Neurotherapeutics最新文献_第7页

Safety and efficacy of Igk-TATk-CDKL5 gene therapy in mosaic CDKL5 deficiency Igk-TATk-CDKL5基因治疗镶嵌性CDKL5缺乏症的安全性和有效性。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00727

Giorgio Medici , Marianna Tassinari , Manuela Loi , Angelica Marina Bove , Beatrice Casadei Garofani , Greta Volpedo , Nicola Mottolese , Gabriele Matteoli , Viviana Lo Martire , Chiara Berteotti , Giulia Candini , Federica Trebbi , Antonella Riva , Pasquale Striano , Giovanna Zoccoli , Giulia Curia , Stefania Trazzi , Elisabetta Ciani

CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene, resulting in early-onset seizures, developmental delays, and cognitive and sensorimotor impairments. While emerging therapies show promise, substantial challenges remain in developing a cure for CDD. In our prior work, we developed an innovative gene therapy strategy based on an Igk-TATk-CDKL5 fusion protein, which enhances brain distribution of the therapeutic protein, significantly improving treatment efficacy in a Cdkl5 knockout male mouse model. However, CDKL5 dosage sensitivity may pose challenges in patients with mosaic loss of CDKL5 function, potentially limiting the treatment's effectiveness or even exacerbating clinical symptoms. In this study, we aimed to address this gap by evaluating the safety and efficacy of Igk-TATk-CDKL5 therapy in a heterozygous female mouse model (Cdkl5 +/−), which better represents the majority of human CDD patients. We found that introducing Igk-TATk-CDKL5 significantly improved behavioral phenotypes and corrected brain structural defects, such as dendritic morphology and connectivity. Importantly, no adverse effects were observed in the brain or peripheral organs (e.g., the heart), indicating that CDKL5 overexpression in the heterozygous condition was well tolerated. These findings support the therapeutic potential of Igk-TATk-CDKL5 and suggest that a possible cross-correction mechanism may contribute to its efficacy, even in the context of mosaic CDKL5 deficiency. This approach may therefore offer promising therapeutic outcomes for patients with CDD.

CDKL5缺乏性障碍（CDKL5 Deficiency Disorder， CDD）是一种由x连锁CDKL5基因突变引起的严重神经发育障碍，可导致早发性癫痫发作、发育迟缓以及认知和感觉运动障碍。虽然新兴疗法显示出希望，但在开发治疗CDD的方法方面仍存在重大挑战。在我们之前的工作中，我们开发了一种基于Igk-TATk-CDKL5融合蛋白的创新基因治疗策略，该策略增强了治疗蛋白的脑分布，显著提高了Cdkl5敲除雄性小鼠模型的治疗效果。然而，CDKL5剂量敏感性可能对CDKL5功能马赛克丧失的患者构成挑战，可能限制治疗的有效性，甚至加重临床症状。在本研究中，我们旨在通过在杂合雌性小鼠模型（Cdkl5 +/-）中评估Igk-TATk-CDKL5治疗的安全性和有效性来解决这一空白，该模型更好地代表了大多数人类CDD患者。我们发现，引入Igk-TATk-CDKL5显著改善了行为表型并纠正了脑结构缺陷，如树突形态和连通性。重要的是，在大脑或外周器官（如心脏）中未观察到不良反应，这表明CDKL5在杂合条件下的过表达是耐受良好的。这些发现支持了Igk-TATk-CDKL5的治疗潜力，并提示一种可能的交叉校正机制可能有助于其疗效，即使在马赛克CDKL5缺乏的情况下。因此，这种方法可能为CDD患者提供有希望的治疗结果。

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引用次数: 0

Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS 靶向TDP-43的抗体可减轻ALS脑脊液诱导的致病途径。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00737

Amélie Poulin-Brière , Silvia Pozzi , Jean-Pierre Julien

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43^A315T of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43^WT. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.

肌萎缩性侧索硬化症（ALS）是一种无法治愈的神经退行性疾病，其特征是胞浆中TAR DNA结合蛋白43 （TDP-43）的错误定位和积累。我们之前报道了在表达als连锁突变体TDP-43A315T的转基因小鼠模型中，单克隆抗体E6特异性结合TDP-43的RNA识别Motif 1 （RRM1）结构域，具有保护作用。本研究通过将散发型ALS患者的脑脊液（CSF）注入表达人TDP-43WT的转基因小鼠体内14天，测试了E6抗体在散发型ALS动物模型中的作用。在这种疾病模型中，鞘内注射或体外注射E6抗体都具有保护作用。因此，接种csf的E6抗体可减少运动和认知障碍，减轻TDP-43蛋白病变，防止皮层和脊髓神经元的神经丝（Nf）紊乱。注射E6抗体可减少脊髓运动神经元的丢失和神经肌肉连接处的去神经支配。此外，E6抗体促进了与小胶质细胞活化的保护性表型相关的特征的转换，其特征是增强吞噬功能和减少促炎细胞因子的分泌。结果表明，针对TDP-43的RRM1结构域的免疫治疗可能对ALS患者CSF触发的致病途径具有保护作用。

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引用次数: 0

Talin 1 plays a significant role in the development of tolerogenic dendritic cells, which may contribute to the progression of multiple sclerosis Talin 1在耐受性树突状细胞的发展中起重要作用，这可能有助于多发性硬化症的进展。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00731

Kouichi Ito

引用次数: 0

Nanoparticle and epothilone D combinatorial intervention improves motor performance and regeneration in chronic cervical spinal cord injury 纳米颗粒和艾替隆D联合干预可改善慢性颈脊髓损伤的运动表现和再生。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00742

Sarah E. Hocevar , Brian C. Ross , Samantha R. Schwartz , Brooke M. Smiley , Brian J. Cummings , Aileen J. Anderson , Lonnie D. Shea

Spinal cord injury (SCI) causes the loss of motor function below the site of injury due to neuron loss and the severing of spinal tracts. The injury leads to the recruitment of circulating myeloid cells that create an inflammatory microenvironment and exacerbate cell death, with subsequent migration of fibroblasts and astrocytes that contribute to scar tissue that inhibits regeneration. Herein, we investigated a combinatorial treatment in a chronic cervical hemisection model involving cargo-less nanoparticles (NPs) administered acutely, and a multichannel bridge and microtubule stabilizer delivered chronically. NPs administration acutely for one-week post-injury contributed to improved paw placement on a ladder beam relative to vehicle control. Four weeks after injury, damaged tissue was resected, and a microporous, multichannel PLG bridge was inserted to reduce scar tissue and provide a substrate for axon regrowth. Epothilone D (epoD), a microtubule stabilizer, was also administered to further decrease fibrotic scar formation and improve axon elongation. Mice receiving a scaffold with NP treatment or epoD treatment had improved motor performance, but the combination of NP and epoD maximally improved function. In conjunction with this improved performance, mice that received NPs or epoD exhibited increased neuromuscular junction innervation, robust axon growth into the bridge, and both oligodendrocyte and Schwann-cell myelination of regenerating axons. Collectively, these results suggest that a combinatorial treatment plan targeting inflammation and scarring, a substrate for growth, and growth-promoting factors can improve motor performance following SCI.

脊髓损伤（SCI）是由于神经元丧失和脊髓束切断而导致损伤部位以下运动功能丧失。损伤导致循环骨髓细胞的募集，形成炎症微环境，加剧细胞死亡，随后成纤维细胞和星形胶质细胞迁移，形成疤痕组织，抑制再生。在此，我们研究了慢性颈椎半切模型的组合治疗，包括急性给药无货物纳米颗粒（NPs）和慢性给药多通道桥和微管稳定剂。相对于车辆控制，损伤后一周内急性给予NPs有助于改善脚爪在梯梁上的放置。损伤后4周，切除受损组织，插入微孔多通道PLG桥以减少疤痕组织并为轴突再生提供基质。微管稳定剂Epothilone D （epoD）也可进一步减少纤维化瘢痕形成并改善轴突伸长。接受NP处理或epoD处理的支架小鼠的运动性能得到改善，但NP和epoD的组合最大程度地改善了功能。与此同时，接受NPs或epoD的小鼠表现出神经肌肉连接处神经支配增加，轴突向桥内生长强劲，再生轴突的少突胶质细胞和雪旺细胞髓鞘形成。总之，这些结果表明，针对炎症和瘢痕形成、生长基质和生长促进因子的组合治疗方案可以改善脊髓损伤后的运动表现。

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引用次数: 0

Synergistic mitochondrial impairment by endogenously elevated cyanide and hydrogen sulfide in Down syndrome; commentary on: Cyanide overproduction impairs cellular bioenergetics in Down syndrome 唐氏综合征患者体内氰化物和硫化氢升高引起的协同线粒体损伤评论：氰化物过量产生损害唐氏综合症的细胞生物能量学。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00757

Andrew A. Pieper , Bindu D. Paul

引用次数: 0

Intrathecal STAT3 inhibitor Bt354 ameliorates chronic constriction injury-induced nociceptive sensitization by modulating neuroinflammation 鞘内STAT3抑制剂Bt354通过调节神经炎症改善慢性收缩损伤诱导的伤害性敏化。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00763

Hao-Jung Cheng , Nan-Fu Chen , Yueh-Chiao Tang , Po-Chang Shih , Wu-Fu Chen , Ya-Jen Chiu , Chun-Sung Sung , Zhi-Hong Wen

Neuropathic pain poses a significant societal and clinical burden and is closely linked to neuroinflammation of the central nervous system. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of inflammatory processes and has been implicated in the development of nociceptive hypersensitivity. In this study, we aimed to elucidate the therapeutic potential and underlying mechanisms of STAT3 inhibition in a rodent model of neuropathic pain. Using behavioral assessments of nociceptive sensitivity and immunofluorescence analysis, we investigated the analgesic mechanisms of the intrathecal STAT3 inhibitor, Bt354, in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. Cellular and molecular markers of glial activation and inflammation were examined to assess the effects of Bt354 on neuroinflammatory pathways. Intrathecal administration of Bt354 significantly reduced CCI-induced mechanical allodynia and thermal hyperalgesia, accompanied by a marked decrease in phosphorylated STAT3 (pSTAT3) expression in spinal neurons. Bt354 treatment attenuated the polarization of M1-type microglia and A1-type astrocytes, suppressed inflammasome-related signaling, and mitigated neuroinflammatory responses. Importantly, Bt354 inhibited the nuclear translocation of neuronal pSTAT3, which is a critical step in regulating pro-inflammatory gene transcription. Moreover, CCI-induced angiogenesis and microglial phosphorylation of CREB and P38 were mitigated by pSTAT3 inhibition. These findings suggest that STAT3 plays a central role in the pathogenesis of neuropathic pain by regulating glial cell polarization and neuroinflammation. Targeting STAT3 with Bt354 may represent a promising therapeutic strategy for treating neuropathic pain.

神经性疼痛是一个重要的社会和临床负担，与中枢神经系统的神经炎症密切相关。信号换能器和转录激活因子3 （STAT3）是炎症过程的关键调节因子，并与伤害性超敏反应的发展有关。在这项研究中，我们旨在阐明STAT3抑制在啮齿动物神经性疼痛模型中的治疗潜力和潜在机制。通过伤害性敏感性行为评价和免疫荧光分析，我们研究了鞘内STAT3抑制剂Bt354对坐骨神经慢性收缩损伤（CCI）大鼠的镇痛机制。检测神经胶质活化和炎症的细胞和分子标志物，以评估Bt354对神经炎症通路的影响。鞘内给药Bt354可显著降低cci诱导的机械异常性痛和热痛觉过敏，并伴有脊髓神经元中磷酸化STAT3 （pSTAT3）表达的显著降低。Bt354治疗可减弱m1型小胶质细胞和a1型星形胶质细胞的极化，抑制炎性小体相关信号传导，减轻神经炎症反应。重要的是，Bt354抑制了神经元pSTAT3的核易位，这是调节促炎基因转录的关键步骤。此外，cci诱导的血管生成和小胶质细胞CREB和P38的磷酸化被pSTAT3抑制减轻。这些发现表明STAT3通过调节神经胶质细胞极化和神经炎症在神经性疼痛的发病机制中起核心作用。Bt354靶向STAT3可能是治疗神经性疼痛的一种有前景的治疗策略。

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引用次数: 0

Effectiveness of Anti-CD20 B cells depleting therapy versus conventional treatment in severe Anti-N-methyl-d-aspartate receptor encephalitis: A real-world multi-center prospective cohort study 抗cd20b细胞消耗疗法与常规治疗在严重抗n -甲基-d-天冬氨酸受体脑炎中的有效性：一项现实世界多中心前瞻性队列研究

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00766

Baojie Wang , Yuxiu Xiao , Yufeng Chu , Chunjuan Wang , Hao Sun , Teng Huang , Danqing Qin , Xuetao Cao , Shuai Guo , Haotian Zhao , Xiumin Zhao , Shougang Guo

Approximately 25 %–40 % of anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) patients develop refractory disease with prolonged neurological deficits. We aim to evaluate the efficacy of B cell depletion therapy (BCDT) via CD20 antibodies versus conventional first-line immunotherapy only (intravenous methylprednisolone for 5 days, 0.4 g/kg intravenous immunoglobulin for 5 days, and ≥4 consecutive plasma exchange treatments, non-BCDT group) in treatment of severe NMDARE in the real-world setting. From multicenter cohort of severe NMDARE, 108 patients (ofatumumab group 36; rituxixmab group 36; non-BCDT group 36) were prospectively reviewed. The primary end point was the proportion of patients to achieving good outcomes (modified Rankin Scale scores ≤2) at 3 months. Secondary end points included longitudinal outcomes assessed by mRS scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores, cognitive function and adverse events (AEs). BCDT demonstrated a higher frequency of mRS scores ≤2 compared to non-BCDT at 3 months (ofatumumab 63.9 % vs. non-BCDT 36.1 %, p < 0.001; rituximab 55.6 % vs. non-BCDT 36.1 %, p = 0.007, respectively). Ofatumuamb showed superior therapeutic response at 1 month compared to both rituximab-treated patients (mean CASE score: 5.89 vs 7.91, p = 0.025) and non-BCDT treated patients (mean CASE score: 5.89 vs 9.97, p < 0.0001). All groups improved over 12 months, with significantly higher complete remission rates in BCDT groups (70.8 %–75 % vs. 55.6 %, p < 0.05). Five of 33 patients (15.2 %) experienced persistent mild cognitive impairment. AEs were mild-to moderate in severity. We calculated the probability of relapse-free as ofatumumab and rituximab reduced risk of disease relapses compared to non-BCDT (ofatumumab vs. non-BCDT: HR, 0.193; 95 % CI, 0.062–0.6; p = 0.007; rituximab vs. non-BCDT: HR, 0.265; 95 % CI, 0.089–0.787; p = 0.029). Therefore, we suggest that BCDT effectively promoted neurological recovery, and reduced relapse risk with favorable safety, while ofatumumab demonstrated superior efficacy in controlling early disease severity.

大约25% - 40%的抗n -甲基-d-天冬氨酸受体脑炎（NMDARE）患者发展为顽固性疾病，伴有长期的神经功能缺损。我们的目标是评估在现实世界中，通过CD20抗体的B细胞消耗疗法（BCDT）与传统的一线免疫疗法（静脉注射甲基强的松龙5天，静脉注射0.4 g/kg免疫球蛋白5天，连续≥4次血浆交换治疗，非BCDT组）治疗严重NMDARE的疗效。来自严重NMDARE多中心队列的108例患者（ofatumumab组36例；rituxxmab组36例；non-BCDT组36例）进行前瞻性回顾。主要终点是3个月时获得良好结局（修正Rankin量表评分≤2）的患者比例。次要终点包括mRS评分和自身免疫性脑炎临床评估量表（CASE）评分、认知功能和不良事件（ae）评估的纵向结局。3个月时，BCDT组mRS评分≤2的频率高于非BCDT组（ofatumumab组63.9%，非BCDT组36.1%,p < 0.001；利妥昔单抗组55.6%，非BCDT组36.1%,p = 0.007）。与利妥昔单抗治疗的患者（平均病例评分：5.89 vs 7.91, p = 0.025）和非bcdt治疗的患者（平均病例评分：5.89 vs 9.97, p < 0.0001）相比，Ofatumuamb在1个月时显示出更好的治疗反应。所有组在12个月内均有改善，BCDT组的完全缓解率明显更高（70.8% - 75% vs. 55.6%, p < 0.05）。33例患者中有5例（15.2%）出现持续性轻度认知障碍。ae的严重程度为轻度至中度。我们计算了无复发的概率，因为与非bcdt相比，ofatumumab和利妥昔单抗降低了疾病复发的风险（ofatumumab与非bcdt: HR， 0.193; 95% CI, 0.062-0.6; p = 0.007；利妥昔单抗与非bcdt: HR， 0.265; 95% CI, 0.089-0.787; p = 0.029）。因此，我们认为BCDT可有效促进神经系统恢复，降低复发风险，且安全性较好，而ofatumumab在控制早期疾病严重程度方面具有优越的疗效。

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引用次数: 0

Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases 在神经退行性疾病中，TCA循环中的异常s -亚硝基化有助于线粒体功能障碍、能量损害和突触丧失。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00708

Tomohiro Nakamura , Anamika Sharma , Stuart A. Lipton

Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.

神经元突触活动很大程度上依赖于线粒体能量的产生，因为突触传递需要大量的ATP。因此，线粒体功能障碍是突触丧失的一个关键潜在因素，而突触丧失与阿尔茨海默病和其他神经认知障碍的认知能力下降密切相关。越来越多的证据表明，升高的氮氧化应激损害线粒体的生物能量功能，导致突触变性。在这篇综述中，我们强调了一氧化氮（NO）依赖的翻译后修饰（PTMs）的病理生理作用，特别是半胱氨酸残基的s -亚硝基化，以及它们对线粒体代谢的影响。我们专注于三羧酸循环酶的病理s -亚硝基化，特别是α-酮戊二酸脱氢酶，以及电子传递链蛋白。这种异常的PTM破坏了线粒体的能量产生。此外，我们讨论了异常蛋白s -亚硝基化对线粒体动力学和线粒体自噬的影响，进一步导致线粒体功能障碍和突触丢失。最后，我们研究了目前在神经退行性疾病临床前模型中改善s -亚硝基化介导的线粒体功能障碍的策略，并探索了在硝基氧化应激背景下恢复线粒体代谢的神经疗法的未来发展方向。

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引用次数: 0

The GPR120 agonist TUG-891 mitigates ischemic brain injury by attenuating endoplasmic reticulum stress and apoptosis via the PI3K/AKT signaling pathway GPR120激动剂TUG-891通过PI3K/AKT信号通路减轻内质网应激和细胞凋亡，从而减轻缺血性脑损伤。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00735

Panxi Sun , Lili Wei , Xue Qin , Jia Luo , Dongsheng Fan , Yong Chen

Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.

大量研究证实，omega-3脂肪酸主要通过激活G蛋白偶联受体120 （GPR120）信号通路提供心血管保护。然而，这种受体的天然激活剂往往缺乏足够的强度和精度。TUG-891是最近合成的一种选择性GPR120激活剂，在多种疾病中显示出显著的治疗潜力。本研究旨在评价TUG-891对缺血性脑损伤的神经保护作用。为此，我们建立了小鼠大脑中动脉远端闭塞（dMCAO）的体内模型，同时建立了HT22细胞氧糖剥夺/再灌注的体外模型。结果表明，TUG-891能明显增强dMCAO大鼠神经功能，减少脑梗死体积，减轻病理性损伤。此外，在体内和体外实验中，TUG-891均能显著降低氧化应激水平、内质网应激相关标记物和关键凋亡调节因子，从而抑制细胞凋亡。此外，我们发现TUG-891影响PI3K/Akt信号通路，在体外应用抑制剂LY294002可使TUG-891的保护作用失效。这项综合研究揭示了TUG-891通过多靶点机制，包括氧化应激缓解、内质网应激调节和生存途径激活，对缺血性卒中的治疗潜力。在生物学模型中观察到的一致的神经保护强调了其对进一步临床开发的转化价值。

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引用次数: 0

Two roads diverged in multiple sclerosis: When is switching therapy effective? 多发性硬化症的两条不同道路：转换治疗何时有效？

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 DOI: 10.1016/j.neurot.2025.e00734

Anthony T. Reder

引用次数: 0