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更新于：2026-06-06

TGN-020

更新于：2026-06-06

概要

概要

基本信息

药物类型

小分子化药

别名

TGN-020

靶点

AQP4

作用方式

抑制剂

作用机制

AQP4抑制剂(水通道蛋白 4抑制剂)

治疗领域

神经系统疾病

在研适应症

脑水肿

非在研适应症-

原研机构

Niigata University

在研机构

Niigata University

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

项与 TGN-020 相关的临床试验

JPRN-UMIN000005626

/ CompletedN/AIIT

Clinical study using positron emission tomography(PET) - PET imaging of Aquapolin-1,4 using TGN020

开始日期2011-06-01

申办/合作机构-

100 项与 TGN-020 相关的临床结果

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100 项与 TGN-020 相关的转化医学

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100 项与 TGN-020 相关的专利（医药）

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项与 TGN-020 相关的文献（医药）

2026-06-01·EXPERIMENTAL EYE RESEARCH

Aquaporin-4 participates in the migration of retinal Müller cells by facilitating water transport and cytoskeleton reorganization

Article

作者: Capurro, Claudia ; Ford, Paula ; Netti, Vanina ; Di Giusto, Gisela ; Cocca, María Azul ; Echevarría, Miriam ; Cutrera, Nicolás

Müller cells are essential for retinal integrity and respond to injury by activating cell proliferation, migration and differentiation into a neuronal-like phenotype for tissue remodeling. Aquaporin-4 (AQP4), the most abundant water channel of the retina, contributes to water transport and the proliferation of Müller cells, but its role in the migration of these cells remains poorly understood. Because cell migration requires localized volume changes and cytoskeletal remodeling, and AQP4 has been linked to cytoskeleton dynamics, we investigated the contribution of AQP4 to Müller cell migration. MIO-M1 migrating Müller cells were exposed to TGN-020 (TGN, AQP4 inhibitor) or vehicle and we evaluated: cell migration (wound healing), AQP4, Actin and Vimentin (immunocytochemistry) and the kinetics of cell volume (videomicroscopy). Our results show that AQP4 inhibition decreased cell migration and water transport in the lamellipodia of Müller cells exposed to hypertonic media, without affecting cell volume regulation. In migrating cells, TGN also reduced the anisotropy of F-Actin fibers, which indicates their degree of organization, and changed Vimentin localization closer to the plasma membrane. Finally, the activation of the PI3K pathway regulates AQP4 expression in migrating cells. These findings identify, for the first time, a critical role of AQP4 in the migration of Müller cells, not only facilitating volume changes for lamellipodia formation but also the remodeling of the Actin and Vimentin cytoskeleton. Our results suggest the possibility of targeting AQP4 expression and/or function as a novel therapeutic strategy to prevent glial scar formation.

2026-05-01·Journal of Cerebral Blood Flow and Metabolism

Perivascular macrophage depletion impairs glymphatic clearance and amplifies cortical hyperexcitability: Preclinical insights with clinical validation

Article

作者: Hou, Changkai ; Zhao, Guoguang ; Tang, Ting ; Wang, Bangyue ; Ren, Wen ; Wei, Penghu ; Fu, Bin ; Liu, Quanlei ; Luo, Yumin ; Dai, Yang ; Shan, Yongzhi ; Xu, Jinkun

Perivascular macrophages (PVMs) are increasingly recognized as key players in maintaining brain homeostasis, yet their role in maintaining neurovascular–metabolic homeostasis has not been fully explored. We hypothesized that PVM depletion compromises cerebrospinal fluid-interstitial fluid exchange through glymphatic system (GS) dysfunction, thereby exacerbating cortical hyperexcitability manifested as increased epilepsy susceptibility and seizure intensity. Using clodronate liposomes (CLOs), we achieved >85% PVM depletion in mice. Following pentylenetetrazole (PTZ) challenge, PVM-depleted mice exhibited anxiety-like behaviors (reduced center time, p < 0.05), impaired working memory (decreased spontaneous alternation, p < 0.05), and increased cortical hyperexcitability, including shorter seizure latency and elevated EEG total power ( p < 0.05). Mechanistically, PVM loss led to dysregulation of extracellular matrix components (increased laminin and collagen IV), impairing perivascular space integrity and GS function (reduced CSF tracer clearance, p < 0.05). AQP4 inhibition with TGN-020 further exacerbated PTZ-induced EEG abnormalities (increased total power, p < 0.05). Analysis of human epileptic tissue confirmed elevated collagen IV deposition in the seizure focus ( p < 0.05) and a trend toward increased PVM density ( p = 0.0638). These results highlight PVMs as essential modulators of the glymphatic–metabolic axis, linking vascular health to brain excitability. Targeting the PVM–GS interface offers therapeutic potential for disorders involving vascular dysfunction and neuronal hyperexcitability.

2026-02-01·Advanced Science

Amelioration of Post‐Stroke Edema and Microcirculatory Dysfunction via Targeted AQP4 Inhibition While Preserving the Glymphatic System

Article

作者: Yanchao Liu ; Wenchao Liu ; Ran Li ; Jiaming Zhou ; Shixing Su ; Yu Wu ; Min Chen ; Fa Jin ; Hong Liu ; Yu Cai ; Lei Jin ; Xifeng Li ; Chuanzhi Duan ; Xingwu Liu ; Shenquan Guo ; Xin Zhang ; Longxiang Li ; Zeyu Yang ; Boyang Wei

Abstract:

Cerebral edema and hypoperfusion, hallmark pathologies of both hemorrhagic and ischemic stroke, critically compromise clinical outcomes. Astrocytic aquaporin‐4 (AQP4) not only drives post‐stroke brain edema progression but also maintains the protective clearance function of the glymphatic system. Herein, systemic AQP4 inhibition using TGN‐020 (TGN) paradoxically exacerbates global glymphatic dysfunction despite alleviating cerebral edema and microcirculatory dysfunction following subarachnoid hemorrhage (SAH). To overcome this therapeutic dilemma, an angiopep‐2‐functionalized lipid nanoparticle (A‐LNP) platform enabling lesion‐targeted TGN delivery is engineered. This system reverses the detrimental effects of TGN on the post‐SAH glymphatic system while enhancing the therapeutic benefits of TGN in mitigating cerebral edema and microcirculatory dysfunction. Remarkably, TGN demonstrates multimodal efficacy in ischemic stroke by mitigating the no‐reflow phenomenon, alleviating blood‐brain barrier disruption, and suppressing neuroinflammation. The A‐LNP system retains the protective effects of TGN without compromising global glymphatic function, leading to enhanced therapeutic efficacy. These findings confirm the feasibility of using functional nanoparticles to enhance the protective effects of AQP4 inhibition while minimizing adverse effects on the glymphatic system, offering a promising therapeutic strategy for both stroke subtypes.

项与 TGN-020 相关的新闻（医药）

2026-01-08

·BioHealth Nexus

水通道蛋白-4除了对深睡眠很重要，还是其他脑内疾病的靶点吗？

1. 神经科学视角的转变：类淋巴系统在大脑生理学的传统认知中，中枢神经系统（CNS）被认为缺乏淋巴引流。直到 2012 年，Nedergaard 团队提出了“类淋巴系统”（Glymphatic System）概念，揭示了大脑如何通过血管周围空间（PVS）实现脑脊液（CSF）与间质液（ISF）的交换来清除代谢废物 1。在这一系统中，水通道蛋白-4 (AQP4) 扮演了核心动力门控的角色。其高度表达在星形胶质细胞足突上，决定了水分子在大脑实质与血管周隙之间的转运速率 4。2. AQP4 的分子架构与超分子组装 AQP4 的功能不仅取决于其数量，更取决于其精密复杂的结构排布。2.1 异构体多样性 M1 与 M23 异构体：由不同的翻译起始位点产生。M23 具有极强的自我组装能力，在膜上形成“正交阵列粒子”（OAPs），这是高效导水的物理基础。M1 则倾向于以四聚体分散存在，负责调节 OAPs 的尺寸。 AQP4x（通读异构体）：通过翻译终止密码子“通读”（Readthrough）产生，具有延长的 C 端。它是实现 AQP4 在血管周围精准“极化”分布的关键。2.2 极化分布与锚定在健康大脑中，AQP4 高度集中在与脑血管紧密接触的星形胶质细胞足突上（覆盖率 20%-$60\%$），这种现象称为“极化” 。这种定位由 alpha-共轴蛋白及肌营养不良蛋白相关蛋白复合物（DAPC）支撑固定 6。3. 深睡眠：类淋巴系统运作的黄金窗口深睡眠（NREM N3阶段）是 AQP4 执行“排毒”任务的核心时段。间质空间扩张：进入深睡眠后，去甲肾上腺素（NE）水平降至最低，导致脑细胞收缩，细胞外间隙体积增加约60%，显著降低了流体阻力。同步神经震荡（慢波）：2024 年《Nature》研究揭示，数亿神经元在深睡眠中的同步慢波活动会产生周期性的离子波，驱动流体循环。研究者称之为“共同放电，共同洗浴”（Neurons that fire together, shower together） 10。动力泵送：同步化的神经活动配合动脉舒缩（Vasomotion），为 CSF 流入提供了物理推力，而 AQP4 则确保流体能够高效穿透足突进入脑实质。4. 疾病关联机制：AQP4 的“双刃剑”作用 AQP4 功能失调是多种脑部疾病的核心病理环节，但在不同病症中表现不同。4.1 阿尔茨海默病（AD）与蛋白沉积清除危机：AD 患者常伴随 AQP4 “去极化”（即从足突错位到胞体），导致 $\beta$-淀粉样蛋白）和 Tau 蛋白清理效率下降多达 70%。性别易感性：2025 年研究发现，雌激素和孕激素的丧失会诱发 AQP4 极化受损，这解释了女性患 AD 风险更高的机制。恶性循环：睡眠碎片化导致 AQP4 无法排毒，A$\beta$ 沉积又反过来破坏睡眠结构，加速病情。4.2 脑水肿：从益友到损友急性期（损友）：在中风或创伤早期，水分通过 AQP4 通道大量涌入受损细胞，引发致命的“细胞毒性脑水肿” 。此时抑制 AQP4 能减轻肿胀。后期（益友）：在血脑屏障崩溃后的“血管源性水肿”阶段，AQP4 反而协助重吸收细胞外多余水分并排水。4.3 其他神经/精神疾病帕金森病 (PD)：alpha-突触核蛋白积累破坏 AQP4 极化复合物，限制其排出，加剧神经变性。亨廷顿病 (HD)：D-葡萄糖清除效率在 HD 早期即下降，伴随 AQP4 极化丧失和锚定蛋白 SNTA1 减少。癫痫与偏头痛：AQP4 负责钾离子缓冲。其功能障碍导致 K+积聚，诱发神经元过度兴奋（癫痫）或皮层扩散性抑制（偏头痛先兆）。精神分裂症：前额叶皮层 AQP4 异常上调且极化受损，与炎症细胞因子水平升高密切相关。肌萎缩侧索硬化症 (ALS)：运动神经元区域 AQP4 表现出普遍的去极化分布，可能贡献了神经变性过程。5. 药物研发前沿：从孔道开关到全系统调控5.1 研发策略的重大转向曾经 AQP4 被认为“难成药”，因为其水孔道极窄且缺乏结合口袋。传统方案：试图直接堵住水孔。虽有候选药，但面临严重的肾脏脱脱靶风险（AQP4 也存在于肾脏）。现代方案：转向调节“水管的位置”。通过增强 AQP4x 异构体的比例（通读增强剂），让 AQP4 能够稳固“归位”到足突，从而提升深睡眠排毒效率。5.2 核心在研药物 AQP4 增强剂（针对排毒/AD）： TGN-073：首个 AQP4 促进剂，实验显示其能提高41% 的类淋巴转运能力，显著减少 Abeta沉积。米非司酮 (Mifepristone)：最新研究揭示其可作为 AQP4 激动剂，促进脑出血后的血肿清除。 AQP4 抑制剂（针对水肿/中风）： AER-271 (SIM0307)：已成功完成 I 期临床试验。作为抑制剂，它在急性期减少水分涌入，保护大脑不因水肿坏死 13。 TGN-020：研究最广泛的小分子抑制剂，在动物模型中能减少 2 倍以上的脑肿胀。间接调节剂（老药新用）：右美托咪定：模拟慢波睡眠，恢复 AQP4 极化分布，预防术后认知障碍。褪黑素：通过激活维生素 D 受体上调锚定蛋白 DTNA，在睡眠不足时维持 AQP4 的极化状态。总结水通道蛋白-4 是大脑“水冷与排毒系统”的核心阀门。深睡眠通过 ISS 扩张和神经元同步化慢波，为 AQP4 提供了最高效的运作环境。针对 AQP4 的药物开发正处于从“救命型（抑制水肿）”向“预防型（增强排毒）”并进的突破期。通过高分辨率 MRI 监测深睡眠期间 AQP4 的流体交换效率，未来有望在认知症状出现前十年识别并干预高危人群，守护大脑的长期健康。引用的著作 Glymphatic system: a self-purification circulation in brain - Frontiers, 访问时间为一月 8, 2026， https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2025.1528995/full Cerebral small vessel disease: The impact of glymphopathy and sleep disorders - PMC, 访问时间为一月 8, 2026， https://pmc.ncbi.nlm.nih.gov/articles/PMC12052786/ Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation - PubMed Central, 访问时间为一月 8, 2026， https://pmc.ncbi.nlm.nih.gov/articles/PMC9995113/ Loss of aquaporin-4 results in glymphatic system dysfunction via ..., 访问时间为一月 8, 2026， https://elifesciences.org/articles/82232 The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration - MDPI, 访问时间为一月 8, 2026， https://www.mdpi.com/1422-0067/26/23/11536 Evaluation of gliovascular functions of AQP4 readthrough isoforms - Frontiers, 访问时间为一月 8, 2026， https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2023.1272391/full Mechanisms Underlying AQP4 Accumulation in Astrocyte Endfeet | Request PDF, 访问时间为一月 8, 2026， https://www.researchgate.net/publication/279631676_Mechanisms_Underlying_AQP4_Accumulation_in_Astrocyte_Endfeet Tracking Sleep-Linked Brain Fluid Dynamics Using Modified fNIRS: A Novel Noninvasive Window into Glymphatic Function | bioRxiv, 访问时间为一月 8, 2026， https://www.biorxiv.org/content/10.1101/2025.10.27.684357v1.full-text Gonadal hormones and aquaporin-4: Preclinical insights into ..., 访问时间为一月 8, 2026， https://pubmed.ncbi.nlm.nih.gov/40938768/ Our Sleep, Brain Aging, and Waste Clearance, 访问时间为一月 8, 2026， https://erictopol.substack.com/p/our-sleep-brain-aging-and-waste-clearance Aquaporin-4 square array assembly: Opposing actions of M1 and M23 isoforms - PNAS, 访问时间为一月 8, 2026， https://www.pnas.org/doi/10.1073/pnas.2235843100 The Collapse of Brain Clearance: Glymphatic-Venous Failure, Aquaporin-4 Breakdown, and AI-Empowered Precision Neurotherapeutics in Intracranial Hypertension - MDPI, 访问时间为一月 8, 2026， https://www.mdpi.com/1422-0067/26/15/7223 Debate on Glymphatic System Reexamines Sleep's Role in Alzheimer Disease Pathology, 访问时间为一月 8, 2026， https://www.neurologylive.com/view/debate-glymphatic-system-reexamines-sleep-role-alzheimer-disease-pathology Aquaporin-4 in glioblastoma: a nexus of glymphatic dysfunction, edema, immune evasion, and treatment resistance - Frontiers, 访问时间为一月 8, 2026， https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2025.1685491/full The Therapeutic Potential of Glymphatic System Activity to Reduce ..., 访问时间为一月 8, 2026， https://www.mdpi.com/1422-0067/26/15/7552

100 项与 TGN-020 相关的药物交易

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