Neurotherapeutics最新文献_第7页

Network-based prediction and real-world patient data observation identify doxycycline as a repurposable drug in Alzheimer's disease 基于网络的预测和现实世界患者数据观察确定强力霉素是阿尔茨海默病的可重复使用药物。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-02-13 DOI: 10.1016/j.neurot.2026.e00836

Marina Bykova , Ehud Karavani , Michael Danziger , Reina Tonegawa-Kuji , William Martin , Zhendong Sha , Andrew A. Pieper , Michal Rosen-Zvi , Feixiong Cheng

Alzheimer's disease (AD), a leading global cause of dementia, disability, and mortality, represents a critical unmet need for effective therapeutic interventions. Drug repurposing offers an expedited pathway to address this challenge compared to traditional drug development. Here, we leveraged network-based prediction and real-world patient data validation, a comprehensive strategy to identify unanticipated therapeutic applications for existing medications. Traumatic brain injury (TBI), a major risk factor for earlier and more severe AD, exhibits heterogenous clinical outcomes influenced by genetic susceptibility, suggesting that TBI-diagnosed populations represent a cohort enriched for neurodegeneration vulnerability. Building on this premise, we integrated network-based multi-omics and endophenotypic disease modules from individuals with TBI and AD histories with large real-world patient data analysis from insurance claims to prioritize repurposable drugs. A network proximity algorithm applied to TBI- and AD-associated gene sets identified statistically ranked candidates, including doxycycline and irbesartan. We then assessed all candidates' AD risk reduction potential using a nationwide Medicare database encompassing nearly 9 million individuals. In a retrospective observational study of AD-free elderly individuals monitored for up to 3 years, propensity-score adjusted survival analyses demonstrated a significantly reduced cumulative incidence of AD in doxycycline and irbesartan-prescribed individuals, with risk ratios of 0.92 and 0.83, respectively, at a 95 % confidence interval. These findings nominate doxycycline and irbesartan as potential repurposable drugs for AD and demonstrate the translational potential of synergizing network-based prediction with real-world patient evidence in drug repurposing for neurodegenerative disease if broadly applied.

阿尔茨海默病（AD）是全球导致痴呆、残疾和死亡的主要原因之一，对有效治疗干预措施的需求尚未得到满足。与传统药物开发相比，药物再利用为解决这一挑战提供了一条快速途径。在这里，我们利用基于网络的预测和现实世界的患者数据验证，一种全面的策略来识别现有药物的意外治疗应用。创伤性脑损伤（TBI）是早期和更严重AD的主要危险因素，其临床结果受遗传易感性的影响存在异质性，这表明TBI诊断人群代表了一个神经变性易感性丰富的群体。在此前提下，我们将基于网络的多组学和来自TBI和AD病史个体的内表型疾病模块与来自保险索赔的大量真实患者数据分析相结合，以优先考虑可重复使用的药物。网络接近算法应用于TBI和ad相关基因集，确定了统计上排名的候选基因，包括强力霉素和厄贝沙坦。然后，我们使用包含近900万人的全国医疗保险数据库评估所有候选人的AD风险降低潜力。在一项对无AD的老年人进行长达3年监测的回顾性观察研究中，倾向评分调整的生存分析显示，在服用多西环素和厄贝沙坦的人群中，AD的累积发病率显著降低，风险比分别为0.92和0.83，可信区间为95%。这些发现表明强力霉素和厄贝沙坦是潜在的可重复利用的阿尔茨海默病药物，并证明了如果广泛应用，基于网络的预测与现实世界患者证据在神经退行性疾病药物再利用方面的协同转化潜力。

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引用次数: 0

A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models 一种由16个氨基酸组成的肽延缓ALS模型中运动神经元退化和致病症状的进展。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-26 DOI: 10.1016/j.neurot.2025.e00806

Cheng-Yung Lin , Bing-Chang Lee , Po-Hsiang Zhang , Shao-Chi Lu , Wei-Zen Chang , Chia-Chuan Wang , Huai-Jen Tsai

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.

肌萎缩性侧索硬化症（ALS）是一种进行性运动神经元退行性疾病。尽管对ALS发病机制的了解有所进展，但药物开发仍远远落后。过表达nogoa的肌肉细胞分泌磷酸甘油酸激酶1 （Pgk1）的减少可抑制MNs （NOMNs）的神经突生长。然而，细胞外Pgk1 （ePgk1）的管理减少磷酸化- cofilin (p-Cofilin)，生长锥塌陷的标志，并减轻MN变性。通过抑制p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3信号通路，改善SOD1-G93A als小鼠NSC34神经细胞的NOMNs和运动。在这里，我们鉴定了两个基于pgk1的16个氨基酸（aa）短肽FD-1和FD-2，它们具有与全长ePgk1相当的神经保护作用。在条件培养基中培养的NSC34细胞中，FD-1或FD-2 （FD-1/ 2）可降低p-Cofilin并促进nomn。此外，我们发现，在氧化应激的als样SOD1-G93A NSC34细胞中，外源添加FD-1/ 2可以减少磷酸化tau - s396的积累和43 kDa的交换反应DNA结合蛋白（TDP-43）的细胞质错定位。在注射FD-1/-2的斑马鱼胚胎中，我们观察到尾端初级MNs分支增加。在c9orf72敲低和hTDP-43-G348C mRNA过表达的斑马鱼胚胎注射FD-1/ 2后，轴突生长和运动功能得以恢复。此外，在SOD1-G93A als小鼠中静脉注射FD-1/ 2可延缓神经肌肉连接处的去神经支配，保存脊髓前角MNs的细胞体，增加握力，改善运动能力，延长生存期。因此，这两种16-aa短FD肽在功能上与全长417-aa ePgk1相当，因此有望用于治疗ALS。

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引用次数: 0

Transcranial direct current stimulation is safe and feasible in hyperacute ischemic stroke (DICAST-SF trial) 经颅直流电刺激治疗超急性缺血性脑卒中是安全可行的。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-02-01 DOI: 10.1016/j.neurot.2026.e00844

Matej Slovak , David Kemlink , Pavel Dusek , Petra Rekova , Vratislav Fabian , Martin Jurka , Davide Carone , Alistair Perry , George W.J. Harston , Evzen Ruzicka , Dagmar Altmanova , Lukas Lambert , Andrea Burgetova , Helena Knotkova , Abhishek Datta , Marom Bikson , Michael A. Nitsche , Mersedeh Bahr-Hosseini , Jeffrey L. Saver

Cathodal transcranial direct current stimulation (C-tDCS) is a potential neuroprotective method in the hyperacute phase of ischemic stroke. We aimed to assess safety, tolerability, feasibility, and potential efficacy of C-tDCS in stroke patients with salvageable penumbra. DICAST-SF was a double-blind, randomized, sham-controlled (3 active: 1 sham), 3 + 3 dose-escalation trial. Inclusion criteria were stroke due to occlusion of the internal carotid or middle cerebral artery, last known well time within 24 h, substantial penumbra on CT perfusion, and ineligibility for mechanical thrombectomy. We applied C-tDCS at six dose tiers over the affected primary motor cortex. The primary safety outcome was the symptomatic intracranial hemorrhage (SICH) rate at 24 h post-stimulation. Secondary outcomes included the rates of asymptomatic intracranial hemorrhage (AICH), early neurological deterioration, serious adverse events, and 90-day mortality. Tolerability was assessed by completion rate and questionnaires. Feasibility threshold was defined as median randomization-to-C-tDCS start time within 10 min in the last ten patients. Twenty five patients were enrolled (19 active, 6 sham), mean age 81 (SD 12) years, 16 women, median NIHSS 8 (IQR 6–16). Ten active and 4 sham patients were treated with thrombolysis. No SICH occurred. Three AICH (2 post-thrombolysis) occurred in the active arm. Rates of early deterioration, serious adverse events, and mortality (4 active vs. 2 sham) were comparable. C-tDCS was well tolerated and feasible, median randomization-to-C-tDCS start time was 8 (7–9) min. C-tDCS in hyperacute stroke was safe, well tolerated, and feasible. Findings support further evaluation in larger efficacy trials.

Trial registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801446.

阴极经颅直流电刺激（C-tDCS）是缺血性脑卒中超急性期一种潜在的神经保护方法。我们的目的是评估C-tDCS在可修复半暗区脑卒中患者中的安全性、耐受性、可行性和潜在疗效。DICAST-SF是一项双盲、随机、假对照（3例有效：1例假）、3 + 3剂量递增试验。纳入标准为颈内动脉或大脑中动脉闭塞所致卒中，已知最后时间在24小时内，CT灌注有明显半暗影，不适合机械取栓。我们在受影响的初级运动皮层上以六个剂量层应用C-tDCS。主要的安全性指标是刺激后24小时的症状性颅内出血（siich）率。次要结局包括无症状颅内出血（AICH）、早期神经系统恶化、严重不良事件和90天死亡率。通过完成率和问卷调查来评估耐受性。可行性阈值定义为最后10例患者中位随机化至c - tdcs开始时间在10分钟内。纳入25例患者（19例活跃，6例假），平均年龄81岁（SD 12）， 16例女性，中位NIHSS 8 （IQR 6-16）。活动性患者10例，假性患者4例。未发生SICH。活动组发生3例AICH（溶栓后2例）。早期恶化率、严重不良事件和死亡率（4例主动vs 2例假手术）具有可比性。C-tDCS具有良好的耐受性和可行性，中位随机化到C-tDCS的起始时间为8（7-9）分钟。C-tDCS在超急性卒中中的安全性、耐受性良好且可行。研究结果支持在更大规模的疗效试验中进一步评估。试用注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT04801446。

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引用次数: 0

Intranasal (R)-ketamine modulates depression symptom and neurotransmitters-associated human brain connectivity 鼻内氯胺酮调节抑郁症状和神经递质相关的人脑连接。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2025-11-12 DOI: 10.1016/j.neurot.2025.e00790

Zhenxiang Zang , An’ning Li , Zhifang Zhang , Tingfang Wu , Xiongying Chen , Kaini Qiao , Alimire Paerhati , Zhi Yang , Gang Wang

Racemic (R,S)-ketamine exerts rapid antidepressant effects, and growing evidence suggests its R-isomer may offer sustained efficacy with fewer side effects. However, the neurobiological mechanisms underlying (R)-ketamine’s action in the human brain are largely unknown. To address this, we acquired resting-state fMRI data from 32 healthy volunteers 24 h before and after intranasal administration of (R)-ketamine (n = 24) or placebo (n = 8). We primarily assessed changes in long-range functional synchrony using degree centrality (DC) and elucidated the sources of these changes with functional connectivity (FC) analysis. (R)-ketamine significantly decreased DC in a key cognitive-motor integration hub: the supplementary motor area/middle cingulate cortex (SMA/MCC, cluster-corrected P < 0.05). Critically, the reduction of DC was absent under the placebo condition, yielding a significant group-by-time interaction (P = 0.01). The reduction in long-range synchrony of the SMA/MCC was primarily driven by attenuated FC with both the dorsal medial prefrontal cortex/dorsal anterior cingulate cortex (dMPFC/dACC) and the cerebellum, and was spatially correlated with serotonin, norepinephrine, and acetylcholine neurotransmitter profiles. More importantly, the clinical relevance of the neuroimaging phenotypes was established in an independent Major Depressive Disorder (MDD) cohort, where FC between the SMA/MCC and dMPFC/dACC significantly correlated with depressive symptom severity (HAMD score, P = 0.019). This study provides novel, system-level evidence that intranasal (R)-ketamine modulates specific human brain networks by attenuating long-range synchrony in the SMA/MCC. The link between the neuroimaging phenotype, depression-relevant neurotransmitter profiles, and clinical symptom severity may offer a plausible therapeutic mechanism of (R)-ketamine.

外消旋（R，S）-氯胺酮具有快速的抗抑郁作用，越来越多的证据表明其R-异构体可能提供持续的疗效，副作用更少。然而，(R)-氯胺酮在人脑中的作用的神经生物学机制在很大程度上是未知的。为了解决这个问题，我们获得了32名健康志愿者在鼻内给药(R)-氯胺酮（n = 24）或安慰剂（n = 8）前后24小时的静息状态功能磁共振成像数据。我们主要使用度中心性（DC）评估远程功能同步性的变化，并通过功能连通性（FC）分析阐明这些变化的来源。(R)-氯胺酮显著降低关键认知-运动整合中枢：辅助运动区/中扣带皮层（SMA/MCC，聚类校正P < 0.05）的DC。关键的是，在安慰剂条件下，DC的减少没有出现，产生了显著的组间时间相互作用（P = 0.01）。SMA/MCC的远程同步性降低主要是由前额叶内侧背/前扣带皮层（dMPFC/dACC）和小脑的FC减弱驱动的，并且在空间上与血清素、去甲肾上腺素和乙酰胆碱神经递质谱相关。更重要的是，在独立的重度抑郁症（MDD）队列中建立了神经影像学表型的临床相关性，其中SMA/MCC和dMPFC/dACC之间的FC与抑郁症状严重程度显著相关（HAMD评分，P = 0.019）。本研究提供了新颖的系统级证据，证明鼻内氯胺酮通过减弱SMA/MCC的远程同步来调节特定的人类大脑网络。神经影像学表型、抑郁症相关神经递质谱和临床症状严重程度之间的联系可能提供(R)-氯胺酮的合理治疗机制。

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引用次数: 0

Medicinal cannabis plant extract (NTI164) modifies epigenetic, ribosomal, and immune pathways in paediatric acute-onset neuropsychiatric syndrome 药用大麻植物提取物（NTI164）改变表观遗传、核糖体和免疫途径在儿科急性发作的神经精神综合征。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-01-08 DOI: 10.1016/j.neurot.2025.e00828

Brooke A. Keating , Velda X. Han , Hiroya Nishida , Nader Aryamanesh , Lee L. Marshall , Brian S. Gloss , Xianzhong Lau , Ruwani Dissanayake , Suat Dervish , Mark E. Graham , Shekeeb S. Mohammad , Manoj Kanhangad , Michael C. Fahey , Shrujna Patel , Russell C. Dale

Paediatric acute-onset neuropsychiatric syndrome (PANS) is a syndrome of infection-provoked abrupt-onset obsessive-compulsive disorder (OCD) or eating restriction. Based on the hypothesis that PANS is an epigenetic disorder of immune and brain function, a full-spectrum medicinal cannabinoid-rich low-THC cannabis (NTI164) was selected for its known epigenetic and immunomodulatory properties. This open-label trial of 14 children with chronic-relapsing PANS (mean age 12·1 years; range 4–17; 71 % male) investigated the safety and efficacy of 20 mg/kg/day NTI164 over 12 weeks. Clinical outcomes were assessed using gold standard tools. To define the biological effects of NTI164, blood samples were collected pre- and post-treatment for bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation. NTI164 was well-tolerated, and 12 weeks of treatment decreased the mean Clinical Global Impression-Severity (CGI-S) score from 4·8 to 3·3 (p = 0·002). Significant improvements were observed in emotional regulation (RCADS-P, p < 0·0001), obsessive-compulsive disorder (CYBOCS-II, p = 0·0001), tics (YGTSS, p < 0·0001), attention-deficit hyperactivity disorder (Conner's, p = 0·028), and overall quality of life (EQ-5D-Y, p = 0·011). At baseline, the multi-omic approach revealed that leucocytes from patients with PANS had dysregulated epigenetic (chromatin structure, DNA methylation, histone modifications, transcription factors), ribosomal, mRNA processing, immune, and signalling pathways. These pathways were significantly modulated by NTI164 treatment. NTI164 shows promise as a disease-modifying therapeutic for PANS. Multi-omics reveal broad epigenetic and immune dysregulation in patients, which was modified by NTI164, presenting epigenetic machinery as a therapeutic target in PANS.

小儿急性发作性神经精神综合征（PANS）是一种由感染引起的突发性强迫症（OCD）或饮食限制引起的综合征。基于PANS是一种免疫和脑功能的表观遗传疾病的假设，选择了一种富含大麻素的全谱低thc药用大麻（NTI164），因为它具有已知的表观遗传和免疫调节特性。这项开放标签试验纳入了14名慢性复发性PANS患儿（平均年龄12.1岁，范围4-17岁，71%为男性），研究了20mg /kg/天NTI164治疗12周的安全性和有效性。临床结果采用金标准工具进行评估。为了确定NTI164的生物学效应，在治疗前后收集血液样本进行大细胞和单细胞转录组学、蛋白质组学、磷酸化蛋白质组学和DNA甲基化。NTI164耐受性良好，治疗12周后，平均临床总体印象严重程度（CGI-S）评分从4.8降至3.3 （p = 0.002）。在情绪调节（RCADS-P, p < 0.0001）、强迫症（CYBOCS-II, p = 0.0001）、抽搐（YGTSS, p < 0.0001）、注意缺陷多动障碍（Conner's, p = 0.028）和整体生活质量（EQ-5D-Y, p = 0.011）方面均有显著改善。在基线时，多组学方法显示，来自PANS患者的白细胞具有表观遗传（染色质结构、DNA甲基化、组蛋白修饰、转录因子）、核糖体、mRNA加工、免疫和信号通路失调。NTI164处理显著调节了这些途径。NTI164有望成为pan的一种改善疾病的治疗药物。多组学揭示了患者广泛的表观遗传和免疫失调，这是由NTI164修饰的，表明表观遗传机制是pan的治疗靶点。

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引用次数: 0

Hypoactivity of the prelimbic cortex projecting to the lateral entorhinal cortex contributes to neuropathic pain-induced object recognition memory impairment in mice 投射到外侧内嗅皮层的前边缘皮层活性降低有助于小鼠神经性疼痛诱导的物体识别记忆障碍。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-01-31 DOI: 10.1016/j.neurot.2026.e00842

Siyi Han , Zhuang Liu , Jun Fang , Zhang Wen , Xiaoman Yuan , Fengtian Zhao , Tengxiao Si , Anne Manyande , Bo Li , Jie Wang , Xuebi Tian

Memory impairment is a common comorbidity of chronic pain that significantly compromises patients’ quality of life, yet the underlying neuronal circuit mechanisms remain poorly understood. Here, we employed a spared nerve injury (SNI) mouse model of chronic neuropathic pain and evaluated short-term memory performance using a novel object recognition test (NORT). Mice exhibited mechanical allodynia and object recognition memory (ORM) deficits 21 days following SNI surgery. Functional Magnetic Resonance Imaging (fMRI) analyses revealed a reduction in functional connectivity between the prelimbic cortex (PrL) and the lateral entorhinal cortex (LEC) in SNI mice. Viral tracing confirmed a direct monosynaptic anatomical projection from the PrL to the LEC, originating primarily from PrL layer 5 neurons. c-Fos immunostaining and in vivo calcium fiber photometry further demonstrated that both the PrL and LEC neurons were activated in response to novel object recognition, whereas these neuronal responses were significantly attenuated in SNI mice. Importantly, selective chemogenetic and optogenetic activation of the PrL-LEC pathway improved memory impairment in SNI mice without affecting pain sensitivity or locomotor activity. Chemogenetic inhibition of this pathway impaired ORM performance in normal mice. Our findings underscore the important role of PrL-LEC pathway hypoactivity in mediating short-term memory deficits associated with chronic pain and suggest this circuit as a promising therapeutic target for pain-related cognitive dysfunction.

记忆障碍是慢性疼痛的常见合并症，严重影响患者的生活质量，但其潜在的神经回路机制尚不清楚。在这里，我们采用了慢性神经性疼痛的神经损伤（SNI）小鼠模型，并使用一种新的物体识别测试（NORT）来评估短期记忆表现。小鼠在SNI手术后21天表现出机械异常性疼痛和物体识别记忆（ORM）缺陷。功能磁共振成像（fMRI）分析显示，SNI小鼠的前边缘皮层（PrL）和外侧内嗅皮层（LEC）之间的功能连通性减少。病毒追踪证实了从PrL到LEC的直接单突触解剖投影，主要来自PrL第5层神经元。c-Fos免疫染色和体内钙纤维光度法进一步表明，PrL和LEC神经元在响应新物体识别时都被激活，而SNI小鼠的这些神经元反应明显减弱。重要的是，PrL-LEC通路的选择性化学发生和光遗传激活改善了SNI小鼠的记忆损伤，而不影响疼痛敏感性或运动活性。这一途径的化学发生抑制会损害正常小鼠的ORM表现。我们的研究结果强调了PrL-LEC通路低活性在介导慢性疼痛相关的短期记忆缺陷中的重要作用，并表明该回路是疼痛相关认知功能障碍的有希望的治疗靶点。

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引用次数: 0

Pharmacological characterization and neuroprotective efficacy of ZHB103, a novel long-acting rhKLK1 新型长效rhKLK1 ZHB103的药理特性及神经保护作用

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-01-16 DOI: 10.1016/j.neurot.2025.e00830

Dan Xu , Chenyang Jiang , Chennan Ge , Tao Zhang , Jun Wang , He Wang , Yu Zhuang , Zhen Xu , Na Ding , Bruce Yong Ma

Exogenous plasma kallikrein 1 (KLK1) supplementation is hypothesized to have both immediate and long-lasting actions that may improve outcomes following acute ischemic stroke. ZHB103, a polyethylene glycol (PEG)-modified long-acting recombinant human KLK1 (LA-rhKLK1), has been developed as a candidate for exogenous KLK1 supplementation in stroke patients and for the prevention of stroke. In pharmacokinetic and toxicokinetic studies, ZHB103 exhibited high bioavailability, a prolonged half-life (T_1/2) and no treatment-related adverse effects after intramuscular injection in Sprague–Dawley rats and cynomolgus monkeys. Single-dose or once-weekly administration of ZHB103 demonstrated both short-term and long-term protective effects against ischemic stroke in oxygen-glucose deprivation/reoxygenation models, H₂O₂-induced oxidative stress models and experimental stroke models. Compared with rKLK1 (the proprotein of ZHB103, a short-acting non-PEGylated recombinant KLK1), Sanbexin (Edaravone and Dexborneol concentrated solution for injection) or HUK (human urinary kallidinogenase, a form of tissue kallikrein 1 from urine), ZHB103 promoted cell proliferation, inhibited apoptosis, reduced inflammatory factor levels in the acute stage of stroke models and improved cognitive function recovery during the later recovery stage via a significantly prolonged duration of B2 receptor (B2R)-mediated signaling pathway (eNOS–Akt–ERK1/2–CREB–Bcl-2) activation. The introduction of B2R inhibitor HOE-140 further confirmed, both in vitro and in vivo that ZHB103 exerts its efficacy in stroke treatment through upregulation of B2R and activation of its downstream eNOS signaling pathway. These results suggest that the administration frequency of ZHB103 may be reduced to once weekly, demonstrating the advantages of PEG-conjugation strategy in improving patient compliance among stroke patients in clinical practice.

外源性血浆钾化因子1 （KLK1）补充被假设具有即时和持久的作用，可能改善急性缺血性卒中后的预后。ZHB103是一种聚乙二醇修饰的长效重组人KLK1 (LA-rhKLK1)，已被开发为卒中患者补充外源性KLK1和预防卒中的候选药物。在Sprague-Dawley大鼠和食蟹猴的药代动力学和毒代动力学研究中，ZHB103在肌肉注射后具有较高的生物利用度、较长的半衰期（T1/2）和无治疗相关的不良反应。在氧-葡萄糖剥夺/再氧化模型、h2o2诱导的氧化应激模型和实验性脑卒中模型中，单次或每周一次给予ZHB103均显示出短期和长期的缺血性脑卒中保护作用。与rKLK1 （ZHB103的蛋白，一种短效非聚乙二醇化重组KLK1）、三倍新（依替拉奉和右冰片注射用浓缩溶液）或HUK（人尿钾化酶，一种来自尿液的组织钾化酶1）相比，ZHB103促进细胞增殖，抑制细胞凋亡，通过显著延长B2受体（B2R）介导的信号通路（eNOS-Akt-ERK1/2-CREB-Bcl-2）激活的持续时间，降低脑卒中模型急性期的炎症因子水平，并改善恢复期后期的认知功能恢复。B2R抑制剂HOE-140的引入进一步在体外和体内证实了ZHB103通过上调B2R并激活其下游eNOS信号通路来发挥其治疗脑卒中的功效。上述结果提示，ZHB103的给药频率可降低至每周一次，说明peg偶联策略在临床实践中提高脑卒中患者依从性方面的优势。

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引用次数: 0

Targeting dual specificity tyrosine-phosphorylation-regulated kinase 1A mitigates tauopathy and enhances recovery after repetitive head injury 靶向双特异性酪氨酸磷酸化调节激酶1A减轻重复性头部损伤后的tau病并增强恢复。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-02-05 DOI: 10.1016/j.neurot.2026.e00843

Benoit Melchior , Mackenzie Browning , Robyn McCartan , Carolyn Lai , Coral Hahn-Townsend , Arissa Gratkowski , Alexander Morin , Michael Mullan , Fiona Crawford , Mirta Grifman , Benoit Mouzon

Chronic neuroinflammation and accumulation of phosphorylated Tau (pTau) are hallmark features of several neurodegenerative diseases and are also observed in some individuals who have sustained traumatic brain injury (TBI). Notably, more than 70 % of patients presenting to emergency departments with mild TBI (Glasgow Coma Score of 13–15) exhibit neuropathological alterations despite a normal sensorium, and up to half experience prolonged post-injury symptoms. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a serine/threonine protein kinase that contributes to tau phosphorylation and regulates immune responses. Inhibition of DYRK1A may therefore attenuate both tau pathology and neuroinflammation following injury. Transgenic mice expressing human Tau (hTau) were subjected to repetitive head injury (RHI) over a 3-month period and treated with either vehicle or SM07883, a potent, brain-penetrant DYRK1A inhibitor. Behavioral performance was evaluated using the Rotarod and Barnes Maze tests, and neuropathological assessments were performed six months after the first injury. SM07883 treatment restored locomotor performance in injured animals and ameliorated age-related motor decline in sham-treated mice. These behavioral improvements were accompanied by significant reductions in RHI-induced pTau accumulation within the midbrain and brainstem, along with decreased astroglial and microglial activation in the corpus callosum, brainstem, and cortical regions beneath the injury site. Collectively, these findings demonstrate that DYRK1A inhibition mitigates tau pathology and chronic neuroinflammation following repetitive injury, supporting DYRK1A as a promising therapeutic target for the long-term neurological consequences of TBI.

慢性神经炎症和磷酸化Tau （pTau）的积累是几种神经退行性疾病的标志性特征，在一些持续的创伤性脑损伤（TBI）患者中也可以观察到。值得注意的是，在急诊室就诊的轻度TBI患者（格拉斯哥昏迷评分为13-15）中，超过70%的患者表现出神经病理改变，尽管感觉正常，而且多达一半的患者经历了长期的损伤后症状。双特异性酪氨酸磷酸化调节激酶1A （DYRK1A）是一种丝氨酸/苏氨酸蛋白激酶，有助于tau磷酸化并调节免疫反应。因此，抑制DYRK1A可能会减轻损伤后的tau病理和神经炎症。表达人类Tau蛋白（hTau）的转基因小鼠在3个月的时间内遭受重复性头部损伤（RHI），并接受对照物或SM07883（一种有效的脑渗透DYRK1A抑制剂）治疗。使用Rotarod和Barnes Maze测试评估行为表现，并在第一次损伤后6个月进行神经病理学评估。SM07883治疗恢复了受伤动物的运动能力，并改善了假药治疗小鼠的年龄相关运动能力下降。这些行为改善伴随着中脑和脑干中rhd诱导的pTau积累的显著减少，以及胼胝体、脑干和损伤部位下方皮质区域星形胶质和小胶质细胞激活的减少。总的来说，这些发现表明DYRK1A抑制减轻了重复损伤后的tau病理和慢性神经炎症，支持DYRK1A作为TBI长期神经系统后果的有希望的治疗靶点。

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引用次数: 0

Plasma levels of thrombin-cleaved osteopontin as a surrogate biomarker of subsequent chronic shunt-dependent hydrocephalus development following aneurysmal subarachnoid hemorrhage 血浆凝血酶裂解骨桥蛋白水平作为动脉瘤性蛛网膜下腔出血后继发慢性分流依赖性脑积水的替代生物标志物

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-02-17 DOI: 10.1016/j.neurot.2026.e00856

Kazuaki Aoki, Fumihiro Kawakita, Koichi Hakozaki, Hideki Kanamaru, Reona Asada, Hidenori Suzuki, pSEED group

Chronic shunt-dependent hydrocephalus (SDHC) is a major contributor to poor outcome after aneurysmal subarachnoid hemorrhage (aSAH), reportedly with arachnoid fibrosis implicated in its pathophysiology. In the pathogenesis of fibrosis, N-terminal half of osteopontin (OPN N-half), generated via thrombin cleavage of full-length osteopontin (FL-OPN), is linked to a potent fibrinogenic factor. In this study, clinical data and plasma samples were prospectively collected from 141 consecutive aSAH patients treated with surgical clipping, and plasma FL-OPN and OPN N-half levels were measured. Plasma FL-OPN and OPN N-half levels at days 10–12 post-aSAH were intercorrelated and significantly higher in patients who subsequently developed SDHC. The areas under the receiver-operating characteristic curves (AUCs) for both levels were comparable. Multivariate analysis revealed that plasma OPN N-half levels ≥64.65 pmol/L was independently associated with SDHC development (adjusted odds ratio, 12.87; 95 % confidence interval, 3.69–44.90; p < 0.001) as well as ventricular drainage. In addition, the logistic regression model incorporating ventricular drainage and the optimal cut-off value of plasma OPN N-half levels demonstrated excellent discrimination (AUC, 0.847; 95 % confidence interval, 0.780–0.914) with satisfactory calibration. Based on these findings and prior evidence, OPN N-half appears to be associated with the pathophysiology of SDHC, and its elevation in plasma levels during the subacute phase may serve as a surrogate biomarker for predicting SDHC development in patients with aSAH treated with surgical clipping.

慢性分流依赖性脑积水（SDHC）是动脉瘤性蛛网膜下腔出血（aSAH）后预后不良的主要因素，据报道蛛网膜纤维化与其病理生理有关。在纤维化的发病机制中，通过凝血酶切割全长骨桥蛋白（FL-OPN）产生的骨桥蛋白n端一半（OPN N-half）与一种有效的纤维蛋白原因子有关。在这项研究中，前瞻性地收集了141例连续接受手术夹持治疗的aSAH患者的临床资料和血浆样本，并测量了血浆FL-OPN和OPN n -一半水平。asah后10-12天的血浆FL-OPN和OPN n -一半水平相互关联，并且在随后发展为SDHC的患者中显着升高。两个水平的患者工作特征曲线（auc）下的面积具有可比性。多因素分析显示，血浆OPN N-half水平≥64.65 pmol/L与SDHC的发展（校正优势比为12.87；95%可信区间为3.69-44.90;p < 0.001）以及心室引流独立相关。此外，纳入脑室引流和血浆OPN n -半水平最佳截断值的logistic回归模型具有良好的判别性（AUC为0.847；95%置信区间为0.780-0.914），校准结果令人满意。基于这些发现和先前的证据，OPN N-half似乎与SDHC的病理生理有关，其在亚急性期血浆水平的升高可以作为预测手术切除aSAH患者SDHC发展的替代生物标志物。

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引用次数: 0

Nabiximols improves sleep architecture in multiple sclerosis: A prospective polysomnographic study 纳比昔醇改善多发性硬化症患者的睡眠结构：一项前瞻性多导睡眠图研究。

IF 6.9 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2026-01-01 Epub Date: 2026-01-30 DOI: 10.1016/j.neurot.2026.e00840

Francesco Fortunato , Adriana Saraceno , Stefania Barone, Miriam Sturniolo, Pietro Antonio Bruno, Iolanda Martino, Erika Brescia, Ilaria Sammarra, Paola Valentino, Antonio Gambardella

We aim to evaluate sleep disruption in people with multiple sclerosis (MS) compared to an age- and gender-matched control cohort using patient-reported outcome measures and formal polysomnography (PSG) scoring, and testing the effect of Nabiximols on these measures in people with MS. We enrolled adult individuals with MS who were eligible to receive nabiximols. Clinical variables and self-reported items like Pittsburgh Sleep Quality Index (PSQI) score were collected. Individuals underwent two full-night PSG recordings: baseline and after a 6-week nabiximols trial. Additionally, 24 healthy individuals (18 females; mean age:55.7 ± 9.5 years) were recruited as control cohort. Linear mixed-effects models (LMMs) using clinical and PSG parameters were used. Our cohort of 19 people with MS (16 females; mean age of 50.8 ± 10.2 years) with elevated PSQI (11.7 ± 2.8) exhibited: reduced sleep efficiency (SE)[P < 0.001,q-value = 0.003], reduced total sleep time (TST)[P = 0.0021,q-value = 0.005], higher number of awakenings [P < 0.001,q-value = 0.003], increased arousal-index (AI) [P < 0.001,q-value = 0.003], a greater periodic limb movement index (PLMI) [P < 0.001,q-value = 0.003] and a reduced proportion of REM [P < 0.001,q-value = 0.003] compared with the controls. The 6-weeks nabiximols trial resulted in a significant improvement in the PSQI [β 95%CI = −1.28 (-1.67, −0.88)] and in the following PSG measures: SE [β 95%CI = 1.57 (1.18, 1.95)], TST [β 95%CI = 0.93 (0.46, 1.40)], AI [β 95%CI = −1.41 (−1.79, −1.30)], PLMI [β 95%CI = −1.73 (−2.03, −1.43)] and REM sleep [β 95%CI = 1.44 (1.00, 1.87)]. Our prospective study reported a significant sleep disruption in MS and a great improvement in sleep parameters following a 6-week trial of Nabiximols, as indicated by LMMs using PSQI score and PSG measures. We suggest broadening the therapeutic indications of nabiximols to also include individuals with MS who experience significant sleep disruption.

我们的目的是评估多发性硬化症（MS）患者的睡眠中断，并与年龄和性别匹配的对照队列进行比较，使用患者报告的结果测量和正式的多道睡眠记录仪（PSG）评分，并测试纳比ximols对MS患者这些测量的影响。我们招募了符合接受纳比ximols治疗条件的成年MS患者。收集临床变量和自我报告项目，如匹兹堡睡眠质量指数（PSQI）得分。受试者接受了两次通宵PSG记录：基线和6周纳比昔莫ols试验后。另外，还招募了24名健康个体（18名女性，平均年龄55.7±9.5岁）作为对照。采用结合临床和PSG参数的线性混合效应模型。我们的队列包括19名多发性硬化症患者(16名女性；平均年龄（50.8±10.2岁）PSQI升高（11.7±2.8）表现为：睡眠效率（SE）降低[P < 0.001，q值= 0.003]，总睡眠时间（TST）减少[P = 0.0021，q值= 0.005]，觉醒次数增加[P < 0.001，q值= 0.003]，觉醒指数（AI）升高[P < 0.001，q值= 0.003]，周期性肢体运动指数（PLMI）升高[P < 0.001，q值= 0.003]，REM比例降低[P < 0.001，q值= 0.003]。6周的纳比ximols试验导致PSQI [β 95%CI = -1.28(-1.67, -0.88)]和以下PSG测量显著改善：SE [β 95%CI = 1.57 (1.18, 1.95)], TST [β 95%CI = 0.93 (0.46, 1.40)], AI [β 95%CI = -1.41 (-1.79, -1.30)], PLMI [β 95%CI = -1.73(-2.03, -1.43)]和REM睡眠[β 95%CI = 1.44(1.00, 1.87)]。我们的前瞻性研究报告了在6周的Nabiximols试验后，MS患者出现了明显的睡眠中断，睡眠参数有了很大的改善，lmm使用PSQI评分和PSG测量结果表明。我们建议扩大纳比ximols的治疗适应症，包括有明显睡眠中断的MS患者。

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引用次数: 0