NeurotherapeuticsPub Date : 2025-08-29DOI: 10.1016/j.neurot.2025.e00715
Claudia Maletzki, Thomas Freitag, Adrian Hempelmann, Annabell Wolff, Thomas M Freiman, Sae-Yeon Won, Dirk Koczan, Sina Sender, Pablo A Valdes, Joshua D Bernstock, Florian Gessler, Daniel Dubinski
{"title":"Tumor treating fields alter local coagulation dynamics in glioblastoma patients.","authors":"Claudia Maletzki, Thomas Freitag, Adrian Hempelmann, Annabell Wolff, Thomas M Freiman, Sae-Yeon Won, Dirk Koczan, Sina Sender, Pablo A Valdes, Joshua D Bernstock, Florian Gessler, Daniel Dubinski","doi":"10.1016/j.neurot.2025.e00715","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00715","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive brain tumor, associated with hypercoagulability and thrombosis. Tumor Treating Fields (TTFields), a non-invasive therapy that uses low-intensity, alternating electric fields to disrupt cancer cell division, prolongs survival when used concomitantly with radiochemotherapy. TTFields-treated patients often exhibit distinct recurrence patterns, suggesting a local interaction between TTFields and tumor-associated coagulation, underlying mechanisms remain unclear. This study examined coagulation profiles in TTFields-treated patients' blood, tumor cells, and plasma-derived extracellular vesicles using molecular, hemostaseologic, and phenotypic analyses. Our findings revealed that short-term TTFields exposure significantly prolongs blood coagulation in GBM patients and healthy donors by altering tissue factor (TF) expression and disrupting the extrinsic coagulation pathway. TTFields reduced clot rigidity by decreasing Factor II/FXIII activity and platelet count, without impairing fibrinogen function. Patient-derived GBM cells exposed to TTFields exhibited increased TF abundance. RNA-based microarray analysis of GBM cells confirmed coagulation-related changes, including upregulation of platelet adhesion marker ITGA2, and downregulation of THBS1, a regulator of clotting, platelet aggregation, extracellular matrix remodeling, and tumor invasiveness. Additionally, TXNIP, a coagulation-modulating gene, was downregulated after TTFields exposure, indicating a link to immune regulation in the tumor microenvironment. In an allogeneic co-culture model of patient-derived GBM cells and peripheral blood, TTFields modulated coagulation and immune responses, likely by rebalancing pro- and anticoagulant factors in the tumor microenvironment, reducing the prothrombotic state, and altering inflammatory pathways. These findings provide insights into how TTFields influence coagulation and, eventually, immune regulation, offering strategies to optimize clinical decision-making and mitigating thromboembolic complications in GBM patients.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00715"},"PeriodicalIF":6.9,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962559","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 Talin1 to reprogram dendritic cell activation landscapes: A mechanistically grounded cell therapy for multiple sclerosis model.","authors":"Jia Liu, Xiaorui Guan, Zhen Jia, Bin Li, Yuanbo Cao, Kazuo Sugimoto","doi":"10.1016/j.neurot.2025.e00723","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00723","url":null,"abstract":"<p><p>This study investigated the role of Talin1 in regulating dendritic cell (DC) activation and the neuroprotective benefits of Talin1-knockdown DCs in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Bone marrow-derived DCs (BMDCs) were transduced with shTalin1 lentiviral vectors in vitro. Their morphological and biochemical profiles, surface molecules expression, cytokines production, capacity to induce T cell responses, as well as regulatory mechanisms, were comprehensively assessed. In vivo, Talin1-knockdown BMDCs loaded with the MOG<sub>35-55</sub> peptide were administered preclinically and therapeutically to EAE mice, with subsequent evaluation of EAE development, inflammatory infiltration, demyelination, and Th/Treg responses. Results demonstrated that Talin1 knockdown significantly inhibited the activation of BMDCs, as evidenced by decreased expression of surface molecules (MHCII, CD80, CD86) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), increased expression of anti-inflammatory cytokine (IL-10), differential morphology, ultrastructure, and biochemical characteristics, accompanied by limited ability to stimulate CD4+T cell proliferation and polarization toward Th1 and Th17 subsets. Moreover, RNA-sequencing revealed downregulation of immune/inflammation-related processes and pathways in Talin1-knockdown BMDCs. Mechanistically, inhibition of the TLR4/MyD88/NF-κB pathway in BMDCs contributed to these effects. In vivo, Talin1-knockdown BMDCs significantly delayed the pathogenesis & progression of EAE, alleviated their neurological deficits and pathology, decreased Th1 and Th17 lineage levels, and boosted the abundance of Treg cells. Collectively, these findings indicate that Talin1 orchestrates BMDCs activation, and Talin1-knockdown BMDCs protect against EAE by rebalancing Th1/Th17/Treg dynamics, suggesting a potential approach for the development of precision therapies for MS and other autoimmune disorders.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00723"},"PeriodicalIF":6.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962527","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}
NeurotherapeuticsPub Date : 2025-08-18DOI: 10.1016/j.neurot.2025.e00719
Maria Petrosino, Karim Zuhra, Anna Kieronska-Rudek, Lucia Janickova, Olivier Bremer, Moustafa Khalaf, Brian A Logue, Csaba Szabo
{"title":"Cyanide overproduction impairs cellular bioenergetics in Down syndrome.","authors":"Maria Petrosino, Karim Zuhra, Anna Kieronska-Rudek, Lucia Janickova, Olivier Bremer, Moustafa Khalaf, Brian A Logue, Csaba Szabo","doi":"10.1016/j.neurot.2025.e00719","DOIUrl":"10.1016/j.neurot.2025.e00719","url":null,"abstract":"<p><p>Cyanide exerts its toxic effects primarily by inhibiting mitochondrial Complex IV (Cytochrome c oxidase, CCOx). Recent studies have shown that mammalian cells can endogenously produce cyanide from glycine via a lysosomal pathway. At low concentrations, cyanide may play regulatory roles, but at higher levels, it causes metabolic inhibition. Here we show that Down syndrome (DS) cells and tissues exhibit significant overproduction of cyanide, contributing to cellular metabolic suppression. DS rats show elevated blood cyanide levels, and their tissues generate more cyanide than wild-type controls-both under basal conditions and following glycine supplementation. Similarly, human DS fibroblasts produce higher levels of cyanide than healthy control cells. We attribute this increased cyanide production in DS to the marked downregulation of thiosulfate sulfurtransferase (TST, also known as rhodanese), the key enzyme responsible for cyanide detoxification. Importantly, suppression of lysosomal cyanide production in DS cells (through cyanide scavengers, lysosomal deacidification, or inhibition of serine/glycine conversion) improves cellular bioenergetics and/or enhances cell proliferation rates. Previous work has implicated excessive hydrogen sulfide (H<sub>2</sub>S) production, another endogenous gaseous signaling molecule that inhibits CCOx, in DS-associated metabolic suppression. Our current findings indicate that cyanide overproduction may also contribute to this dysfunction. Cyanide and H<sub>2</sub>S may act cooperatively on the same molecular target. These results open the possibility of developing therapeutic strategies that target cyanide or both cyanide and H<sub>2</sub>S to counteract DS-associated metabolic impairment.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00719"},"PeriodicalIF":6.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883313","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}
NeurotherapeuticsPub Date : 2025-08-18DOI: 10.1016/j.neurot.2025.e00713
Vivek Yedavalli, Hamza Adel Salim, Dhairya Lakhani, Basel Musmar, Nimer Adeeb, Davide Simonato, Yan-Lin Li, Orabi Hajjeh, Muhammed Amir Essibayi, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kühn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Leonard Ll Yeo, Benjamin Yq Tan, Robert W Regenhardt, Jeremy J Heit, Aymeric Rouchaud, Jens Fiehler, Sunil Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Răzvan Alexandru Radu, Mohamad Abdalkader, Piers Klein, Takahiro Ota, Ashkan Mowla, Kareem El Naamani, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor R Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Gaultier Marnat, Hamza Shaikh, Christoph J Griessenauer, David S Liebeskind, Alessandro Pedicelli, Andrea M Alexandre, Tobias D Faizy, Illario Tancredi, Erwah Kalsoum, Boris Lubicz, Aman B Patel, Maurizio Fuschi, Max Wintermark, Adrien Guenego, Adam A Dmytriw
{"title":"Hypoperfusion intensity ratio is associated with follow-up infarct volume in medium vessel occlusions: A multicenter multinational study.","authors":"Vivek Yedavalli, Hamza Adel Salim, Dhairya Lakhani, Basel Musmar, Nimer Adeeb, Davide Simonato, Yan-Lin Li, Orabi Hajjeh, Muhammed Amir Essibayi, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kühn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Leonard Ll Yeo, Benjamin Yq Tan, Robert W Regenhardt, Jeremy J Heit, Aymeric Rouchaud, Jens Fiehler, Sunil Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Răzvan Alexandru Radu, Mohamad Abdalkader, Piers Klein, Takahiro Ota, Ashkan Mowla, Kareem El Naamani, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor R Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Gaultier Marnat, Hamza Shaikh, Christoph J Griessenauer, David S Liebeskind, Alessandro Pedicelli, Andrea M Alexandre, Tobias D Faizy, Illario Tancredi, Erwah Kalsoum, Boris Lubicz, Aman B Patel, Maurizio Fuschi, Max Wintermark, Adrien Guenego, Adam A Dmytriw","doi":"10.1016/j.neurot.2025.e00713","DOIUrl":"10.1016/j.neurot.2025.e00713","url":null,"abstract":"<p><p>Medium vessel occlusion (MeVO) contributes significantly to acute ischemic stroke (AIS). The hypoperfusion intensity ratio (HIR), reflecting collateral circulation via the ratio of Tmax >10s to Tmax >6s volumes, predicts infarct progression in large-vessel occlusions but is unstudied in MeVOs. In this multicenter, multinational retrospective study, we evaluated consecutive patients with MeVO who underwent mechanical thrombectomy with or without intravenous thrombolysis. Inclusion required available follow-up imaging and pretreatment CT perfusion. Follow-up infarct volume (FIV) was measured on CT or MRI 12-36 h post-procedure. Univariable and multivariable linear regression models were used to identify predictors of FIV, with HIR as the primary variable of interest. Among 147 patients (median age 75 years, 57 % female), univariable analysis showed HIR was significantly associated with larger FIV (β = 80 mL; p < 0.001). After adjusting for confounders, HIR remained independently associated with FIV (β = 40 mL; p < 0.001). Tmax >10 s showed the strongest correlation with FIV (r = 0.56; p < 0.001). These findings suggest that higher HIR correlates with larger infarct volumes, underscoring the prognostic role of collateral failure in MeVO and highlighting HIR as a potential imaging marker to guide treatment and outcome prediction.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00713"},"PeriodicalIF":6.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883314","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":"Asparagine endopeptidase (AEP) inhibitor formulation via zein-based nanoparticle improves the therapeutic efficacy toward Alzheimer's disease.","authors":"Xin Meng, Mengmeng Wang, Menghan Yang, Guangxing Wang, Zhenlei Zhao, Zhongyun Xie, Bowei Li, Zhengjiang Qian, Seong Su Kang, Wenhua Zheng, Keqiang Ye","doi":"10.1016/j.neurot.2025.e00718","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00718","url":null,"abstract":"<p><p>Asparagine endopeptidase (AEP) plays a critical role in Alzheimer's disease (AD) by cleaving amyloid precursor protein (APP) at N585 and tau protein at N368. Genetic deletion or pharmacological inhibition of AEP using compound 11a ameliorates AD pathology in murine models. To improve the therapeutic potential of 11a, we synthesized structural analogs and developed a zein-based nanoparticle delivery system to enhance pharmacokinetics. Structural modification, specifically isopropyl substitution of the N-methyl group in 11a, markedly improved blood-brain barrier permeability. The lead compound, 11a-isopropyl, formulated in zein nanoparticles, exhibited superior oral bioavailability and brain exposure. In vivo pharmacodynamic/pharmacokinetic (PK/PD) analyses confirmed dose-dependent AEP inhibition and enhanced substrate stabilization, with the nanoparticle formulation further increasing efficacy. One-month oral administration in 3xTg AD mice demonstrated that 11a-isopropyl, particularly in nanoparticle form, significantly reduced Aβ and tau pathology and improved cognitive performance. These findings indicate that zein-based nanoparticles enhance AEP inhibitor delivery and therapeutic efficacy in AD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00718"},"PeriodicalIF":6.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859392","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":"Gaultheria leucocarpa inhibits Aβ fibrillization and enhances mitophagy-mediated degradation of pathogenic proteins.","authors":"Yue Zhang, Lan Deng, Jing Wei, Lufen Huang, Fei Gao, Lu Yu, Fengdan Zhu, Jianing Mi, Jianming Wu, Fang Ren, Minsong Guo, Xiaogang Zhou, Dalian Qin, Ting Chen, Anguo Wu","doi":"10.1016/j.neurot.2025.e00721","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00721","url":null,"abstract":"<p><p>Alzheimer's disease (AD) pathology involves amyloid-beta (Aβ) accumulation and neuronal toxicity, highlighting the need for therapeutic strategies that can both inhibit Aβ aggregation and promote pathogenic protein clearance. In this study, we identified Gaultheria leucocarpa as a medicinal plant with promising neuroprotective potential. Thioflavin T (ThT) fluorescence screening revealed that extracts from G. leucocarpa (GE), particularly the petroleum ether fraction of G. leucocarpa extract (GPF), effectively inhibited Aβ fibril formation in vitro. In cell-based assays, GPF significantly improved the viability of PC-12 cells exposed to Aβ peptides and fibrils, indicating protection against Aβ-induced cytotoxicity. Furthermore, GPF enhanced mitophagic activity, as demonstrated by increased GFP-LC3 puncta, elevated LC3-II/I ratio, and colocalization of GFP-LC3 with MitoTracker Red. Mechanistic investigations showed that GPF activates mitophagy via the AMPK/ULK1 pathway and inhibits the PI3K/AKT/mTOR pathway, resulting in enhanced degradation of APP and Tau proteins. In Caenorhabditis elegans models relevant to AD, GPF administration led to reduced Aβ deposits, delayed paralysis onset, improved food perception, and decreased oxidative stress. Collectively, these findings demonstrate that GPF exerts dual actions by inhibiting Aβ fibrillization and promoting mitophagy-mediated degradation of pathogenic proteins. The active ingredients identified from GPF extracts represent promising leads for the development of novel neuroprotective agents targeting AD-related pathological mechanisms.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00721"},"PeriodicalIF":6.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859393","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":"Engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in Alzheimer's disease: Rational design, blood-brain barrier penetration, and multi-target therapeutic synergy.","authors":"Lianghong Chen, Yadi Guan, Shaojun Wang, Xu Han, Feng Guo, Yu Wang","doi":"10.1016/j.neurot.2025.e00722","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00722","url":null,"abstract":"<p><p>Alzheimer's disease (AD) presents significant therapeutic challenges due to its multifactorial pathology, the inefficacy of traditional single-target drugs, and the poor bioavailability and limited blood-brain barrier (BBB) penetration of promising multi-target phytochemicals like curcumin, resveratrol, and quercetin. This review systematically examines the rational design and recent advancements in engineered nanoplatforms for brain-targeted co-delivery of phytochemicals in AD. Nanotechnology leverages lipid-based systems (liposomes, solid lipid nanoparticles), polymer-based carriers (PLGA nanoparticles), inorganic nanosystems (gold, selenium nanoparticles), and biologically-derived vehicles to significantly enhance phytochemical stability, targeting efficiency, and brain accumulation. Strategic surface functionalization with BBB-translocating ligands, including transferrin receptor antibodies and RVG29 peptide, combined with stimuli-responsive mechanisms exploiting the pathological microenvironment (pH, enzyme sensitivity), enables efficient BBB penetration and lesion-specific drug release. These nanodrug delivery systems demonstrate substantial cognitive improvement in AD animal models through synergistic multi-pathway effects: inhibiting Aβ aggregation, modulating Tau phosphorylation, reducing neuroinflammation, and enhancing antioxidant activity, often at markedly reduced doses compared to free drugs. While preclinical results are compelling, critical challenges remain in nanocarrier long-term biosafety, scalable manufacturing, and clinical translation. This review provides a comprehensive framework and technical insights for developing efficient, safe, and translatable nanotherapeutics for AD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00722"},"PeriodicalIF":6.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855827","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":"Procedure time and outcomes in acute ischemic stroke with anterior circulation large vessel occlusion in the early and late time windows: A stratified analysis by onset-to-puncture time.","authors":"Kangjia Song, Shuang Qi, Chao Li, Mingchao Shi, Zan Wang, Shouchun Wang","doi":"10.1016/j.neurot.2025.e00717","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00717","url":null,"abstract":"<p><p>Previous studies have suggested that procedure time (PT) is associated with prognosis in patients undergoing endovascular treatment (EVT). However, its relationship with prognosis in different time windows remains unclear. This study aimed to investigate the relationship between PT and outcomes in patients with EVT in early (<6 h) versus late-window (6-24 h) window. In this prospective cohort database, we analyzed consecutive patients undergoing EVT. We assessed the association between PT and 90-day modified Rankin Scale scores (primary outcome) using multivariable ordinal logistic regression, stratified by onset to arterial puncture time (OPT) (<6 h vs. 6-24 h), and adjusted for key confounders. This study included 788 patients, of whom 221 (28.1 %) were female. The median age was 63 years (IQR 54-70), and the median NIHSS score was 13 (IQR 10-16). In the early-window group, longer PT was associated with worse functional outcomes (adjusted common odds ratio [acOR] per 10 min, 1.11; 95 % CI, 1.06-1.16) and higher mortality (adjusted odds ratio [aOR] per 10 min, 1.09; 95 % CI, 1.02-1.18). Conversely, in the late-window group, there was no significant association between PT and functional outcome (acOR per 10 min, 1.04; 95 % CI, 0.99-1.09) or mortality (aOR per 10 min, 1.05; 95 % CI, 0.96-1.14). In this real-world study, for patients with AIS due to LVO within 6 h of onset, longer PT was associated with worse prognosis and higher mortality. However, for patients with an onset time of 6-24 h, the impact of PT on patient outcomes was not significant.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00717"},"PeriodicalIF":6.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835860","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}
NeurotherapeuticsPub Date : 2025-08-06DOI: 10.1016/j.neurot.2025.e00711
Hideo Kimura
{"title":"Hydrogen sulfide/polysulfides signaling and neuronal diseases.","authors":"Hideo Kimura","doi":"10.1016/j.neurot.2025.e00711","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00711","url":null,"abstract":"<p><p>Hydrogen sulfide (H<sub>2</sub>S) and polysulfides including H<sub>2</sub>S<sub>n</sub> (n = 2 or more) regulate neuronal activity, vascular tone, oxytosis/ferroptosis, oxygen sensing, cancer growth and senescence. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) produce H<sub>2</sub>S. Polysulfides are also produced by various enzymes including 3MST. In addition, transient receptor potential ankyrin 1 (TRPA1) channel-an important polysulfide target-modulates sulfur metabolism (including cysteine, H<sub>2</sub>S and polysulfides) and also affects the neurotransmitter GABA. Polysulfides persulfidate the cysteine residues of the target proteins, causing conformational changes that alter their activity. By contrast, H<sub>2</sub>S persulfidates oxidized cysteine residues (e.g., S-nitrosylated- and S-sulfinated) in its targets. H<sub>2</sub>S/polysulfides protect neurons from oxidative stress and thereby protect cells against various forms of cell death including oxytosis and ferroptosis. A deviation from normal H<sub>2</sub>S and polysulfides levels has been suggested to play a role in the pathophysiology of various neuronal- and psychiatric diseases.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00711"},"PeriodicalIF":6.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794962","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":"Sertraline treatment prevents motor dysfunction in a Huntington's disease mouse model and functional decline in patients.","authors":"Marta Garcia-Forn, Carla Castany-Pladevall, Jordi Creus-Muncunill, Arantxa Golbano, Geòrgia Escaramís, Jesús Pérez-Pérez, Uxue Balantzategi, Marina Hernan-Godoy, Verónica Brito, Jaime Kulisevsky, Eulàlia Martí, Esther Pérez-Navarro","doi":"10.1016/j.neurot.2025.e00716","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00716","url":null,"abstract":"<p><p>Molecular alterations underlying Huntington's disease (HD) are not fully elucidated and no curative therapies are available. We have described that increased translation efficiency participates in the motor symptoms in the R6/1 HD mouse model. Here, we evaluated whether sertraline, a widely used antidepressant drug, that modulates translation in cancer cells, could ameliorate motor and cognitive symptoms in HD. We also investigated if alterations in translation efficiency occur in fibroblasts from HD patients and serve as a possible biomarker. As an index of translation efficiency levels, we analyzed puromycin incorporation and phosphorylated 4E-BP1 levels in striatal primary cultures and striatum from R6/1 mice, and in HD patients' fibroblasts, with or without sertraline treatment. Motor learning and coordination were analyzed in treated mice by accelerating rotarod, balance beam and vertical pole tests. Clinical data from the Enroll-HD dataset were analyzed to evaluate the potential effects of sertraline treatment in the disease progression. We report that sertraline treatment: 1) modulates translation efficiency in striatal primary neurons expressing mutant huntingtin; 2) prevents motor dysfunction in R6/1 mice and normalizes translation efficiency in the striatum, and 3) delays the decline in functional performance of HD patients. Moreover, puromycin incorporation is increased in fibroblasts from HD patients in a CAG length-dependent manner and is modulated by sertraline treatment. Altogether, our results suggest sertraline as a promising candidate for HD clinical trials to slow down disease progression and that puromycin incorporation in fibroblasts could serve as a pharmacological biomarker for certain treatments.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00716"},"PeriodicalIF":6.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799741","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}