Neurotherapeutics最新文献

{"title":"Intersection of H₂S and Nrf2 signaling: Therapeutic opportunities for neurodegenerative diseases.","authors":"Priyanka Soni, Shravan Paswan, Bindu D Paul, Bobby Thomas","doi":"10.1016/j.neurot.2025.e00627","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00627","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent a significant global health burden due to their progressive and debilitating nature. While the etiology of these disorders is multifaceted, oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and neuronal antioxidant stress responses, has emerged as a pivotal factor in their pathogenesis. Amongst the cellular defense mechanisms counteracting oxidative stress, signaling cascades regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling axis, play a crucial role. Nrf2 signaling is modulated at multiple levels and regulates redox homeostasis and other cellular processes such as expression of neuroprotective genes, resolution of neuroinflammation, stimulating mitochondrial bioenergetics, facilitating cellular repair, and proteostasis. In recent years, the gaseous molecule or gasotransmitter, hydrogen sulfide (H₂S), was shown to modulate Nrf2-mediated signaling through processes that include disruption of Keap1-Nrf2 interaction, leading to enhanced Nrf2 activation. This review explores the intricate relationship between hydrogen sulfide and Nrf2-Keap1 signaling, highlighting their potential to counteract neurodegenerative processes. The interplay between H₂S and Nrf2 signaling underscores their potential as endogenous regulators of cellular resilience against neurodegeneration. Understanding how gasotransmitters fine-tune the Nrf2-Keap1 pathway opens up new avenues for therapeutic interventions in these neurodegenerative disorders. By elucidating how gasotransmitters influence Nrf2-mediated responses, we aim to underscore promising therapeutic strategies that target oxidative damage, modulate neuroinflammation, and enhance neuronal survival pathways in neurodegenerative diseases.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00627"},"PeriodicalIF":5.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of sex on multiple sclerosis therapy.","authors":"Patricia K Coyle","doi":"10.1016/j.neurot.2025.e00620","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00620","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a female predominant disease. The prototypic affected individual is a young woman of childbearing age. This article emphasizes the current thinking about this disease, using a sex-based approach. It begins with a review of male vs. female differences in the nervous system and immune system, as well as a general discussion of sex hormones. The demographic and clinical impact of sex on MS prognosis and symptoms is covered. Pregnancy, the best studied sex-based condition, is reviewed and includes updated counseling information on fertility and assisted reproductive technology. MS issues in less well studied areas involving puberty, the menstrual cycle and menopause are also presented. The impact of sex on the MS therapeutic response is considered. The final section covers MS considerations in males. This up to date review provides a comprehensive and succinct approach to sex considerations in MS.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00620"},"PeriodicalIF":5.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vibration stimulation to the lower limbs improves freezing of gait and modifies cortical electrical activities in Parkinson's disease.","authors":"Puyuan Wen, Hong Zhu, Amin Chang, Xianwen Chen","doi":"10.1016/j.neurot.2025.e00626","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00626","url":null,"abstract":"<p><p>Muscle vibration, a form of proprioceptive stimulation, is a promising therapeutic method for alleviating freezing of gait in Parkinson's disease. This study aimed to investigate whether vibration stimulation enhances freezing of gait in Parkinson's Disease by modifying sensory-motor integration and cortical excitability. Sixty patients with Parkinson's Disease patients with freezing of gait were enrolled to participate in 10-m Timed Up and Go test with/without lower limbs vibration stimulation during single, cognitive-load, and motor-load task walking. Spatiotemporal gait data were collected from 36 patients during timed up and go tests with unilateral vibration to the less affected or more affected side and bilateral stimulation. Additionally, 22 and 28 patients with and without freezing of gait, respectively, underwent neuroelectrophysiological evaluations with/without vibration stimulation. Spatiotemporal gait and neuroelectrophysiological relative changes in patients with freezing of gait were compared between \"ON\" and \"OFF\" vibration. Our results showed both unilateral and bilateral vibration stimulation improved gait and reduced freezing of gait, with more pronounced effects on the less affected side. Patients with freezing of gait revealed decreased latency afferent inhibition and short interval intracortical inhibition in comparison to patients without freezing of gait and healthy controls. Bilateral vibration stimulation improved latency afferent inhibition and short interval intracortical inhibition, which could be attributed to improvements in gait. Overall, our findings suggested that vibration stimulation improved gait and freezing of gait in Parkinson's disease, potentially by enhancing sensory-motor integration and modifying cortical excitability.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00626"},"PeriodicalIF":5.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to 'Utilization of precision medicine digital twins for drug discovery in Alzheimer's disease', Neurotherapeutics, 22(3), e00553.","authors":"Yunxiao Ren, Andrew A Pieper, Feixiong Cheng","doi":"10.1016/j.neurot.2025.e00628","DOIUrl":"10.1016/j.neurot.2025.e00628","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00628"},"PeriodicalIF":5.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel purine derivatives mitigate hypoxia ischemia related brain injury through agrin, zyxin and synaptotagmin proteins.","authors":"Aloïse Mabondzo, Clémence Disdier, Amal Bouzid, Khadidja Side Larbi, Amalia Tsintzou, Auriane Maïza, Boram Kim, Narciso Costa, Rania Harati, Anvi Laetitia Nguyen, Alain Pruvost, Hervé Galons, Nassima Oumata, Jean Armengaud, Marlou Knijnenburg, Gaurav Verma, Henrik Hagberg, Pierre Gressens, Xiaodi F Chen, Rifat A Hamoudi, Barbara S Stonestreet","doi":"10.1016/j.neurot.2025.e00621","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00621","url":null,"abstract":"<p><p>Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns resulting in motor and cognitive impairment. Therapeutic hypothermia is the only treatment approved for HIE. Consequently, there is a critical requirement for additional treatments for hypoxic-ischemic (HI) brain injury because hypothermia is only partially protective. Pharmacological therapeutics are as yet not available to treat HIE. Therefore, we developed a novel trisubstituted purine-derivative drug (BRT_002) to attenuate HI related brain injury. The safety of BRT_002 was confirmed by treating adult rats with BRT_002 (100 ​mg/kg) for 7 days. Postnatal day-7 rats exposed to sham surgery or carotid ligation and 8% FiO₂ for 90 ​min were given BRT_002 (30 ​mg/kg) or placebo intraperitoneally (IP) immediately, 24, and 48 ​h after the induction of HI. Pharmacokinetic studies revealed suitable systemic and brain exposure to BRT_002. Treatment with BRT_002 reduced neuropathological infarct volumes in the neonatal rats. Bioinformatics analyses of proteomic data identified upregulation of Agrin, Zyxin and Syt5 (p ​< ​0.05) in both brain hemispheres in the male and female neonatal rats after treatment with BRT_002. BRT_002 also augmented mitochondrial respiration and produced metabolic changes in mouse neurons exposed to oxygen-glucose deprivation in vitro. Protein-protein interactions suggest that Syt5 interacts with major participants required to attenuate injury and/or facilitate parenchymal brain repair through Fblim1 that include Agrin, Zyxin, Vegfa, Vwf and mitochondrial targets. Our study provides preclinical findings that could serve as a foundation for future clinical trials of this novel purine derivative for the treatment of newborns exposed to HIE.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00621"},"PeriodicalIF":5.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applications of artificial intelligence in drug discovery for neurological diseases.","authors":"Sean Ekins, Thomas R Lane","doi":"10.1016/j.neurot.2025.e00624","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00624","url":null,"abstract":"<p><p>Neurological disease encompasses over 1000 disorders, exacts a massive human health and financial toll as well as being a story of extremes. At one end are diseases that are complex and heterogeneous affecting millions, while at the other there are monogenic and rare diseases, with a handful of individuals. What are absent are drugs that can treat or cure the disease. Discovering these is challenging, held back by extreme costs to develop them or in some cases by the limited understanding of the diseases. After decades of drug discovery research there is now considerable data available which can be used to help develop novel compounds more strategically. This includes high throughput screening data with targets, crystal structures of proteins implicated in neurological diseases and adjacent data such as properties of molecules like blood brain barrier permeability as well as an array of in vitro and in vivo toxicity endpoints valuable for any drug targeting the central nervous system. While computational tools have been developing and applied to neurological diseases for decades, we are now in the age of machine learning and artificial intelligence (AI). This promises the potential to expedite the identification and discovery of new molecules. Whether by using individual computational techniques or complex end-to-end approaches, scientists can narrow the molecules they make and test as well as study more targets or diseases which might have been out of reach previously. This review highlights the many different applications of AI potentially enabling new discoveries and treatments for neurological diseases.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00624"},"PeriodicalIF":5.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current perspectives on endovascular therapy for large core ischemic stroke.","authors":"Chloe A Mutimer, Bruce C V Campbell","doi":"10.1016/j.neurot.2025.e00622","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00622","url":null,"abstract":"<p><p>Historically, patients with ischemic stroke and an extensive region of irreversibly injured ischemic core were excluded from endovascular thrombectomy trials due to concerns about limited benefit and high procedural risk. This has fundamentally changed with the publication of five strongly positive randomized controlled trials in this group of patients since 2022 and a sixth trial that showed consistent trends and was positive in per protocol analysis and long-term follow-up. This narrative review summarizes the key findings of these trials, including imaging selection criteria, functional and safety outcomes, and long-term benefits. Across trials, thrombectomy consistently improved functional outcomes at 3-months and 12-months. Absolute functional independence (modified Rankin Scale score 0-2) rates were lower than the trials that enrolled patients with smaller ischemic core volumes, but still significantly favored thrombectomy. Safety outcomes demonstrated a reduction in mortality with EVT and no significant increase in rates of symptomatic intracerebral hemorrhage. While guidelines are being updated to include large core thrombectomy, real-world decision-making remains complex, requiring careful consideration of patient-specific factors, including functional status, infarct location, and patient preferences. Future research should focus on exploring adjunctive therapies and accelerated systems of care to further improve outcomes in this patient population.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00622"},"PeriodicalIF":5.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep brain stimulation improves symptoms across all dimensions in treatment-resistant depression.","authors":"N Runia, G J J Mol, D A J P Denys, H Ardon, G Beute, M Bot, D A de Waardt, D W W de Knijff, R J T Mocking, P Notten, G J M Rutten, P R Schuurman, P van den Munckhof, J van Laarhoven, G A van Wingen, I O Bergfeld","doi":"10.1016/j.neurot.2025.e00623","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00623","url":null,"abstract":"<p><p>Deep brain stimulation (DBS) reduces depressive symptom scores in many patients with treatment-resistant depression (TRD). However, it is unclear whether the observed improvement is similar across various symptom dimensions (e.g., anhedonia, anxiety, insomnia) or if some require additional clinical attention. Using a retrospective chart review, we assessed the trajectory of HAM-D-17 and MADRS scores during vALIC or slMFB DBS treatment within different symptom dimensions (HAM-D-17: 1) affective/anhedonia, 2) somatic/anxiety, 3) insomnia; MADRS: 1) affective/anhedonia, 2) anxiety/vegetative, 3) hopelessness) after at least a 25 ​% symptom reduction (partial response) at any time during their treatment course (n ​= ​34 for HAM-D-17, n ​= ​25 for MADRS). Results showed that each of the assessed symptom dimensions was significantly reduced compared to baseline at each of the assessed time periods (last follow-up: 2-15 years) after (partial) DBS response onset, which occurred at a median of approximately 2.5 months. Additionally, there was a significant interaction effect between symptom dimension and time period (HAM-D-17: F (12,1655.46) ​= ​5.46, p ​< ​0.001; MADRS: F (12,938.73) ​= ​2.40, p ​< ​0.01). Model coefficients indicated that insomnia symptoms (HAM-D-17) and anxiety/vegetative symptoms (MADRS) improved at a slower rate than the other symptom dimensions. Additionally, higher baseline scores in the HAM-D-17 somatic/anxiety dimension were significantly associated with a larger percentage reduction in overall symptoms after DBS (n ​= ​39, F (1,32) ​= ​12.371, p ​< ​0.01). Our findings demonstrate that DBS for TRD effectively treats depressive symptoms in all dimensions, although insomnia symptoms may improve at a slower rate, and that patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00623"},"PeriodicalIF":5.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing working memory in MCI: Modulating alpha-gamma coupling and gamma oscillations via rTMS.","authors":"Xiao Yuan, Xiaochen Zhang, Jingnan Sun, Renren Li, Jing Ma, Chenxi Pan, Meng Liu, Hualan Yang, Dan Yang, Fangyun Li, Zhi Bie, Zhen Hu, Yunxia Li","doi":"10.1016/j.neurot.2025.e00619","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00619","url":null,"abstract":"<p><p>Cross-frequency coupling (CFC), particularly the interaction between alpha and gamma oscillations, is a pivotal mechanism implicated in cognitive function, with potential for modulation by repetitive transcranial magnetic stimulation (rTMS). This study aimed to investigate the impact of high-frequency rTMS (HF rTMS) on CFC and visual working memory (VWM) in individuals with mild cognitive impairment (MCI). Twenty MCI patients and twenty healthy controls were administered 10Hz rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). Our critical findings indicate that post-intervention, MCI patients exhibited significant enhancements in VWM performance, notably under low memory load. These improvements correlated with a reduction in occipital gamma activity, and were concurrent with strengthened phase-amplitude coupling (PAC) between frontal alpha and occipital gamma oscillations. The results underscore the capacity of alpha-band HF rTMS to modulate neural activity, offering a promising, non-invasive strategy for enhancing cognitive performance in MCI.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00619"},"PeriodicalIF":5.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response.","authors":"Hui Sun, Shenrui Guo, Hongfu Jin, Lin Ding, Yuanyuan Chen, Yu Zhang, Kun He, Qi Huang, Jinyuan Gu, Suyun Chen, Hui Wang, Chenglai Fu, Yafu Yin, Weiwei Cheng","doi":"10.1016/j.neurot.2025.e00618","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00618","url":null,"abstract":"<p><p>Cerebral glucose hypometabolism has been consistently associated with Alzheimer's disease (AD). With extensive efforts to eliminate AD pathologies, including the removal of amyloid-β ​(Aβ) plaques and hyperphosphorylated Tau, strategies aimed at restoring glucose metabolism in the brain regions most affected by AD are believed to have significant clinical implications. In this study, we demonstrated that glucose hypometabolism preceded neuronal death in triple-transgenic AD (3xTg-AD) mice, likely attributable to reduced expression of glucose transporter type 1 (GLUT1) or glucose transporter type 3 (GLUT3). Furthermore, we observed aberrant activation of the integrated stress response (ISR) pathway in AD models, with Aβ and Tau phosphorylation contributing to the activation of the ISR and subsequent reduction in GLUT1/3 expression. Inhibiting ISR activation by utilizing the ISR inhibitor ISRIB can effectively restore GLUT1/3 expression in both in vitro and in vivo models. Importantly, ISRIB treatment improved cognitive function and brain glucose metabolism in 3xTg-AD mice. Our findings suggest that targeting the ISR pathway to restore GLUTs expression may be a potential therapeutic strategy for AD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00618"},"PeriodicalIF":5.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}