Neurotherapeutics最新文献_第5页

Association between “weekend warrior” physical activity and the incidence of neurodegenerative diseases 周末战士 "体育锻炼与神经退行性疾病发病率之间的关系。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00430

Yuye Ning , Meilin Chen , Jiaqi An , Manyun Tang , Gary Tse , Jeffrey Shi Kai Chan , Changying Zhao , Yingying Liu , Xinjun Lei , Hua Qiang , Chuan Bai , Hongbing Li , Hang Yu , Yang Yan , Duolao Wang , Guoliang Li

While guidelines recommend 150 min of moderate to vigorous physical activity (MVPA) weekly to enhance health, it remains unclear whether concentrating these activities into 1–2 days of the week, “weekend warrior” (WW) pattern, has the same benefit for neurodegenerative diseases (NDDs). This study aimed to evaluate the associations of WW pattern and the risk of NDDs. This prospective study was conducted using accelerometer-based physical activity data for a full week from June 2013 to December 2015 in the UK Biobank. These individuals were categorized into distinct physical activity patterns, including the WW pattern (i.e., over 50% or 75% of recommended MVPA achieved over 1–2 days), regular pattern, and inactive pattern. Cox proportional hazards model was used to evaluate the association between physical activity patterns and outcomes. Compared to inactive group, WW pattern and regular pattern was similarly linked to a reduced risk of all-cause dementia (WW: Hazard Ratio [HR]: 0.68, 95% Confidence Interval [CI]: 0.56–0.84; regular: HR: 0.86, 95% CI: 0.67–1.1) and all-cause Parkinsonism (WW: HR: 0.47, 95% CI: 0.35–0.63; regular: HR: 0.69, 95% CI: 0.5–0.95). When the exercise threshold was increased to 75% of MVPA, both patterns still were associated with decreased risk of incident all-cause dementia (WW: HR: 0.61, 95% CI: 0.41–0.91; regular: HR: 0.76, 95% CI: 0.63–0.92) and all-cause Parkinsonism (WW: HR: 0.22, 95% CI: 0.10–0.47; regular: HR: 0.59, 95% CI: 0.46–0.75). Concentrating recommended physical activities into 1–2 days per week is associated with a lower incidence of NDDs.

虽然指南建议每周进行 150 分钟的中度到剧烈运动（MVPA）以增强体质，但将这些活动集中在一周中的 1-2 天，即 "周末战士"（WW）模式，是否对神经退行性疾病（NDDs）有同样的益处，目前仍不清楚。本研究旨在评估 "周末战士 "模式与 NDDs 风险之间的关联。这项前瞻性研究使用了英国生物库中 2013 年 6 月至 2015 年 12 月期间基于加速计的整周体力活动数据。这些人被分为不同的体力活动模式，包括WW模式（即在1-2天内达到推荐MVPA的50%或75%以上）、常规模式和非活跃模式。采用 Cox 比例危险模型评估体力活动模式与结果之间的关系。与不活动组相比，WW 模式和常规模式同样与全因痴呆风险降低有关（WW：危险比 [HR]：0.68，95% 置信区间 [CI]：0.56-0.84; regular：HR：0.86，95% CI：0.67-1.1）和全因帕金森病（WW：HR：0.47，95% CI：0.35-0.63；常规：HR：0.69，95% CI：0.5-0.95）。当运动阈值提高到 MVPA 的 75% 时，这两种模式仍与全因痴呆症（WW：HR：0.61，95% CI：0.41-0.91；常规：HR：0.76，95% CI：0.63-0.92）和全因帕金森病（WW：HR：0.22，95% CI：0.10-0.47；常规：HR：0.59，95% CI：0.46-0.75）的发病风险降低相关。将推荐的体育活动集中在每周 1-2 天进行与 NDD 的发病率较低有关。

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引用次数: 0

Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+) 皮下注射依加替莫德 PH20 治疗全身性肌无力：3 期随机非劣效性研究 (ADAPT-SC) 和长期开放标签扩展研究 (ADAPT-SC+) 的中期分析。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00378

James F. Howard Jr. , Tuan Vu , George Li , Denis Korobko , Marek Smilowski , Li Liu , Fien Gistelinck , Sophie Steeland , Jan Noukens , Benjamin Van Hoorick , Jana Podhorna , Filip Borgions , Yuebing Li , Kimiaki Utsugisawa , Heinz Wiendl , Jan L. De Bleecker , Renato Mantegazza , the ADAPT-SC and ADAPT-SC+ Study Groups

ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 mg or efgartigimod IV 10 mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 mg and efgartigimod IV 10 mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 mg and efgartigimod IV 10 mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG.

ADAPT-SC（NCT04735432）旨在评估全身性肌无力（gMG）患者皮下注射（SC）依夫加替莫德 PH20 与静脉注射（IV）依夫加替莫德的非劣效性。ADAPT-SC+（NCT04818671）是一项开放标签扩展研究，旨在评估依夫加替莫德PH20 SC的长期安全性、耐受性和疗效。ADAPT-SC的成年参与者被随机分配接受4个治疗周期，每周一次服用依加替莫德PH20 SC 1000毫克或依加替莫德静脉注射10毫克/千克，然后进行7周的随访。主要终点是第4周（第四次给药后1周）总免疫球蛋白G（IgG）水平与基线相比的百分比变化。次要疗效终点是评估肌无力日常生活活动（MG-ADL）和定量肌无力（QMG）应答者的人数和百分比，以及每项指标总分与基线相比的平均变化。该研究达到了主要终点，证明依加替莫德PH20 SC 1000毫克与依加替莫德静脉注射10毫克/千克在IgG总降低率方面无劣效性。两个治疗组在首次给药后1周就出现了有临床意义的改善，在第4周达到最大改善。在ADAPT-SC+中继续使用依加替莫德PH20 SC治疗周期已证明具有长期安全性，并能持续改善MG-ADL总分。ADAPT-SC 和 ADAPT-SC+ 的研究结果显示了与安慰剂对照 ADAPT 研究相似的安全性和有效性。总之，这些研究结果支持依加替莫德 PH20 SC 1000 毫克与依加替莫德静脉注射 10 毫克/千克之间的非劣效性，以及依加替莫德 PH20 SC 用于治疗广大 gMG 患者的长期安全性、耐受性和有效性。

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引用次数: 0

Predictors of pharyngeal electrical stimulation treatment success in tracheotomised stroke patients with dysphagia: Secondary analysis from PHADER cohort study 吞咽困难的气管切开中风患者咽部电刺激治疗成功的预测因素：PHADER 队列研究的二次分析。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00433

Ivy Cheng , Philip M. Bath , Shaheen Hamdy , Paul Muhle , Satish Mistry , Rainer Dziewas , Sonja Suntrup-Krueger

Pharyngeal electrical stimulation (PES) has emerged as a promising intervention for neurogenic dysphagia, with potential benefits in reducing dysphagia severity in stroke patients. PES may facilitate decannulation in tracheotomised stroke patients with dysphagia, yet the predictive factors for treatment success have not been investigated in detail. This study used data from the PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) study to identify predictive factors for PES treatment success among patients with post stroke dysphagia who required mechanical ventilation and tracheotomy. Multiple linear regression was performed to predict treatment success, as measured in improvement in dysphagia severity rating scale (DSRS), accounting for age, sex, stroke type, lesion location, baseline National Institutes of Health Stroke Scale (NIHSS) score, feeding status, time from stroke onset to PES, PES perceptual threshold and PES stimulation intensity at the first session. Cox regression was conducted to identify the predictors for decannulation for all participants. Ninety-eight participants (mean [SD] age = 66.6 [13.0]; male 73.5%) were included in the analyses. Regression analyses showed that early intervention (p = 0.004) and younger age (p = 0.049) were significant predictors for treatment success. For participants who received PES during tracheotomy (n = 60; mean [SD] age = 66.6 [11.2]; male 73.3%), supratentorial stroke (p = 0.033) and feeding status at baseline (p = 0.025) were predictors of treatment success. Among all participants, early intervention was associated with higher likelihood of decannulation (p = 0.026). These results highlight the importance of timely intervention, age and stroke location in PES treatment success for stroke patients with mechanical ventilation and tracheotomy.

咽部电刺激（PES）已成为治疗神经源性吞咽困难的一种很有前景的干预方法，在降低中风患者吞咽困难的严重程度方面具有潜在的益处。咽部电刺激可帮助气管切开的中风患者解除吞咽困难，但治疗成功的预测因素尚未得到详细研究。本研究利用欧洲神经源性吞咽困难PHAryngeal电刺激注册（PHADER）研究的数据，确定了需要机械通气和气管切开的卒中后吞咽困难患者中 PES 治疗成功的预测因素。在考虑了年龄、性别、卒中类型、病变位置、美国国立卫生研究院卒中量表（NIHSS）基线评分、喂养状态、从卒中发生到 PES 治疗的时间、PES 感知阈值和首次治疗时的 PES 刺激强度后，采用多元线性回归预测治疗成功率（以吞咽困难严重程度评分量表（DSRS）的改善程度为衡量标准）。我们对所有参与者进行了 Cox 回归，以确定取消通气的预测因素。98 名参与者（平均 [SD] 年龄 = 66.6 [13.0]；男性占 73.5%）参与了分析。回归分析表明，早期干预（p = 0.004）和年龄较小（p = 0.049）是治疗成功的重要预测因素。对于在气管切开术中接受 PES 的参与者（n = 60；平均 [SD] 年龄 = 66.6 [11.2]；男性占 73.3%），上脑卒中（p = 0.033）和基线时的喂养状态（p = 0.025）是治疗成功的预测因素。在所有参与者中，早期干预与更高的解禁可能性相关（p = 0.026）。这些结果凸显了及时干预、年龄和卒中位置对机械通气和气管切开的卒中患者 PES 治疗成功的重要性。

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引用次数: 0

Identifying responders to vagus nerve stimulation based on microstructural features of thalamocortical tracts in drug-resistant epilepsy 根据耐药性癫痫丘脑皮质束的微观结构特征识别迷走神经刺激的应答者。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00422

The mechanisms of action of Vagus Nerve Stimulation (VNS) and the biological prerequisites to respond to the treatment are currently under investigation. It is hypothesized that thalamocortical tracts play a central role in the antiseizure effects of VNS by disrupting the genesis of pathological activity in the brain. This pilot study explored whether in vivo microstructural features of thalamocortical tracts may differentiate Drug-Resistant Epilepsy (DRE) patients responding and not responding to VNS treatment. Eighteen patients with DRE (37.11 ± 10.13 years, 10 females), including 11 responders or partial responders and 7 non-responders to VNS, were recruited for this high-gradient multi-shell diffusion Magnetic Resonance Imaging (MRI) study. Using Diffusion Tensor Imaging (DTI) and multi-compartment models - Neurite Orientation Dispersion and Density Imaging (NODDI) and Microstructure Fingerprinting (MF), we extracted microstructural features in 12 subsegments of thalamocortical tracts. These characteristics were compared between responders/partial responders and non-responders. Subsequently, a Support Vector Machine (SVM) classifier was built, incorporating microstructural features and 12 clinical covariates (including age, sex, duration of VNS therapy, number of antiseizure medications, benzodiazepine intake, epilepsy duration, epilepsy onset age, epilepsy type - focal or generalized, presence of an epileptic syndrome - no syndrome or Lennox-Gastaut syndrome, etiology of epilepsy - structural, genetic, viral, or unknown, history of brain surgery, and presence of a brain lesion detected on structural MRI images). Multiple diffusion metrics consistently demonstrated significantly higher white matter fiber integrity in patients with a better response to VNS (p_FDR < 0.05) in different subsegments of thalamocortical tracts. The SVM model achieved a classification accuracy of 94.12%. The inclusion of clinical covariates did not improve the classification performance. The results suggest that the structural integrity of thalamocortical tracts may be linked to therapeutic effectiveness of VNS. This study reveals the great potential of diffusion MRI in improving our understanding of the biological factors associated with the response to VNS therapy.

迷走神经刺激（VNS）的作用机制和对治疗产生反应的生物学先决条件目前正在研究之中。据推测，丘脑皮质束在 VNS 的抗癫痫作用中起着核心作用，它能扰乱大脑中病理活动的起源。这项试验性研究探讨了丘脑皮质束的体内微结构特征是否能区分对 VNS 治疗有反应和无反应的耐药性癫痫（DRE）患者。这项高梯度多壳弥散磁共振成像（MRI）研究招募了18名DRE患者（37.11 ± 10.13岁，10名女性），包括11名对VNS治疗有反应或部分反应者和7名无反应者。利用弥散张量成像（DTI）和多区室模型--神经元定向弥散和密度成像（NODDI）和微结构指纹（MF），我们提取了丘脑皮质束 12 个亚段的微结构特征。这些特征在应答者/部分应答者和非应答者之间进行了比较。癫痫类型--局灶性或全身性；是否存在癫痫综合征--无综合征或 Lennox-Gastaut 综合征；癫痫的病因--结构性、遗传性、病毒性或未知；脑部手术史；以及是否存在在结构性 MRI 图像上检测到的脑部病变）。在丘脑皮质束的不同亚段，多种弥散指标一致显示，对 VNS 反应较好的患者白质纤维完整性明显更高（pFDR < 0.05）。SVM 模型的分类准确率达到 94.12%。加入临床协变量并未提高分类性能。结果表明，丘脑皮质束的结构完整性可能与 VNS 的治疗效果有关。这项研究揭示了弥散核磁共振成像在提高我们对与 VNS 治疗反应相关的生物学因素的认识方面的巨大潜力。

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引用次数: 0

Mendelian randomization demonstrates a causal link between peripheral circulating acylcarnitines and intracranial aneurysms 孟德尔随机试验证明，外周循环的酰基肉碱与颅内动脉瘤之间存在因果关系。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00428

Ying Wang , Kang Xie , Junyu Wang , Fenghua Chen , Xi Li , Longbo Zhang

Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.

颅内动脉瘤（IA）是导致蛛网膜下腔出血（SAH）并危及生命的最常见脑血管疾病。长期的血管结构重塑被认为是颅内动脉瘤的主要病理生理特征。然而，引发这一病理生理过程的致病因素尚不明确。最近，在 IAs 患者中发现了外周循环蛋白和代谢物的异常，并与破裂有关。我们采用孟德尔随机分析法（MR）全面研究了血液代谢物和蛋白质与 IAs 之间的潜在因果关系。我们利用FinnGen研究的数据和Bakker等人发表的GWAS数据集，应用双样本MR探讨了外周循环代谢物（191种血液代谢物）和蛋白质（1398种蛋白质）与IAs之间的潜在因果关系。进一步的两步中介MR分析表明，高血压作为内膜损伤和破裂的诱因之一，中介了棕榈酰肉碱、硬脂酰肉碱和2-十四碳烯酰肉碱与内膜损伤之间的因果关系。总之，我们的研究表明，血液中代谢的棕榈酰肉碱、硬脂酰肉碱和 2-十四碳烯酰肉碱与 IAs 的形成和破裂有因果关系。高血压部分介导了这种因果效应。

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引用次数: 0

MeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome MeCP2 基因疗法可改善皮特-霍普金斯综合征小鼠模型的疾病表型。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00376

The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists. We reprogrammed patient skin derived fibroblasts into induced neuronal progenitor cells. Interestingly, we discovered that MeCP2 levels were decreased in PTHS patient iNPCs relative to healthy controls and that both iNPCs and iAstrocytes displayed defects in function and differentiation in a mutation-specific manner. When Tcf4^+/− mice were genetically crossed with mice overexpressing MeCP2, molecular and phenotypic defects were significantly ameliorated, underlining and important role of MeCP2 in PTHS pathology. Importantly, post-natal intracerebroventricular gene replacement therapy with adeno-associated viral vector serotype 9 (AAV9)-expressing MeCP2 (AAV9.P546.MeCP2) significantly improved iNPC and iAstrocyte function and effectively ameliorated histological and behavioral defects in Tcf4^+/− mice. Combined, our data suggest a previously unknown role of MeCP2 in PTHS pathology and common pathways that might be affected in multiple neurodevelopmental disorders. Our work highlights potential novel therapeutic targets for PTHS, including upregulation of MeCP2 expression or its downstream targets or, potentially, MeCP2-based gene therapy.

神经发育障碍皮特-霍普金斯综合症（PTHS）的临床症状与雷特综合症（RTT）患者相似。然而，RTT 是由 MECP2 基因突变引起的，而 PTHS 则是由 TCF4 基因突变引起的。这两种疾病的机理共性尚不清楚，但它们的共同症状表明可能存在趋同的通路级干扰。我们将患者皮肤衍生成纤维细胞重新编程为诱导神经元祖细胞。有趣的是，我们发现与健康对照组相比，PTHS 患者 iNPCs 的 MeCP2 水平降低，而且 iNPCs 和 iAstrocytes 都以突变特异性的方式显示出功能和分化缺陷。当 Tcf4+/- 小鼠与过表达 MeCP2 的小鼠进行基因杂交时，分子和表型缺陷明显改善，突出了 MeCP2 在 PTHS 病理中的重要作用。重要的是，用表达 MeCP2 的 9 号血清型腺相关病毒载体（AAV9）（AAV9.P546.MeCP2）进行出生后脑室内基因替代治疗，可显著改善 iNPC 和 iAstrocyte 的功能，并有效改善 Tcf4+/- 小鼠的组织学和行为学缺陷。综上所述，我们的数据表明，MeCP2 在 PTHS 病理学中的作用以及在多种神经发育障碍中可能受影响的共同通路之前是未知的。我们的研究突显了 PTHS 潜在的新型治疗靶点，包括上调 MeCP2 表达或其下游靶点，或潜在的基于 MeCP2 的基因疗法。

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引用次数: 0

Long non-coding RNA SNHG12 regulates leptomeningeal collateral remodeling via RGMa after ischemic stroke 长非编码 RNA SNHG12 通过 RGMa 调节缺血性脑卒中后的脑膜侧支重塑

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00429

Anan Jiang , Zijie Wang , Ruiqi Cheng , Shaoru Zhang , Qisi Wu, Xinyue Qin

Leptomeningeal anastomoses or pial collateral arteries are crucial for restoring cerebral blood flow (CBF) after an ischemic stroke. Vascular smooth muscle cells (VSMCs) are hypothesized to regulate the extent of this adaptive response, while the specific molecular mechanisms underlying this process are still being investigated. SNHG12, a long non-coding RNA, has been shown to influence several diseases related angiogenesis, including osteosarcoma and gastric cancer. However, the role of SNHG12 in contractile VSMC dedifferentiation during collateral arteriogenesis-related strokes remains unclear. Here we demonstrated that SNHG12 is a positive regulator of MMP9 and VSMC dedifferentiation, which enhances pial collateral arteriogenesis following cerebrovascular occlusion. Pial collateral remodeling is limited by the crosstalk between SNHG12-MMP9 signaling in VSMCs, which is mediated through repulsive guidance molecule a (RGMa) regulation. Thus, targeting SNHG12 may represent a therapeutic strategy for improving collateral function, neural tissue health, and functional recovery following ischemic stroke.

缺血性脑卒中后，脑膜吻合口或髓侧动脉对恢复脑血流（CBF）至关重要。据推测，血管平滑肌细胞（VSMC）可调节这种适应性反应的程度，而这一过程的具体分子机制仍在研究之中。SNHG12 是一种长非编码 RNA，已被证明可影响多种与血管生成相关的疾病，包括骨肉瘤和胃癌。然而，SNHG12 在侧支动脉生成相关中风过程中的收缩性 VSMC 去分化中的作用仍不清楚。在这里，我们证明了SNHG12是MMP9和VSMC去分化的正向调节因子，它能增强脑血管闭塞后的髓侧动脉生成。VSMC中SNHG12-MMP9信号之间的串扰限制了髓侧动脉重塑，而这种串扰是通过排斥性引导分子a（RGMa）调控介导的。因此，靶向 SNHG12 可能是改善缺血性中风后侧支功能、神经组织健康和功能恢复的一种治疗策略。

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引用次数: 0

Fibroblast growth factor 3 contributes to neuropathic pain through Akt/mTOR signaling in mouse primary sensory neurons 成纤维细胞生长因子3通过小鼠初级感觉神经元中的Akt/mTOR信号转导导致神经性疼痛

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00383

Neuropathic pain (NP), a severe chronic pain condition, remains a substantial clinical challenge due to its complex pathophysiology and limited effective treatments. An association between the members of the Fibroblast Growth Factors (FGFs), particularly Fgf3, and the development of NP has become evident. In this study, utilizing a mouse model of NP, we observed a time-dependent increase in Fgf3 expression at both mRNA and protein levels within the dorsal root ganglia (DRG). Functional studies revealed that blocking Fgf3 expression mitigated nerve injury induced nociceptive hypersensitivity, suggesting its pivotal role in pain modulation. Moreover, our findings elucidate that Fgf3 contributes to pain hypersensitivity through the activation of the Akt/mTOR signaling in injured DRG neurons. These results not only shed light on the involvement of Fgf3 in nerve injury-induced NP but also highlight its potential as a promising therapeutic target for pain management. This study thereby advances our understanding of the molecular mechanisms underlying NP and opens new avenues for the development of effective treatment strategies.

神经病理性疼痛（NP）是一种严重的慢性疼痛症状，由于其病理生理学复杂且有效治疗方法有限，因此仍是一项巨大的临床挑战。成纤维细胞生长因子（FGFs）成员，尤其是 Fgf3，与神经性疼痛的发展之间的关联已变得显而易见。在这项研究中，我们利用小鼠 NP 模型观察到，背根神经节（DRG）内 Fgf3 的 mRNA 和蛋白质水平的表达均出现了随时间变化的增加。功能研究显示，阻断 Fgf3 的表达可减轻神经损伤引起的痛觉过敏，这表明它在疼痛调节中起着关键作用。此外，我们的研究结果还阐明了Fgf3是通过激活损伤的DRG神经元中的Akt/mTOR信号转导而导致痛觉过敏的。这些结果不仅揭示了 Fgf3 参与神经损伤诱导的 NP 的过程，而且突出了它作为疼痛治疗靶点的潜力。这项研究从而推进了我们对 NP 潜在分子机制的理解，并为开发有效的治疗策略开辟了新途径。

引用次数: 0

A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer's disease Δ9-四氢大麻酚和大麻二酚的组合可调节阿尔茨海默病动物模型海马中谷氨酸的动态变化。

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-09-01 DOI: 10.1016/j.neurot.2024.e00439

Nuria Sánchez-Fernández , Laura Gómez-Acero , Anna Castañé , Albert Adell , Leticia Campa , Jordi Bonaventura , Verónica Brito , Silvia Ginés , Francisco Queiróz , Henrique Silva , João Pedro Lopes , Cátia R. Lopes , Marija Radošević , Xavier Gasull , Rodrigo A. Cunha , Attila Köfalvi , Samira G. Ferreira , Francisco Ciruela , Ester Aso

A combination of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ⁹-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ⁹-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.

以前曾有研究表明，非精神活性剂量的Δ9-四氢大麻酚（Δ9-THC）和大麻二酚（CBD）组合可减轻阿尔茨海默病（AD）动物模型 APP/PS1 小鼠的认知能力下降。然而，Δ9-THC 和 CBD 治疗特性的神经生物学基础尚未完全清楚。考虑到谷氨酸能活动失调是导致阿尔茨海默病认知障碍的原因之一，本研究评估了这两种天然大麻素的组合可能逆转这种阿尔茨海默病动物模型海马内谷氨酸动态变化的假设。有趣的是，我们的研究结果表明，长期使用Δ9-THC 和 CBD（而不是单独使用其中任何一种）可以降低 APP/PS1 小鼠的细胞外谷氨酸水平和海马的基础兴奋性。这些影响与谷氨酸突触功能和结构的显著变化无关，因为在大麻素处理的小鼠身上没有观察到突触可塑性、谷氨酸信号转导或这些突触关键成分水平的相关变化。相反，我们的数据表明，这些大麻素效应与谷氨酸摄取的控制和/或海马网络的调节有关。综上所述，这些结果支持将这些天然大麻素结合在一起以对抗发生在 AD 大脑中的兴奋毒性的潜在治疗特性。

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引用次数: 0

Microbiome and micronutrient in ALS: From novel mechanisms to new treatments. ALS 中的微生物组和微量营养素：从新机制到新疗法

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY

Neurotherapeutics

Pub Date : 2024-08-31 DOI: 10.1016/j.neurot.2024.e00441

Jun Sun, Yongguo Zhang

Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.

肌萎缩侧索硬化症是一种神经退行性疾病。尽管进行了大量研究，但 ALS 的治疗仍面临挑战。最近的 ALS 研究表明，菌群失调（如肠道微生物群中微生物多样性和有益功能的丧失）与 ALS 的肠道炎症和肠道完整性的改变相关。微生物组和微生物代谢物通过肠道-微生物组-神经元轴在 ALS 发病机制中的新概念和作用已慢慢被神经病学研究领域所认识。在此，我们将讨论微生物组（包括细菌、真菌和病毒）在 ALS 研究中的最新进展。我们将讨论我们对ALS中微生物代谢物的理解。微营养是指必需维生素、矿物质和其他微量营养素的摄入量。我们将总结与微营养和渐冻症有关的文献。此外，我们还将考虑微生物组和微营养在 ALS 的发展和治疗中的相互影响。我们还将进一步提出，机理研究和转化研究应从 "不相信 "转变为 "有说服力的独创性"，从 "实验室研究 "转变为 "床旁应用"，从而为 ALS 的诊断和治疗提供新的策略。

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引用次数: 0