Neurotherapeutics最新文献

{"title":"Montelukast alleviates neuroinflammation and improves motor functions in the line 61 model of Parkinson's disease: An exploratory study.","authors":"Katharina Strempfl, Marco Zattoni, Heike Mrowetz, Michael S Unger, Nikolaos Schörghofer, Barbara Altendorfer, Jörg Neddens, Stefanie Flunkert, Birgit Hutter-Paier, Yachao He, Johan Wallin, Rodolphe W Poupardin, Frank Pietrantonio, Nadine Paiement, Horst Zerbe, Thomas Felder, Per Svenningsson, Ludwig Aigner","doi":"10.1016/j.neurot.2025.e00690","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00690","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative movement disorder of high global burden. Uncertainties regarding its exact etiology have been hindering the development of curative therapies. As microglia, the brain's immune cells, are suspected to contribute to neurodegeneration by instigating neuroinflammation, existing anti-inflammatory agents could potentially serve as disease-modifying treatments for PD. Here we evaluated the impact of montelukast, a leukotriene receptor antagonist and anti-inflammatory drug, on motor symptoms and neuropathology in an α-synuclein transgenic mouse model (Line 61) for early onset/genetic PD. Two -weeks -old male Line 61 mice and non-transgenic littermates received daily 10 ​mg/kg montelukast or vehicle orally for 10 weeks. Motor functions were assessed through behavioral tests. Brain tissue was analyzed via unbiased transcriptomics, biochemically, and histologically for various parameters, including microglial and inflammation mediators. Upon montelukast treatment, Line 61 mice significantly improved their beam walk performance compared to vehicle -treated mice. The striatum and cerebellum of the montelukast -treated group showed microglial changes toward a smaller but more ramified appearance. Transcriptomics analysis revealed SGK1, a serine/threonine kinase upstream of NFκB and known target in PD, as the most downregulated gene in the striatum of montelukast -treated animals. This downregulation correlated with reduced striatal protein levels of activated IκB kinase, suggesting a reduced NFκB pathway activity upon montelukast treatment. Thus, oral montelukast administration might be promising for the management of PD, with specific effects on motor coordination and balance.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00690"},"PeriodicalIF":6.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765033","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":"Preoperative network activity predicts the response to subthalamic DBS for Parkinson's disease.","authors":"Prashin Unadkat, An Vo, Yilong Ma, Chris C Tang, Vijay Dhawan, Martin Niethammer, Nha Nguyen, Shichun Peng, Akash Mishra, Ritesh Ramdhani, Albert Fenoy, Silvia Paola Caminiti, Daniela Perani, David Eidelberg","doi":"10.1016/j.neurot.2025.e00699","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00699","url":null,"abstract":"<p><p>Quantitative imaging markers to aid in the selection of Parkinson's disease (PD) patients for surgical interventions such as subthalamic nucleus deep brain stimulation (STN-DBS) are currently lacking. Using metabolic PET and network analysis we identified and validated a treatment-induced topography, termed STN StimNet. Stimulation-mediated changes in network expression correlated with concurrent motor improvement in independent STN-DBS cohorts scanned on and off stimulation. Moreover, STN StimNet measurements off stimulation correlated with local field potentials recorded from the STN, whereas intraoperative modulation of cortical activity by STN stimulation correlated with contributions to the network from corresponding brain regions. These findings suggested that stimulation-mediated clinical responses are influenced by baseline StimNet expression. Indeed, we found that motor outcomes following STN-DBS were predicted by preoperative network expression measured using metabolic PET or resting-state fMRI. To illustrate the potential utility of these measures in selecting optimal candidates for DBS surgery, STN StimNet expression was computed in scans from 175 PD patients (0-21 years from diagnosis). The resulting values were used to identify those individuals likely to derive meaningful benefit from a potential STN-DBS procedure. This approach suggests that preoperative network quantification provides unique information regarding baseline brain circuitry, which may be useful in surgical decision making.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00699"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753898","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":"From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.","authors":"Akash Roy, Valina L Dawson, Ted M Dawson","doi":"10.1016/j.neurot.2025.e00712","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00712","url":null,"abstract":"<p><p>GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00712"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753897","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":"Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.","authors":"Tomohiro Nakamura, Anamika Sharma, Stuart A Lipton","doi":"10.1016/j.neurot.2025.e00708","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00708","url":null,"abstract":"<p><p>Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00708"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743323","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":"The role of gasotransmitters in Parkinson's disease: Interplay of nitric oxide, carbon monoxide, and hydrogen sulfide.","authors":"Jennifer L O'Connor, Dionisia M Fountos, Bita Firouzan, Fateme Azizi, Rasoul Ghasemi, Khosrow Kashfi","doi":"10.1016/j.neurot.2025.e00710","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00710","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative condition marked by dopaminergic neuron loss and α-synuclein accumulation. In recent years, a growing body of work has explored the roles of endogenous gasotransmitters-namely nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S)-in pathways relevant to PD pathology. Though traditionally viewed as toxic, these molecules may, under regulated conditions, influence oxidative stress, neuroinflammation, and mitochondrial function in ways that could be therapeutically significant. NO illustrates this complexity. At physiological concentrations, it supports synaptic function and cerebral blood flow. Yet, when overproduced, it promotes oxidative damage and disrupts mitochondrial processes. Therapeutic strategies include NOS enzyme inhibition and controlled-release NO donors. Nanoparticle-based delivery systems have also been proposed to fine-tune local NO availability, though their clinical relevance remains to be fully validated. CO, produced via heme oxygenase-1 (HO-1), has shown cytoprotective and anti-inflammatory effects. While promising in modulating redox signaling and apoptosis, any therapeutic use of CO requires careful dose regulation to avoid toxicity. H₂S, whose levels appear diminished in PD models, has demonstrated antioxidant, anti-inflammatory, and mitochondrial-supportive effects in preclinical studies. As with NO and CO, maintaining balanced levels of H₂S is critical-both too little and too much can cause harm, making precise delivery essential. This review examines the involvement of NO, CO, and H₂S in PD-related stress responses, emphasizing how their effects vary across experimental models and remain only partially understood.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00710"},"PeriodicalIF":5.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718155","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":"Redox modulation of the complement cascade contributes to synapse loss in Alzheimer's disease.","authors":"Chang-Ki Oh, Yubo Wang, Stuart A Lipton","doi":"10.1016/j.neurot.2025.e00707","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00707","url":null,"abstract":"<p><p>Neuroinflammation is characterized by activation of the immune response in the central nervous system (CNS). In Alzheimer's disease (AD), this involves stimulation of glial cells, including microglia and astrocytes, that surround senile plaques and affected neurons. The complement system is a crucial component of the innate immune system, responsible for rapidly eliminating pathogens and dead or dying cells, while also influencing the magnitude and duration of the inflammatory immune response. Moreover, the complement system plays both neuroprotective and neurodestructive roles. In AD, dysregulation of the complement system contributes to excessive microglial phagocytosis of synapses, with such synaptic loss representing the major correlate to cognitive decline in the course of the disease. However, the detailed mechanism for complement activation in AD had remained poorly understood until the discovery that complement factors were aberrantly S-nitrosylated, representing a redox-mediated posttranslational modification that controls the complement cascade. Nitrosative stress, caused by excessive generation of reactive nitrogen species (RNS), including nitric oxide (NO)-related species, had been recognized as a critical factor in the pathogenesis and progression of AD. Recent publications highlighted in this review support the notion that the NO-related species support aberrant S-nitrosylation of complement proteins, leading to pathological activation of the complement system, thus contributing to synaptic loss in AD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00707"},"PeriodicalIF":5.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718230","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":"Efficacy and safety of efavirenz in Niemann-Pick disease type C.","authors":"Jordi Gascón-Bayarri, Inmaculada Rico, Cristina Sánchez-Castañeda, María Dolores Ledesma, Thiago Carnaval, Helena Bejr-Kasem, Jaume Campdelacreu, Anna Ferrer, Laura Rodríguez-Bel, Mónica Cos, Eugenia de Lama, Adolfo López de Munain, Idoia Rouco, Celia Pérez-Sousa, María Cerdán, Nuria Muelas, María Dolores Sevillano, Pablo Mir, Jesús Villoria, Sebastián Videla","doi":"10.1016/j.neurot.2025.e00706","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00706","url":null,"abstract":"<p><strong>Introduction: </strong>In search of disease-modifying treatments for the Niemann-Pick disease type C (NPC), this Phase II single-arm clinical trial evaluated the safety and efficacy of efavirenz, a reverse transcriptase inhibitor that potentially ameliorates neuronal cholesterol turnover, typically impaired in this rare lysosomal storage disorder.</p><p><strong>Material and methods: </strong>Patients 14 years of age or older with genetically confirmed NPC received efavirenz 25 mg/day (Weeks 1-26) or 100 mg/day (Weeks 27-52) orally on top of standard care including miglustat. The primary endpoint was the proportion of response, defined as lack of deterioration in a composite outcome of cognitive performance. Secondary endpoints included the quantitative scores of several clinical neuropsychological assessment tools, some relevant neurological signs and symptoms, and imaging and biological specimen-based biomarkers. Measures were taken repeatedly over time and were analyzed using generalized linear mixed models.</p><p><strong>Results: </strong>Sixteen patients 15-60 years of age were enrolled. All (100.0 %, 95 % exact confidence interval: 79.4-100.0 %) met the primary endpoint response criterion at Week 52. Quantitative neuropsychological assessments yielded more nuanced results, with relative preservation of learning, memory and executive control, and subtle impairments of verbal fluency, selective and divided attention, and cognitive inhibition. Some patients had better responses than others, allowing us to set two well-differentiated subgroups that differed essentially in the time since symptoms onset. No efavirenz-related or serious adverse events were reported.</p><p><strong>Conclusion: </strong>Efavirenz appears to be a safe, easy-to-use, new targeted therapeutic option which slows the rate of NPC progression. The benefits of efavirenz are greater if started earlier.</p><p><strong>Trial registration: </strong>Registered on the European Union Clinical Trials Register (EurdraCT) on December 20th, 2019 under the number: 2019-004498-18 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004498-18/ES/). The first patient was enrolled on May 25th, 2022.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00706"},"PeriodicalIF":5.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699118","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":"Targeting macro- and micro-nutrient regulation of H₂S signaling for the aging brain.","authors":"Matthew Godwin, Christopher Hine","doi":"10.1016/j.neurot.2025.e00638","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00638","url":null,"abstract":"<p><p>Global growth in aged population demographics is a testament to medical and societal innovations over the past 100 years. However, with advanced age comes declines in various organs and tissues, thus limiting quality of life in one's later years. There are numerous hypotheses for what the driving and causative factors are for biological aging, with each proposing molecular targets and their therapeutic strategies. One such hypothesis is that dysfunctions in cellular and systemic redox homeostasis are to blame, in that aging-related increases in oxidative stress and diminished thiol-mediated protections and signaling activity drive macromolecular damage leading to tissue failure, particularly in the brain. Addressing redox dysfunction has been somewhat a challenge clinically, as antioxidant supplementation has not shown to be universally effective at slowing the aging process. Thus, geroscience interventions that can bolster our endogenous redox machinery may be more effective. In this review, we highlight hydrogen sulfide (H₂S) and its associated metabolism and gasotransmitter signaling as potent redox mechanisms that can be leveraged via macro- and/or micro-nutrient interventions. Specifically, dietary restriction (DR) and iron status greatly impact the enzymatic and non-enzymatic production, metabolism, and thiol modifications of H₂S. As both DR and iron status can have profound impacts on redox homeostasis and aging in the brain, we discuss how all these factors are intertwined in glioblastoma (GBM) and neurodegeneration, two of the most significant aging-related disorders of the brain that limit both lifespan and healthspan.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00638"},"PeriodicalIF":5.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659690","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":"Special Edition: Therapeutic advances in multiple sclerosis.","authors":"Patricia K Coyle","doi":"10.1016/j.neurot.2025.e00697","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00697","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00697"},"PeriodicalIF":5.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619436","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":"Early versus delayed DCB for sICAS.","authors":"Xiaofei Sun, Yayue Liu, Lucynda Pham, Guangwen Li","doi":"10.1016/j.neurot.2025.e00689","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00689","url":null,"abstract":"<p><p>In recent years, drug-coated balloons (DCB) have been increasingly used for intervention therapy of intracranial atherosclerotic stenosis (ICAS) with significant efficacy. However, the timing of DCB intervention therapy remains controversial, and there are few published studies that further investigated this. This study aimed to evaluate the clinical outcomes of early (≤21 days) versus delayed (21-42 days) DCB treatment in patients with ICAS. Symptomatic ICAS (sICAS) patients who underwent DCB angioplasty between August 2021 and March 2024 were included in the study. Based on the time from the last qualifying event (QE) to the procedure, patients were divided into an early group (≤21 days) and a delayed group (21-42 days). The efficacy and safety of DCB angioplasty, including perioperative complications and restenosis, were recorded and compared between the two groups. A total of 186 patients were enrolled, with 75 in the early group and 111 in the delayed group where all patients underwent DCB angioplasty successfully. The delayed group showed significantly lower postoperative residual stenosis (10 ​% vs. 20 ​%, P ​= ​0.041) and restenosis rates (10.81 ​% vs. 22.67 ​%, P ​= ​0.029) at the 12-month follow-up compared to the early group. The delayed group also had numerically lower perioperative complication rates (5.41 ​% vs. 9.33 ​%, P ​= ​0.303) and recurrence rates (7.21 ​% vs. 9.33 ​%, P ​= ​0.601), however these differences were not statistically significant. Our study concludes that in patients with sICAS, performing DCB angioplasty within 21 days may carry a higher degree of residual stenosis and an increased long-term risk of restenosis.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00689"},"PeriodicalIF":5.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601069","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}