Neurotherapeutics最新文献

{"title":"Intrathecal STAT3 inhibitor Bt354 ameliorates chronic constriction injury-induced nociceptive sensitization by modulating neuroinflammation.","authors":"Hao-Jung Cheng, Nan-Fu Chen, Yueh-Chiao Tang, Po-Chang Shih, Wu-Fu Chen, Ya-Jen Chiu, Chun-Sung Sung, Zhi-Hong Wen","doi":"10.1016/j.neurot.2025.e00763","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00763","url":null,"abstract":"<p><p>Neuropathic pain poses a significant societal and clinical burden and is closely linked to neuroinflammation of the central nervous system. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of inflammatory processes and has been implicated in the development of nociceptive hypersensitivity. In this study, we aimed to elucidate the therapeutic potential and underlying mechanisms of STAT3 inhibition in a rodent model of neuropathic pain. Using behavioral assessments of nociceptive sensitivity and immunofluorescence analysis, we investigated the analgesic mechanisms of the intrathecal STAT3 inhibitor, Bt354, in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. Cellular and molecular markers of glial activation and inflammation were examined to assess the effects of Bt354 on neuroinflammatory pathways. Intrathecal administration of Bt354 significantly reduced CCI-induced mechanical allodynia and thermal hyperalgesia, accompanied by a marked decrease in phosphorylated STAT3 (pSTAT3) expression in spinal neurons. Bt354 treatment attenuated the polarization of M1-type microglia and A1-type astrocytes, suppressed inflammasome-related signaling, and mitigated neuroinflammatory responses. Importantly, Bt354 inhibited the nuclear translocation of neuronal pSTAT3, which is a critical step in regulating pro-inflammatory gene transcription. Moreover, CCI-induced angiogenesis and microglial phosphorylation of CREB and P38 were mitigated by pSTAT3 inhibition. These findings suggest that STAT3 plays a central role in the pathogenesis of neuropathic pain by regulating glial cell polarization and neuroinflammation. Targeting STAT3 with Bt354 may represent a promising therapeutic strategy for treating neuropathic pain.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00763"},"PeriodicalIF":6.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258647","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":"Activation of GABA transmission by clonazepam reverses the autistic-like phenotypes of the Cav3.2 knockout mice.","authors":"Shao-Feng Liang, Yang Ming, Hsien-Ting Huang, Raymond Y Lo, Supin Chompoopong, Chien-Chang Chen, Ingrid Y Liu","doi":"10.1016/j.neurot.2025.e00761","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00761","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, accompanied by restricted and repetitive behaviors. ASD is a lifelong condition that causes a heavy medical and societal burden. To date, there are no disease-modifying, mechanism-targeted treatments approved for core ASD symptoms. In human studies, loss-of-function mutations in the CACNA1H gene, which encodes the T type Cav3.2 calcium channel, have been associated with ASD. However, animal and molecular studies investigating the underlying mechanism in ASD patients with CACNA1H mutations are lacking. In this study, we performed a series of behavioral assays to phenotype the Cav3.2 systemic knockout (Cav3.2KO) mice. The Cav3.2KO mice exhibited ASD-like behaviors, including impaired social novelty, increased self-grooming behavior, and deficits in recognition and retrieval of fear memory. Notably, enhancing γ-aminobutyric acid (GABA) signaling via administration a low-dose of clonazepam (CLZ) rescued these behavioral impairments in the Cav3.2KO mice. Furthermore, we found that the intrinsic GABA level was significantly reduced in the frontal cortex of Cav3.2KO mice, suggesting that GABA transmission was impaired in the Cav3.2KO mice. Together, our findings suggest that loss-of-function in the Cav3.2 channel contributes to ASD-like phenotypes through disrupted GABAergic signaling and that pharmacological enhancement of GABAergic signaling may offer a potential therapeutic approach for individuals with ASD carrying the CACNA1H mutations.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00761"},"PeriodicalIF":6.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258682","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":"Prevalence of hypogammaglobulinemia after non-anti-CD20 therapies and impact of switching to rituximab/ocrelizumab in multiple sclerosis.","authors":"Marine Perriguey, Camille Rigollet, Sean A Freeman, Lisa Graille-Avy, Jean-Christophe Lafontaine, Bruno Lemarchant, Tifanie Alberto, Sarah Demortière, Clémence Boutiere, Audrey Rico, Frédéric Hilézian, Pierre Durozard, Jean Pelletier, Adil Maarouf, Hélène Zéphir, Bertrand Audoin","doi":"10.1016/j.neurot.2025.e00760","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00760","url":null,"abstract":"<p><p>Some people with multiple sclerosis (PwMS) exhibit reduced serum immunoglobulin (Ig) levels, potentially due to disease-modifying therapies (DMTs), which raises concerns about initiating anti-CD20 therapies. We assessed the frequency of hypogammaglobulinemia in PwMS who previously received non-anti-CD20 DMTs and evaluated short-term Ig level changes after switching to rituximab (RTX) or ocrelizumab (OCR). This retrospective study included PwMS starting RTX or OCR, with or without prior DMT exposure. Patients were grouped as treatment-naïve or receiving fingolimod (FING), natalizumab (NTZ), or moderate-efficacy DMTs (interferons, glatiramer acetate, dimethyl fumarate, or teriflunomide) before the switch. Among 417 included patients, 89 were treatment-naïve, 207 had received FING, 70 NTZ, and 51 moderate-efficacy DMTs. Before switching, hypogammaglobulinemia (IgG level <7 ​g/L) was rare in treatment-naïve and moderate-efficacy DMT groups (2 ​%) but more frequent after FING (29 ​%) and NTZ (14 ​%) treatment. One year after initiating RTX/OCR, IgG level slightly decreased in treatment-naïve patients (p ​< ​0.05), remained stable in NTZ and moderate-efficacy DMT groups, and increased significantly in FING-treated patients (8.0-8.6 ​g/L, p ​< ​0.0001), with a decline in hypogammaglobulinemia prevalence (29 ​%-21.5 ​%). FING exposure was associated with frequent IgG hypogammaglobulinemia, but switching to RTX/OCR was not linked to a short-term decrease in IgG level; instead, it led to a significant increase in level. These findings support that hypogammaglobulinemia should not be an absolute contraindication to switching to RTX/OCR after FING discontinuation given their efficacy in preventing MS reactivation. A secondary de-escalation strategy may be considered based on individual risk profiles and IgG level trajectories.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00760"},"PeriodicalIF":6.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232974","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":"Whole transcriptome analysis of peripheral blood mononuclear cells from de novo and drug-naive Parkinson's disease patients.","authors":"Francisco Navarrete, Marina Guillot-Fernández, Lorena Martínez-Hostyn, Daniela Navarro, José A Molina, Jose P López-Atalaya, Jorge Manzanares","doi":"10.1016/j.neurot.2025.e00762","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00762","url":null,"abstract":"<p><p>Blood-based biomarkers represent a highly convenient and minimally invasive method to improve the diagnosis of Parkinson's disease (PD), particularly at early stages. In this study, we present a comprehensive analysis of transcriptional changes in peripheral blood mononuclear cells (PBMCs) from de novo and drug-naive, recently diagnosed PD patients (n ​= ​23) and healthy sex- and age-matched controls (n ​= ​16). Whole-transcriptome analysis revealed differentially expressed genes (DEGs) in PBMCs from PD patients, including genes with immune-related functions such as CHI3L1, FAM198B, ID3, MDX1, and PROK2. Gene set enrichment analysis (GSEA) further identified alterations in immune pathways, including the IL-6/JAK/STAT3 signaling pathway and the complement cascade, associated with PD. We performed cross-validation using two independent whole-blood transcriptomic datasets from PD patients to assess the reproducibility and biological relevance of our findings. Both comparisons showed moderate but highly significant correlations in gene expression patterns. Overall, our results reveal robust and reproducible transcriptional alterations in PBMCs from early-stage PD patients, underscoring the contribution of immune dysregulation to PD pathogenesis. These findings support the potential of PBMC transcriptomics as a valuable platform for biomarker discovery in Parkinson's disease.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00762"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213083","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":"Beyond the synapse: Bassoon mutations drive epilepsy through Astrocyte-Neuron crosstalk.","authors":"Xindi Li, Ronald P Hart, Zhiping P Pang","doi":"10.1016/j.neurot.2025.e00753","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00753","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00753"},"PeriodicalIF":6.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207082","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":"Neuroprosthetic closed-loop strategy for sustained blood pressure reduction via simultaneous stimulation and recording from the spinal cord.","authors":"Mingeun Cho, Minhye Choo, Matthew Koh, Sunguk Hong, Junseung Mun, Juho Koo, ChangHwa Oh, Sung-Min Park","doi":"10.1016/j.neurot.2025.e00758","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00758","url":null,"abstract":"<p><p>Sympathetic hyperactivity is a common feature observed in both primary and secondary hypertension, and neuromodulation-based therapies targeting this overactivity are under active investigation. The intermediolateral nucleus (IML) in the spinal cord plays a central role in sympathetic regulation, and its direct stimulation induces a transient, frequency-dependent reduction in blood pressure. However, this effect gradually diminishes as the baroreflex restores blood pressure to baseline. Therefore, this study aims to develop a closed-loop (CL) stimulation system that adjusts parameters in real-time based on neural activity recorded from the IML and to enhance and prolong the transient antihypertensive effect. This strategy was evaluated in normotensive and angiotensin II-induced hypertensive rat models and compared to open-loop (OL) stimulation of equal intensity. In both models, CL stimulation produced a more sustained blood pressure reduction than that of OL stimulation. These findings suggest that CL spinal cord stimulation offers a more effective and durable therapeutic option for treating hypertension.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00758"},"PeriodicalIF":6.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207043","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":"Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.","authors":"Meixiang Huang, Yannan Li, Ajit G Thomas, Anjali Sharma, Wathsala Liyanage, Tomáš Tichý, Lukáš Tenora, Yu Su, Jisu Ha, Niyada Hin, Mizuho Obayashi, Pavel Majer, Rangaramanujam M Kannan, Takashi Tsukamoto, Gianluca Ursini, Rana Rais, Barbara S Slusher, Xiaolei Zhu","doi":"10.1016/j.neurot.2025.e00759","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00759","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00759"},"PeriodicalIF":6.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182022","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":"Synergistic mitochondrial impairment by endogenously elevated cyanide and hydrogen sulfide in Down syndrome; commentary on: Cyanide overproduction impairs cellular bioenergetics in Down syndrome.","authors":"Andrew A Pieper, Bindu D Paul","doi":"10.1016/j.neurot.2025.e00757","DOIUrl":"10.1016/j.neurot.2025.e00757","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00757"},"PeriodicalIF":6.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177012","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":"Metabolomics and lipidomics study on serum metabolite signatures in Alzheimer's disease and mild cognitive impairment.","authors":"Yingren Mai, Fengjie Huang, Hongyan Mi, Zhiyu Cao, Yiqi Li, Kejun Zhou, Jun Liu, Guoxiang Xie, Wang Liao","doi":"10.1016/j.neurot.2025.e00756","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00756","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major causes of dementia in the elderly, with metabolic alterations not fully understood. In this study, we quantitatively profiled serum metabolites of participants in 2 independent cohorts. Based on the data from cohort 1 (22 AD patients, 19 MCI patients and 19 cognitively normal participants (CN)), we identified 32 differential metabolites in AD and 49 in MCI serum. Notably, differential metabolites related to amino acid (AA), organic acid, fatty acid (FA), phosphatidylcholine (PC), sphingomyelin (SM) metabolism in AD and free fatty acid (FFA), acylcarnitine, PC, SM in MCI were strongly associated with cognitive level, memory, attention and execution function as evaluated by cognitive scales. Pathway analysis based on the differential metabolites revealed perturbation in pathways related to phospholipid metabolism, sphingolipid metabolism, AAs metabolism, beta oxidation of FAs, and carnitine metabolism. Using random forest (RF), support vector machine (SVM) and Boruta analysis for classification and validated by gradient boosting (GB), logistic regression (LR) and RF diagnostic model, we identified panels of 10 metabolites in AD and 13 metabolites in MCI that effectively discriminate AD and MCI individuals from CN with high accuracy, sensitivity and specificity. The diagnostic accuracy of the models was further validated in an independent cohort 2, consisting of 20 AD, 20 MCI and 20 CN individuals, with consistent results.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00756"},"PeriodicalIF":6.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177014","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":"LINE-1 hypomethylation in cell-free DNA of high-grade glioma patients correlates with tissue levels and is associated with reduced DNMT1 and H4K20me3 expression.","authors":"Angeliki-Ioanna Giannopoulou, Panagiotis Skouras, Panagiotis Sarantis, Alkinoos Armoundas, Kostas Palamaris, Antonios N Gargalionis, Athanasia Sepsa, Efstathios Boviatsis, Theodosis Kalamatianos, George Stranjalis, Penelope Korkolopoulou, Sarantis Chlamydas, Athanasios G Papavassiliou, Christina Piperi","doi":"10.1016/j.neurot.2025.e00754","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00754","url":null,"abstract":"<p><p>Gliomas exhibit diverse genetic, molecular, and histological profiles with limited liquid biopsy biomarkers. Loss of Long Interspersed Nuclear Element-1 (LINE-1) methylation confers to genomic instability and tumorigenesis, primarily mediated by DNA methyltransferase 1 (DNMT1) through interaction with histone H4 lysine 20 trimethylation (H4K20me3) and histone H3 lysine 9 trimethylation (H3K9me3). The present study evaluates the utility of liquid biopsy in detecting LINE-1 methylation in gliomas and potential correlations with DNMT1, H4K20me3, H3K9me3 tissue levels, clinicopathological characteristics and patients' survival. LINE-1 methylation was measured in cell-free DNA (cfDNA) of glioma patients' plasma prior to surgery or any adjuvant therapy and age-matched controls as well as in glioma tissues along with DNMT1, H4K20me3 and H3K9me3 expression. LINE-1 methylation content in plasma cfDNA and tissue samples was decreased significantly in grade 4 gliomas compared to controls (p ​< 0.0001, respectively). Similarly, DNMT1, H4K20me3 and H3K9me3 expression was significantly reduced in grade 4 cases compared to grade 2 (p ​< 0.0001). cfLINE-1 methylation was positively correlated with tissue LINE-1 methylation levels (p ​= 0.036) as well as with DNMT1 and H4K20me3 tissue expression in grade 4 samples (p ​< 0.0001, respectively). Moreover, low LINE-1 methylation plasma levels and tissue expression of DNMT1, H4K20me3 and H3K9me3 were correlated with worse overall survival in the entire cohort (p ​= 0.041, ​p ​= 0.016, ​p ​< 0.0001, ​p ​= 0.001, respectively). The present study supports the utility of liquid biopsy for the detection of LINE-1 hypomethylation, as a complementary prognostic biomarker for grade 4 tumors.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00754"},"PeriodicalIF":6.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176990","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}