Neurotherapeutics最新文献_第10页

Simvastatin-induced neuroprotective effect after brain injury is mediated by mitochondrial protection through modulation of the 18 kDa translocator protein 辛伐他汀诱导的脑损伤后神经保护作用是通过调节18 kDa转运蛋白介导的线粒体保护。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-20 DOI: 10.1016/j.neurot.2025.e00803

Reem Sakas , Tom Fishboom , Aviv Ben-Menashe , Yaseen Awad-Igbaria , Rana Nasra , Abraham O. Samson , Eilam Palzur , Jean F. Soustiel

Traumatic brain injury (TBI) remains a leading cause of mortality and chronic disability. Among therapeutic agents investigated, simvastatin has emerged as a potential therapeutic opportunity for management of TBI although its mechanism of action has not been yet elucidated. Recent advance in 3D molecular docking simulations has suggested a possible interaction between simvastatin and the 18 kDa translocator protein (TSPO). Accumulating evidence suggest that The TSPO may play a pivotal role following TBI with TSPO ligands enhancing mitochondrial function and survival. Here, we examined the neuroprotective effects of simvastatin on cognitive and locomotor functions, histopathological outcome, and mitochondrial respiration following TBI in rats. In addition, molecular docking/interactions of simvastatin with TSPO were simulated. The current result show that simvastatin treatment significantly improved cognitive recovery in Morris water maze, motor performance in rotarod test, and neuronal density in the lesion area and hippocampus compared with untreated TBI groups. Importantly, these effects were attenuated by PK11195 pretreatment. Moreover, molecular docking simulations revealed that simvastatin exhibits a high binding affinity to TSPO, suggesting that its beneficial role could be the result of TSPO modulation. Furthermore, simvastatin treatment restored mitochondrial respiration by enhancing oxygen consumption rates across various respiratory states. In contrast, comparative analyses revealed that PK11195 attenuated simvastatin-induced respiratory enhancement, providing strong evidence for a TSPO-mediated mechanism of action of simvastatin. In conclusion, the current result highlights simvastatin's therapeutic potential in mitigating mitochondrial dysfunction and promoting neuroprotection effects following TBI. Our findings underscore mitochondrial protection as an important therapeutic target in TBI.

创伤性脑损伤（TBI）仍然是导致死亡和慢性残疾的主要原因。在研究的治疗药物中，辛伐他汀已成为治疗TBI的潜在治疗机会，尽管其作用机制尚未阐明。3D分子对接模拟的最新进展表明辛伐他汀与18kda转运蛋白（TSPO）之间可能存在相互作用。越来越多的证据表明，TSPO可能在TBI后发挥关键作用，TSPO配体增强线粒体功能和存活。在这里，我们研究了辛伐他汀对大鼠脑外伤后认知和运动功能、组织病理学结果和线粒体呼吸的神经保护作用。此外，模拟辛伐他汀与TSPO的分子对接/相互作用。目前的研究结果显示，与未治疗的TBI组相比，辛伐他汀治疗显著改善了Morris水迷宫认知恢复、rotarod测试运动表现以及损伤区和海马的神经元密度。重要的是，这些效应被PK11195预处理减弱。此外，分子对接模拟显示辛伐他汀对TSPO具有高结合亲和力，表明其有益作用可能是TSPO调节的结果。此外，辛伐他汀治疗通过提高各种呼吸状态的耗氧量来恢复线粒体呼吸。相比之下，对比分析显示PK11195减弱了辛伐他汀诱导的呼吸增强，为辛伐他汀的tspo介导的作用机制提供了强有力的证据。总之，目前的结果强调了辛伐他汀在减轻TBI后线粒体功能障碍和促进神经保护作用方面的治疗潜力。我们的发现强调线粒体保护是TBI的重要治疗靶点。

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引用次数: 0

Transcranial near-infrared therapy restores synaptic resilience by reshaping signaling landscapes in sleep-deprived tauopathy 经颅近红外治疗通过重塑睡眠剥夺的牛头病的信号景观来恢复突触弹性。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.neurot.2025.e00780

Yue Dong , Sheng Wang , Xiaoyun Liu , Yinchang Wang , Yimeng Song , Yuping Wang

Chronic sleep deprivation (SD) is a prevalent and modifiable risk factor that accelerates neurodegeneration and exacerbates cognitive decline in Alzheimer's disease (AD). Here, we demonstrate that 808 nm transcranial near-infrared (tNIR) therapy reverses cognitive impairment in tauopathy mice subjected to chronic SD through multi-level molecular and circuit restoration. Behavioral and electrophysiological assessments revealed that tNIR reinstated hippocampal-dependent memory and long-term potentiation. Multi-omics profiling uncovered that tNIR orchestrates a coordinated remodeling of GPCR–cAMP–CREB signaling, synaptic vesicle cycling, and excitatory-inhibitory neruotransmission, encompassing glutamatergic, GABAergic, and retrograde endocannabinoid pathways. Lipidomic analyses identified selective remodeling of membrane microdomains, with phospholipids such as MGDG(16:0/20:2) and LPC(20:4) positively correlating with genes governing calcium signaling, vesicle dynamics, and synaptic plasticity. In parallel, tNIR suppressed stress-associated lipid–gene networks linked to oxidative damage and apoptosis. Proteomic data revealed upregulation of antioxidant enzymes (e.g., SOD2) and suppression of pro-apoptotic mediators, supporting mitochondrial resilience. Collectively, these multi-omics signatures converge on restored neurotransmitter turnover, stabilized excitatory–inhibitory balance, and reestablished a synaptically supportive microenvironment. This study provides the first evidence that tNIR therapy counteracts the compounded effects of chronic sleep deprivation and tau pathology on memory, thereby establishing a clinically relevant dual-burden framework for investigating sleep–neurodegeneration interactions. Our findings position tNIR as a non-invasive, systems-level neuromodulatory approach for mitigating sleep-related cognitive vulnerability in neurodegeneration.

慢性睡眠剥夺（SD）是一种普遍且可改变的危险因素，可加速阿尔茨海默病（AD）的神经变性和认知能力下降。在这里，我们证明了808 nm经颅近红外（tNIR）治疗通过多层次的分子和电路恢复逆转慢性SD牛头病小鼠的认知障碍。行为和电生理评估显示，tNIR恢复海马依赖记忆和长期增强。多组学分析发现，tNIR协调了GPCR-cAMP-CREB信号、突触囊泡循环和兴奋-抑制性神经传递的协调重建，包括谷氨酸能、gaba能和逆行内源性大麻素途径。脂质组学分析发现了膜微域的选择性重塑，磷脂如MGDG（16:0/20:2）和LPC（20:4）与钙信号、囊泡动力学和突触可塑性调控基因正相关。同时，tNIR抑制与氧化损伤和细胞凋亡相关的应激相关脂质基因网络。蛋白质组学数据显示抗氧化酶（如SOD2）的上调和促凋亡介质的抑制，支持线粒体恢复。总的来说，这些多组学特征集中于恢复神经递质周转，稳定兴奋-抑制平衡，并重建突触支持微环境。本研究首次提供了证据，证明tNIR治疗可以抵消慢性睡眠剥夺和tau病理对记忆的复合影响，从而为研究睡眠-神经变性相互作用建立了临床相关的双重负担框架。我们的研究结果将tNIR定位为一种非侵入性的系统级神经调节方法，可缓解神经退行性疾病中与睡眠相关的认知脆弱性。

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引用次数: 0

FAAH and MAGL inhibition: Evolving approaches to treating substance use disorders FAAH和MAGL抑制：治疗物质使用障碍的新方法。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-04 DOI: 10.1016/j.neurot.2025.e00814

Charlie J. Maddox , Francis S. Lee , Anjali M. Rajadhyaksha , Arlene Martínez-Rivera

Substance use disorder (SUD) remains a critical public health issue characterized by high rates of relapse and limited effective pharmacotherapies, particularly for non-opioid substances. A key challenge in addressing SUD lies in the persistent neuroadaptations within the brain’s reward circuitry. The endocannabinoid (eCB) system plays a crucial role in modulating reward and reinforcement processes and is disrupted by chronic drug exposure. Recent work highlights the therapeutic potential of indirectly modulating cannabinoid 1 (CB1) receptor signaling by targeting eCB-metabolizing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to restore homeostatic eCB tone. We review and synthesize findings from both genetic and pharmacological studies, highlighting the contributions of FAAH and MAGL across major classes of abused substances and considering their potential as therapeutic targets for SUD treatment.

物质使用障碍（SUD）仍然是一个重要的公共卫生问题，其特点是复发率高，有效药物治疗有限，特别是对非阿片类物质。解决SUD的一个关键挑战在于大脑奖赏回路中持续的神经适应。内源性大麻素（eCB）系统在调节奖励和强化过程中起着至关重要的作用，并被慢性药物暴露所破坏。最近的研究强调了间接调节大麻素1 （CB1）受体信号的治疗潜力，通过靶向eb代谢酶，脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）来恢复稳态eCB张力。我们回顾并综合了遗传学和药理学研究的结果，强调了FAAH和MAGL在主要滥用药物类别中的贡献，并考虑了它们作为SUD治疗靶点的潜力。

引用次数: 0

Infantile epileptic spasms syndrome: Mechanisms and therapeutic approaches 婴儿癫痫性痉挛综合征：机制和治疗方法。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-12-18 DOI: 10.1016/j.neurot.2025.e00822

Carl E. Stafstrom

Infantile epileptic spasms syndrome (IESS) is a developmental and. epileptic encephalopathy with unique clinical and electrographic features, including seizure semiology (spasms), numerous and diverse etiologies spanning structural, genetic and metabolic causes, characteristic interictal (hypsarrhythmia) and ictal (electrodecrement) electroencephalogram (EEG) patterns, and responsiveness to “standard” pharmacological therapies (adrenocorticotrophic hormone, high-dose corticosteroids, vigabatrin) that are not commonly used in other epilepsy syndromes. Despite these long-recognized clinical features and laboratory investigations using a multiplicity of animal models with different epileptogenic mechanisms, the neurobiological underpinnings of IESS remain poorly understood, hampering the development of alternative treatments. This commentary discusses three aspects of IESS intended to raise fundamental clinical and mechanistic issues to afford greater understanding of the syndrome – nomenclature, EEG findings, and selected emerging animal models that might shed light on IESS pathophysiology and guide therapy development.

婴儿癫痫性痉挛综合征（IESS）是一种发展性疾病。癫痫性脑病具有独特的临床和电图特征，包括癫痫符号学（痉挛），多种多样的病因，包括结构、遗传和代谢原因，特征性的间歇期（低心律失常）和间歇期（电减量）脑电图（EEG）模式，以及对“标准”药物治疗（促肾上腺皮质激素、大剂量皮质类固醇、维加巴林）的反应性，这些药物治疗在其他癫痫综合征中不常用。尽管这些长期公认的临床特征和使用多种具有不同癫痫发生机制的动物模型的实验室研究，但IESS的神经生物学基础仍然知之甚少，阻碍了替代治疗的发展。这篇评论讨论了IESS的三个方面，旨在提出基本的临床和机制问题，以便更好地理解该综合征——命名法、脑电图结果和选择的新兴动物模型，这些模型可能会揭示IESS的病理生理学和指导治疗发展。

引用次数: 0

Heterogeneous Deep Gray Matter Iron Deposition Patterns across Multiple Sclerosis Subgroups Defined by the Clinico-Radiological Paradox 临床-放射悖论定义的多发性硬化症亚组中不均匀的深灰质铁沉积模式。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-02-10 DOI: 10.1016/j.neurot.2026.e00848

Jinlin Jiao, Ruisi Gong, Hao Zhang, Xu Huang, Lei Liu, Xiaohan Xu, Huiwen Song, Xiangru Chen, Jibin Cao , Lingling Cui

The clinico-radiological paradox in multiple sclerosis (MS) describes the disconnect between white matter lesion load and clinical disability. This study investigated the role of deep gray matter (DGM) iron deposition in this paradox, specifically regarding cognitive impairment. We classified 134 MS patients into subgroups based on T2-lesion volume (LV) and disability (EDSS): LL/LD, HL/LD, LL/HD, HL/HD, comparing them to 46 healthy controls (HCs). Using quantitative susceptibility mapping (QSM) and volumetric analysis, we assessed iron content and atrophy in DGM nuclei, alongside cognitive testing (MoCA, SDMT). Subgroups with high lesion burden (HL/LD, HL/HD) showed significantly increased iron and atrophy in the globus pallidus, putamen, and caudate versus HCs. A critical group-by-volume interaction on susceptibility was found in the putamen for HL/LD (β=-0.55) and HL/HD (β=-0.35) subgroups. Mediation analysis revealed that putamen volume mediates the effect of iron on cognition, with significant indirect effects on SDMT (β=-0.18) and MoCA (β=-0.14) across all patients. In the HL/HD subgroup, this pathway accounted for 45.8 % of iron's total effect on processing speed (SDMT). Our findings demonstrate heterogeneous DGM iron deposition and identify putaminal iron-induced atrophy as a key mechanistic pathway for cognitive deficits, offering a novel explanation for the paradox and a potential biomarker for cognitive risk stratification.

多发性硬化症（MS）的临床-放射悖论描述了白质病变负荷与临床残疾之间的脱节。本研究调查了深灰质（DGM）铁沉积在这一悖论中的作用，特别是在认知障碍方面。我们根据t2病变体积（LV）和残疾程度（EDSS）将134例MS患者分为LL/LD、HL/LD、LL/HD、HL/HD亚组，并与46例健康对照（hc）进行比较。利用定量敏感性图（QSM）和容量分析，我们评估了DGM核中的铁含量和萎缩，以及认知测试（MoCA， SDMT）。与hcc相比，高病变负荷亚组（HL/LD, HL/HD）的苍白球、壳核和尾状核的铁和萎缩明显增加。壳核对HL/LD亚组（β=-0.55）和HL/HD亚组（β=-0.35）的易感性存在临界组体积相互作用。中介分析显示，壳核体积介导铁对认知的影响，对所有患者的SDMT （β=-0.18）和MoCA （β=-0.14）有显著的间接影响。在HL/HD亚组中，该途径占铁对加工速度（SDMT）总影响的45.8%。我们的研究结果证明了DGM铁沉积的异质性，并确定了铁诱导的壳层萎缩是认知缺陷的关键机制途径，为这一悖论提供了新的解释，并为认知风险分层提供了潜在的生物标志物。

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引用次数: 0

Commentary: Lysosomal enzymes engineered to cross the blood-brain barrier are reshaping the therapeutic landscape of neuronopathic mucopolysaccharidoses 评论：设计用于穿越血脑屏障的溶酶体酶正在重塑神经性粘多糖病的治疗前景。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-10-28 DOI: 10.1016/j.neurot.2025.e00776

Nicolina Cristina Sorrentino , Alessandro Fraldi

引用次数: 0

Asparagine endopeptidase (AEP) inhibitor formulation via zein-based nanoparticle improves the therapeutic efficacy toward Alzheimer's disease 玉米蛋白纳米颗粒制备的天冬酰胺内肽酶（AEP）抑制剂可提高阿尔茨海默病的治疗效果。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 Epub Date: 2025-08-14 DOI: 10.1016/j.neurot.2025.e00718

Xin Meng , Mengmeng Wang , Menghan Yang , Guangxing Wang , Zhenlei Zhao , Zhongyun Xie , Bowei Li , Zhengjiang Qian , Seong Su Kang , Wenhua Zheng , Keqiang Ye

Asparagine endopeptidase (AEP) plays a critical role in Alzheimer's disease (AD) by cleaving amyloid precursor protein (APP) at N585 and tau protein at N368. Genetic deletion or pharmacological inhibition of AEP using compound 11a ameliorates AD pathology in murine models. To improve the therapeutic potential of 11a, we synthesized structural analogs and developed a zein-based nanoparticle delivery system to enhance pharmacokinetics. Structural modification, specifically isopropyl substitution of the N-methyl group in 11a, markedly improved blood-brain barrier permeability. The lead compound, 11a-isopropyl, formulated in zein nanoparticles, exhibited superior oral bioavailability and brain exposure. In vivo pharmacodynamic/pharmacokinetic (PK/PD) analyses confirmed dose-dependent AEP inhibition and enhanced substrate stabilization, with the nanoparticle formulation further increasing efficacy. One-month oral administration in 3xTg AD mice demonstrated that 11a-isopropyl, particularly in nanoparticle form, significantly reduced Aβ and tau pathology and improved cognitive performance. These findings indicate that zein-based nanoparticles enhance AEP inhibitor delivery and therapeutic efficacy in AD.

天冬酰胺内肽酶（AEP）通过在N585位点切割淀粉样前体蛋白（APP）和N368位点切割tau蛋白，在阿尔茨海默病（AD）中发挥关键作用。在小鼠模型中，化合物11a基因缺失或药物抑制AEP可改善AD病理。为了提高11a的治疗潜力，我们合成了结构类似物，并开发了一种基于玉米蛋白的纳米颗粒递送系统来增强其药代动力学。结构修饰，特别是11a中n -甲基的异丙基取代，显著提高了血脑屏障的通透性。玉米蛋白纳米颗粒中的先导化合物11a-异丙基表现出优异的口服生物利用度和脑暴露性。体内药效学/药代动力学（PK/PD）分析证实了剂量依赖性AEP抑制和增强底物稳定性，纳米颗粒配方进一步提高了疗效。在3xTg AD小鼠中口服一个月的11a-异丙基，特别是纳米颗粒形式的11a-异丙基，显著降低了Aβ和tau病理，提高了认知能力。这些发现表明，基于玉米蛋白的纳米颗粒增强了AEP抑制剂在AD中的递送和治疗效果。

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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 Epub Date: 2025-09-24 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

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 Epub Date: 2025-10-09 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

Engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in Alzheimer's disease: Rational design, blood-brain barrier penetration, and multi-target therapeutic synergy 用于阿尔茨海默病植物化学物质脑靶向共递送的工程纳米平台：合理设计、血脑屏障穿透和多靶点治疗协同。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2025-10-01 Epub Date: 2025-08-14 DOI: 10.1016/j.neurot.2025.e00722

Lianghong Chen , Yadi Guan , Shaojun Wang , Xu Han , Feng Guo , Yu Wang

Alzheimer's disease (AD) presents significant therapeutic challenges due to its multifactorial pathology, the inefficacy of traditional single-target drugs, and the poor bioavailability and limited blood-brain barrier (BBB) penetration of promising multi-target phytochemicals like curcumin, resveratrol, and quercetin. This review systematically examines the rational design and recent advancements in engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in AD. Nanotechnology leverages lipid-based systems (liposomes, solid lipid nanoparticles), polymer-based carriers (PLGA nanoparticles), inorganic nanosystems (gold, selenium nanoparticles), and biologically-derived vehicles to significantly enhance phytochemical stability, targeting efficiency, and brain accumulation. Strategic surface functionalization with BBB-translocating ligands, including transferrin receptor antibodies and RVG29 peptide, combined with stimuli-responsive mechanisms exploiting the pathological microenvironment (pH, enzyme sensitivity), enables efficient BBB penetration and lesion-specific drug release. These nanodrug delivery systems demonstrate substantial cognitive improvement in AD animal models through synergistic multi-pathway effects: inhibiting Aβ aggregation, modulating Tau phosphorylation, reducing neuroinflammation, and enhancing antioxidant activity, often at markedly reduced doses compared to free drugs. While preclinical results are compelling, critical challenges remain in nanocarrier long-term biosafety, scalable manufacturing, and clinical translation. This review provides a comprehensive framework and technical insights for developing efficient, safe, and translatable nanotherapeutics for AD.

阿尔茨海默病（AD）由于其多因素病理、传统单靶点药物的无效、姜黄素、白藜芦醇和槲皮素等有前途的多靶点植物化学物质的生物利用度差和血脑屏障（BBB）渗透有限，给治疗带来了重大挑战。本综述系统地探讨了用于AD患者脑靶向共递送植物化学物质的工程纳米平台的合理设计和最新进展。纳米技术利用基于脂质的系统（脂质体、固体脂质纳米颗粒）、基于聚合物的载体（PLGA纳米颗粒）、无机纳米系统（金、硒纳米颗粒）和生物衍生的载体来显著提高植物化学稳定性、靶向效率和脑积累。血脑屏障易位配体（包括转铁蛋白受体抗体和RVG29肽）的策略性表面功能化，结合利用病理微环境（pH、酶敏感性）的刺激反应机制，实现了血脑屏障的有效渗透和病变特异性药物释放。这些纳米药物传递系统通过协同多途径效应在AD动物模型中显示出实质性的认知改善：抑制Aβ聚集，调节Tau磷酸化，减少神经炎症，增强抗氧化活性，通常与游离药物相比，剂量显著降低。虽然临床前结果令人信服，但纳米载体的长期生物安全性、可扩展制造和临床转化方面仍存在关键挑战。这篇综述为开发高效、安全、可翻译的AD纳米疗法提供了一个全面的框架和技术见解。

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引用次数: 0