇是一种植物甾醇，在减轻氧化/亚硝基应激、增强线粒体功能和发挥神经保护作用方面具有前景。在这项研究中，我们调查了β-谷甾醇对偏头痛相关焦虑的影响，以及这种影响是否与减轻氧化/亚硝基应激和改善线粒体功能有关。方法使用硝酸甘油诱导成年雄性 Wistar 大鼠偏头痛。在诱发偏头痛后的 10 天内，每天腹腔注射 β-谷甾醇（10 毫克/千克）。焦虑水平通过开阔地测试（OFT）和孔板测试（HBT）进行评估。对额叶皮层样本进行丙二醛（MDA）、谷胱甘肽（GSH）、活性氧/氮物种、一氧化氮（NO）（氧化/亚硝基应激的标志）和 ATP（线粒体功能的指标）分析。结果偏头痛诱导导致OFT和HBT成绩受损。同时，偏头痛会升高 MDA、活性氧/氮物种和 NO 的水平，同时降低额叶皮质中 GSH 的水平，这表明氧化/亚硝基应激加剧。此外，ATP水平下降，表明线粒体功能障碍。使用β-谷甾醇治疗可明显恢复这两种行为测定的表现，并使 MDA、GSH、活性氧/氮物种、NO 和 ATP 水平恢复正常。结论 β-谷甾醇对偏头痛有抗焦虑作用，这可归因于它能改善氧化/亚硝基应激和增强线粒体功能。

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引用次数: 0

Changes of NLRP3 in serum and cerebrospinal fluid of patients after moderate to severe traumatic brain injury and their predictive values for prognosis 中重度脑外伤后患者血清和脑脊液中 NLRP3 的变化及其对预后的预测价值

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2024-09-20 DOI: 10.1111/cns.70009

Wei Chen, Zhigang Wang, Gengfan Ye, Guangyao Zhu, Shiwei Li, Pandi Chen, Hongcai Wang, Shufeng Zou, Maosong Chen

Background

Traumatic brain injury (TBI) remains a major concern for global health. Recent studies have suggested the role of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), an inflammatory marker, in the cerebrospinal fluid (CSF) and serum as potential indicators of TBI prognosis. The objective of the study was to characterize NLRP3 as a clinically applicable tool for predicting the outcomes of TBI patients.

Methods

A total of 270 patients with moderate to severe TBI were included in this retrospective analysis. Serum and CSF samples were collected at 1-, 3-, 7-, and 21-day post-injury to measure NLRP3 levels. The prognosis of patients was evaluated after 3 months using the Glasgow Outcome Scale (GOS). Patients were categorized into good prognosis (GOS score >3) and poor prognosis (GOS score ≤3) groups. The relationship between NLRP3 levels and prognosis was analyzed.

Results

Patients with poor prognosis had significantly elevated NLRP3 levels in their serum on days 1 and 3 post-injury compared with those with a good prognosis. The difference was more pronounced during these early days compared with days 7 and 21. However, NLRP3 levels in CSF consistently showed a large difference between the two groups throughout the observation period. Receiver operating characteristic analysis revealed that the level of NLRP3 in the CSF on day 3 post-injury had the highest predictive value for prognosis, with an area under the curve of 0.83, followed by the level of NLRP3 in the serum on day 3 post-injury.

Conclusions

The levels of NLRP3, especially in the CSF on day 3 post-injury, can serve as a potential biomarker for predicting prognosis in moderate to severe TBI patients. Early measurement of NLRP3 levels can provide valuable insights into patient outcomes and guide therapeutic strategies.

背景创伤性脑损伤（TBI）仍然是全球健康的一个主要问题。最近的研究表明，脑脊液（CSF）和血清中的炎症标志物 NOD 样受体 pyrin 结构域含蛋白 3（NLRP3）可作为创伤性脑损伤预后的潜在指标。本研究的目的是确定 NLRP3 的特征，将其作为预测创伤性脑损伤患者预后的临床适用工具。方法本次回顾性分析共纳入了 270 名中度至重度创伤性脑损伤患者。在伤后 1、3、7 和 21 天采集血清和脑脊液样本，测量 NLRP3 水平。3 个月后，使用格拉斯哥结果量表（GOS）对患者的预后进行评估。患者被分为预后良好组（GOS评分>3）和预后不良组（GOS评分≤3）。分析了 NLRP3 水平与预后之间的关系。结果与预后良好的患者相比，预后不良的患者在伤后第 1 天和第 3 天血清中的 NLRP3 水平明显升高。与第 7 天和第 21 天相比，早期患者血清中的 NLRP3 水平差异更为明显。然而，在整个观察期间，两组患者脑脊液中的 NLRP3 水平始终存在较大差异。接收器操作特征分析显示，伤后第 3 天 CSF 中的 NLRP3 水平对预后的预测价值最高，曲线下面积为 0.83，其次是伤后第 3 天血清中的 NLRP3 水平。结论 NLRP3水平，尤其是伤后第3天脑脊液中的NLRP3水平，可作为预测中重度创伤性脑损伤患者预后的潜在生物标志物。早期测量 NLRP3 水平可为了解患者预后和指导治疗策略提供有价值的信息。

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引用次数: 0