Neurotherapeutics最新文献

{"title":"Identification of vital sign trajectory phenotypes and treatment response heterogeneity in critically ill patients with ischemic stroke: A multicenter study with external validation","authors":"Lijuan Wang ,&nbsp;Duozi Wang ,&nbsp;Bo Tang ,&nbsp;Jun Duan ,&nbsp;Jie Huang","doi":"10.1016/j.neurot.2026.e00896","DOIUrl":"10.1016/j.neurot.2026.e00896","url":null,"abstract":"<div><div>Critically ill patients with ischemic stroke exhibit heterogeneous hemodynamic patterns, yet previous trajectory-based studies have focused on single vital sign parameters. We conducted a multicenter retrospective cohort study to identify vital sign trajectory phenotypes, evaluate their prognostic value compared with traditional severity scores, and explore treatment response heterogeneity. Using group-based multi-trajectory modeling of six vital signs (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, respiratory rate, and oxygen saturation) during the first 12 h after intensive care unit admission, we analyzed 3100 patients from MIMIC-IV for development and 3951 patients from eICU and Chinese Critical Care Database for external validation. Three distinct phenotypes were identified: tachycardic-tachypneic (25.6%), hypertensive-stable (37.5%), and low-diastolic quiescent (36.8%), with in-hospital mortality rates of 29.7%, 5.9%, and 14.9%, respectively. After multivariable adjustment, the tachycardic-tachypneic phenotype demonstrated significantly elevated in-hospital mortality risk compared with hypertensive-stable (HR 3.55, 95% CI 2.23–5.64), with consistent associations for 28-day (HR 4.38, 95% CI 2.97–6.46) and one-year mortality (HR 4.50, 95% CI 3.35–6.04). Phenotype-based classification outperformed SOFA, SAPS II, and Charlson index for one-year mortality prediction. Exploratory analysis revealed phenotype-specific dose-mortality associations for normal saline volumes, with tachycardic-tachypneic and hypertensive-stable phenotypes showing lower predicted mortality at higher Day 1 vol (2357–3500 mL and 1929–3500 mL), while low-diastolic quiescent showed lower predicted mortality with restricted Day 2 fluids (0–714 mL). Propofol similarly showed differential dose-mortality associations across phenotypes. These findings support trajectory-based phenotyping for early risk stratification and may inform precision-guided therapeutic approaches in critically ill ischemic stroke patients.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00896"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645951","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":"Dual antiplatelet therapy in acute ischemic stroke: Does diabetes mellitus define a target population?","authors":"Simona Nedelcu","doi":"10.1016/j.neurot.2026.e00907","DOIUrl":"10.1016/j.neurot.2026.e00907","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00907"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675347","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":"Treatment approaches to patients with multiple sclerosis and coexisting psoriasis – A longitudinal multicenter observational cohort study","authors":"Tobias Brummer ,&nbsp;Saskia Räuber ,&nbsp;Jasmin Jakob ,&nbsp;Alice G. Willison ,&nbsp;Muriel Schraad ,&nbsp;Maria Protopapa ,&nbsp;Maria Isabel Fleischer ,&nbsp;Joshua M. Boeckers ,&nbsp;Tobias Ruck ,&nbsp;Sven G. Meuth ,&nbsp;Frauke Zipp ,&nbsp;Vinzenz Fleischer ,&nbsp;Stefan Bittner","doi":"10.1016/j.neurot.2026.e00914","DOIUrl":"10.1016/j.neurot.2026.e00914","url":null,"abstract":"<div><div>Neurologists frequently encounter multiple sclerosis (MS) patients with coexisting autoimmune disorders such as psoriasis (PsO). The evolving landscape of immunotherapies has made treatment decisions more complex, yet also opened opportunities for therapies targeting shared immunopathogenic mechanisms. However, evidence for this patient group remains limited to case reports and small series. In this multicenter observational study, 420 MS patients were screened, identifying 38 with PsO. These were compared with MS-only patients regarding demographics, disease course, Expanded Disability Status Scale (EDSS), and disease-modifying therapy (DMT) use. DMT histories, reasons for discontinuation, and adverse events were analyzed. Logistic regression assessed PsO and MS worsening, using dimethyl fumarate (DMF) as reference. MS/PsO patients were older at diagnosis (37.6 vs. 33.0 years). EDSS and disease course showed no statistically significant differences. DMF was most frequently used (68%), with low rates of PsO (8%) and MS worsening (15%). PsO worsening was common under teriflunomide (75%), interferons (38%), and sphingosine-1-phosphate (S1P) modulators (40%). Logistic regression suggested higher odds under teriflunomide (OR = 16.5, <em>p = 0.028</em>), interferons (OR = 16.5, <em>p = 0.004</em>), and S1P-modulators (OR = 8.25, <em>p = 0.047</em>). Anti-CD20 therapies (OR = 2.75, <em>p = 0.257</em>) and natalizumab (OR = 1.83, <em>p = 0.635</em>) showed non-significant trends. Interleukin-17 (IL-17) inhibitors were well tolerated, with &gt;50% stable in both conditions and no significant MS worsening (OR = 1.67, <em>p = 0.546</em>). IL-17 inhibitors and DMF showed a favorable tolerability in MS/PsO. Teriflunomide, interferons, and S1P-modulators frequently exacerbate PsO. CD20 therapies and natalizumab remain effective for MS but may worsen PsO; IL-17–based combinations appear promising in highly active disease.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00914"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147797426","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":"A female-specific role for Slit1 in prenatal stress-induced depression vulnerability","authors":"Kaixuan Xu ,&nbsp;Tu Chen ,&nbsp;Yang Yang ,&nbsp;Weimin Liu ,&nbsp;Huan Guo ,&nbsp;Zheng Gong ,&nbsp;Xinyi Ma ,&nbsp;Jiajia Liu ,&nbsp;Yushan Lu ,&nbsp;Huiping Zhang ,&nbsp;Xiaotang Fan ,&nbsp;Hui Li ,&nbsp;Zhongliang Zhu","doi":"10.1016/j.neurot.2026.e00916","DOIUrl":"10.1016/j.neurot.2026.e00916","url":null,"abstract":"<div><div>Women experience nearly twice the prevalence of depression compared to men and frequently present with comorbid anxiety, with this divergence emerging during adolescence. However, the molecular mechanisms underlying female-specific depression vulnerability remain poorly understood. Here, we found that prenatal stress (PS) induced depressive-like behaviors and selectively downregulated Slit Guidance Ligand 1 (Slit1) expression in the hippocampal dentate gyrus (DG) of female adolescent offspring rats. Furthermore, viral knockdown of Slit1 in the DG induced anxiety- and depressive-like behavioral phenotypes specifically in female rats. In females, Slit1 deficiency reduced the mean fluorescence intensity of the neural stem cell and immature neuron markers Sox2 and DCX in the DG, decreased postsynaptic Homer1, PSD95, and GluA1 expression without affecting Synaptophysin, and diminished the amplitude of sEPSCs. Significantly, the downstream Slit1 effector SLIT-ROBO Rho GTPase-activating protein 2 (Srgap2) was downregulated specifically in Slit1-deficient females. Together, these results suggest that Slit1 disruption selectively affects DG neuroplasticity in females and may contribute to their heightened vulnerability to PS-related depressive-like behaviors, although further mechanistic studies are required to confirm the causal role of Slit1 in these effects.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00916"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849973","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 enhancing myelin regeneration reverses cognitive deficits in a mouse model of intellectual disability","authors":"Pingping Qiao ,&nbsp;He Wang ,&nbsp;Pingping Qu ,&nbsp;Lifang Guo ,&nbsp;Yanbo Zhou ,&nbsp;Tingting Zeng ,&nbsp;Jiang Chen ,&nbsp;Jian Li ,&nbsp;Yimin Hu ,&nbsp;Guiquan Chen","doi":"10.1016/j.neurot.2026.e00906","DOIUrl":"10.1016/j.neurot.2026.e00906","url":null,"abstract":"<div><div>The early postnatal period is a critical window for brain maturation, during which oligodendrogenesis, myelination, and synaptogenesis are dynamically orchestrated to support cognitive development. Clinical studies have associated myelination deficits with intellectual disability (ID), but the molecular mechanisms linking myelin deficits to cognitive dysfunction remain poorly understood. Here, we generated an inducible conditional knockout (icKO) mouse model to selectively ablate 3-phosphoinositide-dependent protein kinase-1 (PDK1) in oligodendrocyte precursor cells (OPCs) during early postnatal development. <em>Pdk1</em> icKO mice exhibited severe deficits in hippocampal oligodendrocyte (OL) maturation, myelination, and excitatory synaptogenesis, accompanied by impaired neuronal activation and profound memory impairments. Mechanistically, PDK1 loss led to suppression of the Akt-mTOR signaling pathway, a critical regulator of OL differentiation and myelination. Strikingly, treatment with clemastine, an FDA-approved pro-myelinating agent, effectively restored oligodendrogenesis, myelination, synaptic integrity, neuronal activity, and cognitive performance in <em>Pdk1</em> icKO mice, in part by reactivating Akt-mTOR signaling. Together, these findings identify PDK1 as a pivotal regulator of postnatal myelination and cognitive maturation, establish a mechanistic link between oligodendroglial dysfunction and ID, and highlight clemastine as a promising therapeutic candidate for cognitive disorders associated with myelination deficits.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00906"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691239","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":"Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models","authors":"Masahiro Ando ,&nbsp;Yuji Okamoto ,&nbsp;Yujiro Higuchi ,&nbsp;Jun-Hui Yuan ,&nbsp;Akiko Yoshimura ,&nbsp;Chikashi Yano ,&nbsp;Risa Nagatomo ,&nbsp;Takahiro Hobara ,&nbsp;Fumikazu Kojima ,&nbsp;Yu Hiramatsu ,&nbsp;Satoshi Nozuma ,&nbsp;Yusuke Sakiyama ,&nbsp;Hiroshi Takashima","doi":"10.1016/j.neurot.2026.e00900","DOIUrl":"10.1016/j.neurot.2026.e00900","url":null,"abstract":"<div><div>Charcot–Marie–Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. <span>l</span>-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used <em>Drosophila</em> models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of <span>l</span>-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. <span>l</span>-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose <span>l</span>-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for <span>l</span>-arginine in MFN2-deficient <em>Drosophila</em>, possibly through effects on mitochondrial dynamics involving complex I. <span>l</span>-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00900"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147601995","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":"RNA-binding protein MBNL2 mitigates neuropathic pain after chemotherapy through destabilizing CCR2 expression in primary sensory neurons","authors":"Keshi Yan ,&nbsp;Ruining Ma ,&nbsp;Bing Wang ,&nbsp;Xiaozhou Feng ,&nbsp;Xinju Li ,&nbsp;Xianglei Meng ,&nbsp;Huijie Shang ,&nbsp;Benjamin M. Kidd ,&nbsp;Maurice S. Swanson ,&nbsp;Huijuan Hu ,&nbsp;Yuan-Xiang Tao","doi":"10.1016/j.neurot.2026.e00905","DOIUrl":"10.1016/j.neurot.2026.e00905","url":null,"abstract":"<div><div>Chemotherapy drug-induced changes of gene expression in the dorsal root ganglion (DRG) are critical for the genesis of chemotherapy-induced neuropathic pain (CINP). However, the mechanisms driving these changes remain elusive. Here, we report the downregulation of muscleblind-like protein 2 (MBNL2), an RNA-binding protein, in the DRG neurons after intraperitoneal injection of paclitaxel. Rescuing this downregulation blocks an increase of the C–C chemokine receptor type 2 (CCR2) in the DRG and mitigates paclitaxel-induced mechanical allodynia, heat and cold hyperalgesia and ongoing pain. Conversely, DRG downregulation of MBNL2 increases the expression of CCR2 in the DRG neurons and leads to CINP-like symptoms in naïve mice. Mechanistically, paclitaxel-induced downregulation of MBNL2 reduces its binding to the 3′-untranslated region of <em>Ccr2</em> mRNA, thereby enhancing the stability of <em>Ccr2</em> mRNA in the DRG. Given that MBNL2 and CCR2 are co-expressed in DRG neurons, these findings suggest that MBNL2 alleviates CINP, likely by destabilizing CCR2 expression in the DRG, and may represent a promising therapeutic strategy for this condition.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00905"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675400","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":"Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models","authors":"Daiyue Li ,&nbsp;Yu Zhang ,&nbsp;Ruonan Wang ,&nbsp;Lingling Jin ,&nbsp;Xiaolin Cui ,&nbsp;Jau-Shyong Hong ,&nbsp;Sheng Li ,&nbsp;Jie Zhao ,&nbsp;Yanjie Guo","doi":"10.1016/j.neurot.2026.e00899","DOIUrl":"10.1016/j.neurot.2026.e00899","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00899"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147601996","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":"PEBP1 inhibition as a therapeutic target for neurological recovery in ischemic stroke","authors":"Yu-Qian Niu ,&nbsp;Ze-Yu Cai ,&nbsp;Hao-Yang Zhi ,&nbsp;Yu-Chun Zhu ,&nbsp;Xin-Yuan Xi ,&nbsp;Zhen Yang ,&nbsp;Dong-Fu Feng","doi":"10.1016/j.neurot.2026.e00912","DOIUrl":"10.1016/j.neurot.2026.e00912","url":null,"abstract":"<div><div>Ischemic stroke poses a substantial clinical and socioeconomic burden due to limited therapeutic efficacy and poor neurological outcomes. To uncover novel gene targets for intervention, we conducted an integrative analysis combining single-cell RNA sequencing with Mendelian randomization using large-scale genomic datasets from the European Bioinformatics Institute (34,593 cases and 624,214 controls), with validation in an independent European Bioinformatics Institute dataset (86,668 cases and 1,503,898 controls) and the UK Biobank (26,052 cases and 487,214 controls). Colocalization analysis identified four core genes—<em>PEBP1</em>, <em>BMP4</em>, <em>APOA1</em> and <em>CD86</em>—strongly associated with ischemic stroke risk, with a posterior probability of a shared causal variant greater than 0.8. Among them, PEBP1 was markedly upregulated post-ischemia, particularly in endothelial cells, as confirmed by quantitative PCR and immunofluorescence in a middle cerebral artery occlusion model. Both pharmacological inhibition of PEBP1 with FerroLOXIN-1 and AAV-BI30-mediated shRNA knockdown reduced cerebral infarct volume, enhanced neuronal survival, and improved neurological functional recovery. <em>In vitro</em>, FerroLOXIN-1 enhanced cell proliferation and viability under oxygen-glucose deprivation conditions, with potential off-target effects of the interventions validated. Mechanistically, these effects were mediated through activation of the Akt/p38 MAPK signaling cascade. These findings highlight PEBP1 as a central mediator of ischemia-induced neuronal injury and a potential therapeutic target. The convergence of transcriptomic, genetic and experimental validation supports the translational relevance of PEBP1 inhibition in post-stroke neuroregeneration.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00912"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147797361","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 Theta–Gamma coupling in Alzheimer's disease: Toward network-based neuromodulation","authors":"Shixie Jiang","doi":"10.1016/j.neurot.2026.e00901","DOIUrl":"10.1016/j.neurot.2026.e00901","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 3","pages":"Article e00901"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654544","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}