Neurotherapeutics最新文献

{"title":"Honokiol attenuates neuroinflammation and enhances remyelination in mouse models of multiple sclerosis through PPARγ-mediated ERK/AKT signalling","authors":"Xueli Yu,&nbsp;Long Wei,&nbsp;Yanghao Zheng,&nbsp;Xueyu Qi,&nbsp;Xiaolin Mu,&nbsp;Qian Wang,&nbsp;Yuxin Hua,&nbsp;Qiyuan Chen,&nbsp;Yaman Zhang,&nbsp;Han Jiang,&nbsp;Ziyue Wang,&nbsp;Peiyan Ni,&nbsp;Wanjun Guo,&nbsp;Wei Deng,&nbsp;Tao Li","doi":"10.1016/j.neurot.2026.e00965","DOIUrl":"10.1016/j.neurot.2026.e00965","url":null,"abstract":"<div><div>Multiple sclerosis is characterized by inflammatory demyelination and insufficient myelin repair, which together drive progressive neurological impairment. While existing immunomodulatory treatments have demonstrated efficacy in reducing acute relapse frequency, they fail to address the critical deficits in oligodendrocyte precursor cell (OPC) differentiation and subsequent remyelination, leaving patients with irreversible neurological disability. This highlights the pressing necessity for pharmacological interventions that can simultaneously mitigate neuroinflammation and stimulate endogenous myelin regeneration. In the present work, we evaluated the therapeutic potential of honokiol, a naturally occurring bioactive polyphenol derived from <em>Magnolia officinalis</em>, using both experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination paradigm. Our results demonstrate that honokiol improved myelin restoration and exerted potent anti-inflammatory effects by suppressing glial activation, modulating inflammatory cytokine profiles, and restoring lipid homeostasis. Transcriptomic analysis indicated a global downregulation of immune-related pathways, and significant upregulation of signalling cascades critically involved in myelination and oligodendrocyte maturation. Molecular dynamics simulations revealed that honokiol stably bound to cannabinoid receptors and peroxisome proliferator-activated receptor gamma (PPARγ) receptor via energetically favourable interactions. In primary OPC cultures, honokiol directly facilitated the differentiation of OPC into mature oligodendrocytes. Pharmacological blockade of PPARγ eliminated both honokiol-induced OPC maturation and subsequent activation of the extracellular signal-regulated kinase/protein kinase B (ERK/AKT) signalling axis. Taken together, these findings indicate that honokiol attenuates neuroinflammation and may facilitate myelin repair through both immunomodulatory actions and direct effects on oligodendrocyte lineage cells, supporting its potential as a disease-modifying strategy for demyelinating disorders.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00965"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous brain alterations in treatment-resistant depression converge on common control networks","authors":"Yiding Han,&nbsp;Haohao Yan,&nbsp;Wenbin Guo,&nbsp;Hengyi Cao","doi":"10.1016/j.neurot.2026.e00932","DOIUrl":"10.1016/j.neurot.2026.e00932","url":null,"abstract":"<div><div>Treatment-resistant depression (TRD) imposes a substantial clinical and societal burden. However, it remains unclear whether neuroimaging abnormalities associated with TRD converge onto specific large-scale brain networks. We systematically reviewed neuroimaging articles comparing patients with TRD to both healthy controls (HCs) and patients with non-treatment-resistant depression (non-TRD), encompassing functional and structural imaging modalities. Using a validated coordinate network mapping (CNM) approach and a normative human brain connectome, we derived TRD-associated networks. Overlap analyses with canonical large-scale networks were performed to delineate the functional architecture of these networks. In addition, spatial correlations between TRD-associated probability maps and whole-brain neurotransmitters density maps to explore potential neurochemical substrates. In the TRD–HC contrast, TRD-associated functional and structural networks were distributed across frontal, cingulate, insular, striatal, and thalamic regions, showing their greatest overlap with the frontoparietal (FPN) and cingulo-opercular network (CON). In the TRD–non-TRD contrast, TRD-associated functional and structural networks were more selectively localized, with predominant overlap confined to the CON. Spatial correlation analyses further anchored these network-level abnormalities to glutamatergic, dopaminergic, and monoaminergic neurotransmitter systems. These findings indicate that the general neurobiological burden of TRD is anchored within large-scale control networks involving the FPN and CON, whereas treatment resistance is characterized by more focal alterations within the CON. This network-based dissociation provides insight into the neural organization of TRD and highlights potential circuit-level targets for therapeutic intervention.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00932"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABAB1R: A molecular bridge linking deep brain stimulation to antidepressant effects——A commentary on “NAcLat-DBS reduces GABAB1R expression of dopamine neurons to correct depressive symptoms in CMS mice\"","authors":"Fang Li,&nbsp;Jing Sun,&nbsp;Ming-Hu Han","doi":"10.1016/j.neurot.2026.e01055","DOIUrl":"10.1016/j.neurot.2026.e01055","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01055"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Clinical Evaluation Guidelines to Accelerate ALS Neurotherapeutic Development in Japan","authors":"Ken Sakushima,&nbsp;Koji Fujita,&nbsp;Masashi Aoki,&nbsp;Naoki Atsuta,&nbsp;Makoto Urushitani,&nbsp;Masahisa Katsuno,&nbsp;Osamu Kano,&nbsp;Yuko Kobayakawa,&nbsp;Toshio Shimizu,&nbsp;Akihiro Hirakawa,&nbsp;Yuishin Izumi","doi":"10.1016/j.neurot.2026.e00999","DOIUrl":"10.1016/j.neurot.2026.e00999","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00999"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and Preclinical Development of a Novel Muscarinic M4 Ago-PAM for the Treatment of Schizophrenia","authors":"Warren Wen PhD,&nbsp;Paul Beckett PhD,&nbsp;Michael Lewis PhD,&nbsp;Derek Chalmers PhD","doi":"10.1016/j.neurot.2026.e01020","DOIUrl":"10.1016/j.neurot.2026.e01020","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01020"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acamprosate in C9orf72 Hexanucleotide Repeat Expansion Amyotrophic Lateral Sclerosis","authors":"Justin Kwan MD,&nbsp;Katelyn Porter CRNP,&nbsp;Sarah Moore CRNP,&nbsp;Laura Danielian MS,&nbsp;Bryan Traynor","doi":"10.1016/j.neurot.2026.e01012","DOIUrl":"10.1016/j.neurot.2026.e01012","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01012"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Provider Attitudes and Perspectives Toward the Use of Physiologically Maintained Deceased for Research","authors":"Parisa Jahangirizadeh BA,&nbsp;Alexander Chen BA,&nbsp;Kasra Sarhadi MD, MPH,&nbsp;Aryan Sandoval BA,&nbsp;Claire Clelland MD, PhD,&nbsp;Douglas Pet MD,&nbsp;Neel Singhal MD, PhD","doi":"10.1016/j.neurot.2026.e00996","DOIUrl":"10.1016/j.neurot.2026.e00996","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00996"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility challenges in implementing a low-carbohydrate high-fat diet for essential tremor: A prospective pilot study from India","authors":"Manvi Lamba MBBS,&nbsp;Sujata Roshan DM Neurology","doi":"10.1016/j.neurot.2026.e01006","DOIUrl":"10.1016/j.neurot.2026.e01006","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e01006"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148951514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain interstitial fluid pharmacokinetics and therapeutic effect of a BBB penetrating amyloid beta antibody measured by microdialysis","authors":"Elin Wik,&nbsp;Amelia D. Dahlén,&nbsp;Ulrika Julku,&nbsp;Mengfei Xiong,&nbsp;Wojciech Michno,&nbsp;Stina Syvänen,&nbsp;Dag Sehlin","doi":"10.1016/j.neurot.2026.e00949","DOIUrl":"10.1016/j.neurot.2026.e00949","url":null,"abstract":"<div><div>The disease-modifying antibody lecanemab for treating Alzheimer's disease (AD) was initially designed to target amyloid-beta (Aβ) protofibrils, i.e. soluble aggregates of Aβ, but it has also been successful in clearing insoluble amyloid plaques in clinical studies. Therefore, this study aimed to investigate how a brain penetrating, bispecific murine variant of lecanemab (RmAb158-scFv8D3) distributes in the brain and interacts with different pools of aggregated Aβ in APP transgenic mice. The alpha-synuclein targeting antibody RmAbSynO2-scFv8D3 was used as control. Further, by performing <em>in vivo</em> high cut-off microdialysis in freely moving animals, brain interstitial fluid (ISF) was continuously collected across 24 h to assess concentrations of free antibody in the brain. <em>Post mortem</em> distribution of the antibodies was analyzed by sequential extraction of brain tissue. RmAb158-scFv8D3 showed rapid ISF clearance as well as a redistribution from brain extracts containing small, soluble Aβ species toward brain extracts containing insoluble, plaque-associated Aβ with time. A treatment effect was detected already at 12 h post injection, whereby the RmAb158-scFv8D3-treated animals showed lower concentrations of the smallest, most soluble Aβ aggregates. Collectively, these findings suggest that within the first 24 h after a single injection of the bispecific RmAb158-scFv8D3 antibody we can capture the antibody's initial brain distribution and interactions with both soluble Aβ aggregates and insoluble, plaque-associated Aβ. These interactions mediate a swift reduction of soluble Aβ, while clearance of insoluble Aβ requires longer treatment time.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00949"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"23 years of mTOR inhibition for tuberous sclerosis: Practical considerations","authors":"David Neal Franz","doi":"10.1016/j.neurot.2026.e00959","DOIUrl":"10.1016/j.neurot.2026.e00959","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00959"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}