Molecular and Cellular Neuroscience最新文献_第5页

Single subanesthetic dose of ketamine exerts antioxidant and antidepressive-like effect in ACTH-induced preclinical model of depression 单次亚麻醉剂量氯胺酮在acth诱导的抑郁症临床前模型中具有抗氧化和抗抑郁样作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-27 DOI: 10.1016/j.mcn.2025.104006

Ana Ivanović , Jelena Petrović , Dušanka Stanić , Jelena Nedeljković , Miloš Ilić , Marin M. Jukić , Bojana Pejušković , Vesna Pešić

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O₂^·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O₂^.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.

下丘脑-垂体-肾上腺（HPA）轴的过度活跃和氧化应激是抑郁症病因病理学中涉及的重要机制。虽然第一种抗抑郁药早在60多年前就被引入临床实践，但大约30% %的抑郁症患者表现出治疗耐药性。一种非竞争性n -甲基-d-天冬氨酸受体拮抗剂氯胺酮显示出有希望的快速抗抑郁作用，并已被批准用于治疗难治疗性抑郁症（TRD）。在本研究中，我们研究了单次亚麻醉剂量氯胺酮（10 mg/kg, ip）对促肾上腺皮质激素（10 μg ACTH/day, sc， 21 天）诱导的TRD啮齿动物模型的抗氧化和抗抑郁样活性。进行行为评估，并测定外周血淋巴细胞（pbl）氧化应激和DNA损伤的血浆生物标志物。我们观察到ACTH在雄性Wistar大鼠中产生了类似抑郁的行为，并显著增加了超氧阴离子（O2·-）、高级氧化蛋白产物（AOPP）、丙二醛（MDA）和总氧化状态（TOS）。这种影响伴随着血浆中抗氧化酶-超氧化物歧化酶（SOD）和对氧氧化酶1 （PON1）活性的降低和pbl DNA损伤的增加。在描述的TRD模型中，我们首次证明了氯胺酮的抗抑郁作用。我们的结果表明氯胺酮是有效的还原氧。-、AOPP、MDA和TOS，同时增强acth大鼠的SOD和PON1活性。总的来说，我们的研究揭示了氯胺酮抗氧化活性的分子机制，从而激励其在临床试验中进一步研究其对ROS代谢和抗氧化防御的影响，特别是在抑郁症中。

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引用次数: 0

Olfactory bulb interneurons – The developmental timeline and targeting defined by embryonic neurogenesis 嗅球中间神经元 - 胚胎神经发生所确定的发育时间表和目标。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-22 DOI: 10.1016/j.mcn.2025.104007

Natalie J. Spence , Eduardo Martin-Lopez , Kimberly Han , Marion Lefèvre , Nathaniel W. Lange , Bowen Brennan , Charles A. Greer

The generation of mouse olfactory bulb (OB) interneurons (INs) is initiated in the embryo but continues throughout life. It is generally agreed that OB INs generated postnatally affect the connectivity of the OB, depending on the timeline of neurogenesis. Here, we focused on OB INs generated embryonically, which have generally received less attention than those generated in the adult. Birthdates of embryonic INs were differentiated by maternal injections of thymidine analogs and their final destinations and phenotypes in the OB analyzed by immunohistochemistry. We found that the first embryonic INs were generated at embryonic day 10 (E10) and continued through the entire embryonic development. Analysis in adult tissues showed that embryonic INs were retained and were distributed across all layers of the OB. Interestingly, an initial lateral preference in cell density was seen in INs generated during E11–E13. Although INs are broadly distributed in the OB, we found that within the granule cell layer (GCL), OB INs distributed mostly in the superficial GCL. Immunostaining for calbindin, parvalbumin, tyrosine hydroxylase, 5T4 and calretinin were lacking co-expression with thymidine analogs labeled cells, suggesting that maturation of embryonic INs occurred slowly following birth. We studied the embryonic neuroblasts migration and differentiation by labeling IN progenitor cells in the lateral ganglionic eminence using in utero electroporation. We found that IN neuroblasts reached the primordial OB as early as E13 and began to differentiate apical dendrites by E15, which extended into the developing external plexiform layer. We established E16 as the embryonic stage at which the prototypical chain of migrating neuroblasts denoting the embryonic rostral migratory stream (RMS) was visible. Collectively, our data highlight the importance of studying OB INs in isolated time windows to better understand the formation of circuits that define the olfactory system function.

小鼠嗅球（OB）中间神经元（INs）的生成始于胚胎，但持续一生。人们普遍认为，出生后生成的嗅球神经元会影响嗅球的连通性，这取决于神经元生成的时间轴。在这里，我们将重点放在胚胎期产生的外胚层 INs 上，因为与成年期产生的外胚层 INs 相比，胚胎期产生的外胚层 INs 通常受到的关注较少。通过母体注射胸苷类似物来区分胚胎 IN 的出生日期，并通过免疫组化分析它们在 OB 中的最终去向和表型。我们发现，第一批胚胎 INs 在胚胎第 10 天（E10）产生，并贯穿整个胚胎发育过程。对成体组织的分析表明，胚胎 INs 保留了下来，并分布于 OB 的所有层。有趣的是，在E11-E13期间生成的INs细胞密度最初具有侧向偏好。虽然 INs 在 OB 中广泛分布，但我们发现在颗粒细胞层（GCL）中，OB INs 主要分布在 GCL 表层。免疫染色的钙宾蛋白、副钙蛋白、酪氨酸羟化酶、5 T4和钙网蛋白与胸苷类似物标记的细胞缺乏共表达，这表明胚胎INs的成熟在出生后缓慢发生。我们利用宫内电穿孔技术标记了外侧神经节突起的IN祖细胞，从而研究了胚胎神经母细胞的迁移和分化。我们发现，IN 神经母细胞早在 E13 就到达了原始 OB，到 E15 开始分化顶端树突，并延伸到发育中的外部丛状层。我们将 E16 确立为胚胎阶段，在这一阶段可以看到代表胚胎喙迁徙流（RMS）的迁徙神经母细胞原型链。总之，我们的数据凸显了在孤立的时间窗口中研究OB INs以更好地了解定义嗅觉系统功能的回路形成的重要性。

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引用次数: 0

Exosome-based therapeutics: Advancing drug delivery for neurodegenerative diseases 基于外泌体的治疗：推进神经退行性疾病的药物输送。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-22 DOI: 10.1016/j.mcn.2025.104004

Sakshi Rai , Suman Kumar Ray , Jagat R. Kanwar , Sukhes Mukherjee

Neurodegenerative disorders include Parkinson's disease, spinal cord injury, multiple sclerosis and Alzheimer's disease, cause gradual neuronal loss, protein misfolding, and accumulation, resulting in severe cognitive and movement deficits. Despite substantial study, therapeutic interventions are hampered by the blood-brain barrier, which prevents medication distribution to the central nervous system. Traditional pharmaceutical methods, such as small compounds, peptides, and inhibitors, have shown minimal effectiveness in addressing this obstacle. Exosomes are nanoscale membrane-bound vesicles that are primarily engaged in intercellular communication. They have the inherent capacity to cross the blood-brain barrier, which allows them to be used as medication delivery vehicles for brain illness therapy. Exosomes may be derived from a variety of cells like microglia, astrocytes identified according to origin, increasing their flexibility as drug delivery vehicles. Advanced engineering approaches optimise exosomes for tailored distribution across the blood-brain barrier, paving the path for novel neurodegenerative disease treatments. This review discusses the promise of exosome-based drug delivery, focussing on their composition, biogenesis, engineering, and applications in treating central nervous system illnesses, eventually overcoming the unmet hurdles of crossing the blood-brain barrier.

神经退行性疾病包括帕金森病、脊髓损伤、多发性硬化症和阿尔茨海默病，这些疾病会导致神经元逐渐丧失、蛋白质错误折叠和堆积，从而造成严重的认知和运动障碍。尽管进行了大量研究，但血脑屏障阻碍了药物进入中枢神经系统，从而阻碍了治疗干预。传统的制药方法，如小化合物、肽和抑制剂，在解决这一障碍方面效果甚微。外泌体是一种纳米级膜结合囊泡，主要参与细胞间通信。外泌体具有穿越血脑屏障的固有能力，因此可用作治疗脑部疾病的药物输送载体。外泌体可以根据来源从小胶质细胞、星形胶质细胞等多种细胞中提取，从而提高了它们作为药物输送载体的灵活性。先进的工程方法优化了外泌体在血脑屏障中的分布，为新型神经退行性疾病治疗铺平了道路。这篇综述讨论了基于外泌体的药物递送的前景，重点是外泌体的组成、生物生成、工程学以及在治疗中枢神经系统疾病中的应用，最终克服跨越血脑屏障这一尚未解决的障碍。

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引用次数: 0

GSK-3β dysregulation in aging: Implications for tau pathology and Alzheimer's disease progression GSK-3β在衰老中的失调：对tau病理和阿尔茨海默病进展的影响

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-20 DOI: 10.1016/j.mcn.2025.104005

A. Rekha , Muhammad Afzal , M. Arockia Babu , Soumya V. Menon , Deepak Nathiya , S. Supriya , Shakti Bedanta Mishra , Sofia Gupta , Kavita Goyal , Mohit Rana , Haider Ali , Mohd Imran

The role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Alzheimer's disease (AD) is critical for linking amyloid-beta (Aβ) and Tau pathology. The activity of GSK-3β is dysregulated in the regulation of Tau hyperphosphorylation, formation of neurofibrillary tangles (NFTs), and production of Aβ by modulating amyloid precursor protein (APP) processing. This review discusses the mechanisms controlling GSK-3β dysregulation in aging and its influence on AD progression, focusing on the role of neuroinflammation, oxidative stress, and defective signaling pathways, including PI3K/Akt and Wnt. Critical analysis is presented for therapeutic strategies targeting GSK-3β using natural compounds (e.g., curcumin, geniposide) and emerging approaches such as TREM2 modulation and miRNA therapies. In preclinical models, these interventions promise to reduce Tau hyperphosphorylation and Aβ burden, along with associated neurodegeneration. Nevertheless, achieving selective GSK-3β inhibition and optimizing drug delivery are still critical barriers to clinical translation. This review underscores the central role of GSK-3β in AD pathogenesis to highlight its potential as a multifaceted therapeutic target of an innovative strategy for treating this complex neurodegenerative disease.

糖原合酶激酶-3β（GSK-3β）在阿尔茨海默病（AD）发病机制中的作用对于将淀粉样β（Aβ）和Tau病理学联系起来至关重要。通过调节淀粉样前体蛋白（APP）的加工过程，GSK-3β的活性在调节Tau过度磷酸化、神经纤维缠结（NFT）的形成和Aβ的产生过程中失调。这篇综述讨论了控制衰老过程中GSK-3β失调的机制及其对AD进展的影响，重点是神经炎症、氧化应激和信号通路缺陷（包括PI3K/Akt和Wnt）的作用。报告还对利用天然化合物（如姜黄素、基尼泊苷）靶向 GSK-3β 的治疗策略以及 TREM2 调节和 miRNA 治疗等新兴方法进行了深入分析。在临床前模型中，这些干预措施有望减少 Tau 过度磷酸化和 Aβ 负担以及相关的神经退行性变。然而，实现 GSK-3β 的选择性抑制和优化给药仍然是临床转化的关键障碍。本综述强调了GSK-3β在AD发病机制中的核心作用，以突出其作为治疗这种复杂神经退行性疾病的创新策略的多方面治疗靶点的潜力。

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引用次数: 0

Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions 急性损伤大脑皮质单细胞转录变化的询问介质：内皮-星形胶质细胞相互作用的见解。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-14 DOI: 10.1016/j.mcn.2025.104003

Caroline de Jager , Eman Soliman , Michelle H. Theus

Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0–C5) in the damaged cortex including as C0-Mobp/Plp1+; C1-Slc1a3/Clu+; C2-Hbb-bs/Hba-a1/Ndrg2+; C3-GFAP/Lcn2+; C4-Gli3/Mertk+, and C5-Cox8a+. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (APP) and Gas6. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells—such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription—indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.

创伤性脑损伤（TBI）引起复杂的细胞和分子变化，给康复和治疗发展带来挑战。尽管分子途径与TBI病理有关，但这些机制的细胞特异性仍未得到充分探讨。在这里，我们研究了内皮细胞（EC） EphA4（一种参与轴突引导的酪氨酸激酶受体）在调节受损大脑皮层细胞特异性转录组变化中的作用。利用实验性TBI模型中的单细胞RNA测序（scRNA-seq），我们绘制了不同细胞类型的转录变化，重点是星形胶质细胞和内皮细胞。我们的分析表明，ec特异性敲除（KO） EphA4会引发星形胶质细胞基因表达的显著改变，并改变主要亚簇。我们在受损皮质中发现了6个不同的星形胶质细胞簇（C0-C5），包括C0-Mobp/Plp1+；C1-Slc1a3 / Clu +;C2-Hbb-bs / Hba-a1 / Ndrg2 +;C3-GFAP / Lcn2 +;C4-Gli3/Mertk+和C5-Cox8a+。我们验证了一个新的表达Mertk和Gas的Sox9+簇，它介导efferocytosis，促进凋亡细胞清除和抗炎反应。EC-KO细胞的转录组学和CellChat分析强调了神经保护通路的上调，包括淀粉样蛋白前体蛋白（APP）和Gas6的增加。预测EC-KO小鼠星形胶质细胞中被调节的关键通路包括氧化磷酸化和FOXO信号，线粒体功能障碍和ephrin B信号。同时，内皮细胞的代谢和信号通路，如神经酰胺和鞘氨醇磷酸代谢和ngf刺激的转录，表明了对损伤后缺氧环境代谢要求的适应性反应。这些发现阐明了星形细胞和内皮细胞反应之间的潜在相互作用，以及皮层组织损伤背后的转录网络。

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引用次数: 0

RBM15 relies on m6A modification to inhibit UBE2C, alleviating hippocampal neuronal injury by limiting microglial inflammation RBM15依靠m6A修饰抑制UBE2C，通过限制小胶质细胞炎症减轻海马神经元损伤。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-04 DOI: 10.1016/j.mcn.2025.103996

Yuehong Wan, Qin Kang, Ji Zhang, Canru Yu, Susu Fang, Dongqin Zou, Wen Chai

Background

Microglia are strongly implicated in the development and progression of epilepsy, yet their impact on pathology remains unclear. This study aimed to explore the effects of ubiquitin-conjugating enzyme 2C (UBE2C) m6A methylation on microglial activation and neuronal injury in epilepsy.

Methods

A mouse model of pilocarpine-induced status epilepticus was constructed, and an in vitro system of HT22 hippocampal neurons was induced with Mg²⁺-free medium and cocultured with BV2 cells. The secretion of TNF-α, IL-6 and iNOS from BV2 cells was measured via qRT–PCR and ELISA. CCK-8 and flow cytometry were performed to verify cell viability and apoptosis. RNA degradation, RIP and Me-RIP assays were performed.

Results

RBM15 levels were decreased, whereas UBE2C levels were increased in the hippocampi of epileptic mice. Silencing UBE2C or overexpressing RBM15 suppressed the release of inflammatory cytokines (TNF-α and IL-6) and the M1 microglia activation marker iNOS in Mg²⁺-free BV2 cells, thereby limiting damage to hippocampal injured neurons. Mechanistically, RBM15 bound to UBE2C mRNA and decreased its stability via m6A methylation. Additionally, RBM15 inhibited the inflammatory activation of BV2 and HT22 neuron injury by inhibiting UBE2C.

Conclusion

The increase in UBE2C m6A modification induced by RBM15 upregulation inhibits hippocampal neuron damage through the suppression of microglial inflammation, providing important clues and potential targets for novel therapeutics for epilepsy.

背景：小胶质细胞与癫痫的发生和发展密切相关，但其对病理的影响尚不清楚。本研究旨在探讨泛素偶联酶2C (UBE2C) m6A甲基化对癫痫小胶质细胞活化和神经元损伤的影响。方法：建立匹罗卡品诱导的小鼠癫痫持续状态模型，用无Mg2+培养基诱导HT22海马神经元体外系统，并与BV2细胞共培养。采用qRT-PCR和ELISA检测BV2细胞分泌TNF-α、IL-6和iNOS的水平。CCK-8和流式细胞术检测细胞活力和凋亡情况。进行RNA降解、RIP和Me-RIP测定。结果：癫痫小鼠海马区RBM15水平降低，UBE2C水平升高。沉默UBE2C或过表达RBM15可抑制无Mg2+ BV2细胞中炎症因子（TNF-α和IL-6）和M1小胶质细胞激活标志物iNOS的释放，从而限制对海马损伤神经元的损伤。机制上，RBM15结合UBE2C mRNA并通过m6A甲基化降低其稳定性。此外，RBM15通过抑制UBE2C抑制BV2的炎症激活和HT22神经元损伤。结论：RBM15上调引起的UBE2C m6A修饰增加通过抑制小胶质细胞炎症抑制海马神经元损伤，为癫痫新疗法提供重要线索和潜在靶点。

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引用次数: 0

P2X7 receptor augments kainic acid-induced nitrosative stress by abrogating GS-HSP25-mediated iNOS inhibition and GSH synthesis in the mouse hippocampus P2X7受体通过消除gs - hsp25介导的iNOS抑制和小鼠海马GSH合成，增强了kainic酸诱导的亚硝应激。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-03-02 DOI: 10.1016/j.mcn.2025.103995

Ji-Eun Kim, Duk-Shin Lee, Su Hyeon Wang, Tae-Cheon Kang

Glutathione (GSH) and heat shock protein 25 (HSP25) reciprocally regulate each other, which maintain redox homeostasis. Since P2X7 receptor (P2X7R) regulates GSH biosynthesis and HSP25 induction, the present study was conducted to explore the role of P2X7R in the reciprocal regulation between HSP25 and GSH in response to kainic acid (KA)-induced nitrosative stress and the related signal pathways, which are largely unknown. The present data demonstrate that P2X7R deletion attenuated KA-induced reductions in total GSH level and nuclear factor-erythroid 2-related factor 2 (Nrf2) intensity/nuclear translocation in astrocytes. P2X7R ablation increased Nrf2 intensity/nuclear translocation in microglia following KA treatment. P2X7R deletion also ameliorated KA-induced inducible nitric oxide synthase (iNOS) and S-nitrosylated-cysteine (SNO-Cys) inductions in microglia and astrocytes. However, P2X7R ablation could not affect KA-induced nuclear Nrf2 translocation and SNO-Cys production in CA3 neurons. Furthermore, P2X7R ablation mitigated S-nitrosylations of glutamine synthase (GS) and alanine-serine-cysteine transporter 2 (ASCT2) induced by KA. HSP25 knockdown increased GSH consumption, astroglial iNOS level and S-nitrosylations of GS and ASCT2, but decreased Nrf2 intensity/nuclear translocation in astrocytes of P2X7R^−/− mice following KA injection. These findings indicate that P2X7R facilitated iNOS upregulation by inhibiting HSP25 induction and nuclear Nrf2 translocation in astrocytes, which augmented nitrosative stress-mediated reduction in GSH biosynthesis in response to KA. Therefore, our data suggest that the targeting of P2X7R-Nrf2-iNOS-GS-HSP25 pathway may be required for the maintenance of GSH-mediated redox homeostasis against nitrosative stress, which would prevent the progression of undesirable consequences from seizures and neuroinflammation.

谷胱甘肽（GSH）和热休克蛋白25 （HSP25）相互调节，维持氧化还原稳态。由于P2X7受体（P2X7R）调节GSH的生物合成和HSP25的诱导，因此本研究旨在探索P2X7R在kainic acid （KA）诱导的亚硝化胁迫下HSP25和GSH相互调节中的作用及其相关信号通路，这些信号通路目前尚不清楚。目前的数据表明，P2X7R缺失减弱了ka诱导的星形胶质细胞中总GSH水平和核因子-红细胞2相关因子2 （Nrf2）强度/核易位的降低。P2X7R消融增加了KA治疗后小胶质细胞中Nrf2强度/核易位。P2X7R缺失也改善了ka诱导的诱导型一氧化氮合酶（iNOS）和s -亚硝基化半胱氨酸（SNO-Cys）在小胶质细胞和星形胶质细胞中的诱导作用。然而，P2X7R消融术不影响ka诱导的CA3神经元核Nrf2易位和SNO-Cys的产生。此外，P2X7R消蚀可减轻KA诱导的谷氨酰胺合成酶（GS）和丙氨酸-丝氨酸-半胱氨酸转运蛋白2 （ASCT2）的s -亚硝基化。HSP25敲除增加了GSH消耗、星形胶质细胞iNOS水平和GS和ASCT2的s -亚硝基化，但降低了注射KA后P2X7R-/-小鼠星形胶质细胞Nrf2强度/核易位。这些发现表明，P2X7R通过抑制星形胶质细胞中HSP25的诱导和核Nrf2的易位，促进了iNOS的上调，从而增强了亚硝化应激介导的GSH生物合成的减少。因此，我们的数据表明，P2X7R-Nrf2-iNOS-GS-HSP25通路可能是维持gsh介导的抗亚硝化应激氧化还原稳态所必需的，这将防止癫痫发作和神经炎症等不良后果的发展。

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引用次数: 0

A microglial kinase ITK mediating neuroinflammation and behavioral deficits in traumatic brain injury 一种介导创伤性脑损伤中神经炎症和行为缺陷的小胶质细胞激酶 ITK。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-01-27 DOI: 10.1016/j.mcn.2025.103994

Ruqayya Afridi , Anup Bhusal , Seung Eun Lee , Eun Mi Hwang , Hoon Ryu , Jong-Heon Kim , Kyoungho Suk

Microglia-mediated neuroinflammation has been implicated in the neuropathology of traumatic brain injuries (TBI). Recently, the expression of interleukin-2-inducible T-cell kinase (ITK) has been detected in brain microglia, regulating their inflammatory activities. However, the role of microglial ITK in TBI has not been investigated. In this study, we demonstrate that ITK expression and activation are upregulated in microglia following an injury caused by controlled cortical impact (CCI) – a mouse model of TBI. Pharmacological inhibition of ITK protein or knockdown of microglial ITK gene expression using adeno-associated virus mitigates neuroinflammation and improves neurological outcomes in the CCI model. Additionally, ITK mRNA expression was found to be increased in the brains of patients with chronic traumatic encephalopathy. An ITK inhibitor reduced the activation of inflammatory responses in both human and mouse microglia in vitro. Collectively, these results suggest that microglial ITK plays a pivotal role in neuroinflammation and mediating behavioral deficits following TBI. Thus, targeting the signaling pathway of microglial ITK may exert protective effects by alleviating neuroinflammation associated with TBI.

小胶质细胞介导的神经炎症与创伤性脑损伤（TBI）的神经病理学有关。近年来，在脑小胶质细胞中检测到白细胞介素2诱导t细胞激酶（interleukin-2-inducible T-cell kinase， ITK）的表达，调节其炎症活性。然而，小胶质ITK在脑外伤中的作用尚未被研究。在这项研究中，我们证明了ITK的表达和激活在创伤性脑损伤小鼠模型——控制性皮质冲击（CCI）损伤后的小胶质细胞中上调。在CCI模型中，使用腺相关病毒对ITK蛋白进行药理学抑制或敲低小胶质细胞ITK基因表达可减轻神经炎症并改善神经预后。此外，在慢性创伤性脑病患者的大脑中发现ITK mRNA表达增加。ITK抑制剂在体外降低了人和小鼠小胶质细胞炎症反应的激活。总之，这些结果表明，小胶质ITK在TBI后的神经炎症和介导行为缺陷中起着关键作用。因此，靶向小胶质ITK信号通路可能通过减轻TBI相关的神经炎症发挥保护作用。

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引用次数: 0

Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling 神经退行性疾病中的线粒体分裂和融合：Ca2+ 信号。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-01-23 DOI: 10.1016/j.mcn.2025.103992

Xuan Liu , Tianjiao Li , Xinya Tu, Mengying Xu, Jianwu Wang

Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca²⁺ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca²⁺ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca²⁺ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca²⁺ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.

神经退行性疾病是一组以神经元结构和功能逐渐丧失为特征的疾病。发病机制是复杂的，涉及多个原因和系统之间的相互作用网络。线粒体和Ca2+信号一直被认为在各种NDs的发展中起重要作用。线粒体的裂变和融合动力学是线粒体质量控制的重要过程，保证了线粒体结构和功能的稳定性。线粒体分裂和融合失衡和Ca2+信号紊乱可加剧NDs的疾病进展。在这篇综述中，我们探讨了AD， PD， ALS和HD中线粒体动力学和Ca2+信号之间的关系，重点关注关键调节蛋白（Drp1, Fis1， Mfn1/2和Opa1）的作用以及线粒体和内质网（MERCs/MAMs）之间的关联结构。我们提供了一个详细的分析，他们参与这四个nd的发病机制。通过整合这些机制，我们旨在阐明它们对疾病进展的贡献，并为针对线粒体动力学和Ca2+信号的治疗策略的发展提供见解。我们还研究了靶向这些通路的药物研究进展，强调了它们作为治疗ndds的治疗靶点的潜力。

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引用次数: 0

Identifying potential genes driving ferroptosis in the substantia nigra and dopaminergic neurons in Parkinson's disease 帕金森病患者黑质和多巴胺能神经元中驱动铁下垂的潜在基因。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-01-21 DOI: 10.1016/j.mcn.2025.103993

Ardra Chakrabarti, Sonia Verma

Parkinson's disease (PD) is a neurodegenerative disorder marked by dopaminergic (DA) neuron degeneration in the substantia nigra (SN). Conventional dopamine replacement therapies provide limited long-term efficacy and significant side effects. Emerging evidence suggests ferroptosis—a form of cell death driven by iron-dependent lipid peroxidation—contributes to PD pathology, though direct evidence linking dysregulation of ferroptosis-related genes in DA neuron loss in PD remains limited. This study explores the expression of ferroptosis-associated genes in the SN and DA neurons of PD patients, identifying potential therapeutic targets. We analyzed two independent RNA-seq datasets, GSE7621 and GSE8397 (GPL-96), from the GEO database to identify common differentially expressed ferroptosis-related genes in the SN of PD patients. We also conducted Gene Ontology and pathway enrichment analyses of these genes to explore the underlying mechanisms and constructed a protein-protein interaction network. The findings were further validated using an additional dataset, GSE49036. We further explored the dysregulation of these ferroptosis-related genes in DA neurons using RNA-seq data GSE169755, derived from DA neurons isolated from the SN of PD patients and controls. Lastly, the proposed hypothesis was experimentally validated in an in vitro PD model. This comprehensive multi-dataset analysis uncovers novel insights into the expression of ferroptosis-related genes in PD, suggesting potential biomarkers and therapeutic targets for mitigating DA neuron loss and PD progression.

帕金森病（PD）是一种以黑质（SN）多巴胺能（DA）神经元变性为特征的神经退行性疾病。传统的多巴胺替代疗法提供有限的长期疗效和显著的副作用。新出现的证据表明，铁中毒是一种由铁依赖性脂质过氧化驱动的细胞死亡形式，有助于帕金森病的病理，尽管直接证据表明，铁中毒相关基因失调与帕金森病的DA神经元损失有关，但仍然有限。本研究探讨PD患者SN和DA神经元中嗜铁相关基因的表达，寻找潜在的治疗靶点。我们分析了GEO数据库中两个独立的RNA-seq数据集GSE7621和GSE8397 (GPL-96)，以确定PD患者SN中常见的差异表达铁衰相关基因。我们还对这些基因进行了基因本体（Gene Ontology）和通路富集分析，探索其潜在机制，并构建了蛋白-蛋白相互作用网络。使用另一个数据集GSE49036进一步验证了这些发现。我们利用从PD患者和对照组的SN分离的DA神经元中提取的RNA-seq数据GSE169755进一步探讨了DA神经元中这些铁中毒相关基因的失调。最后，在体外PD模型中验证了所提出的假设。这项综合的多数据集分析揭示了PD中铁细胞凋亡相关基因表达的新见解，提出了减轻DA神经元丢失和PD进展的潜在生物标志物和治疗靶点。

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引用次数: 0