Neurotherapeutics最新文献

{"title":"Cerebroprotective action of butylphthalide in acute ischemic stroke: Potential role of Nrf2/HO-1 signaling pathway","authors":"Rakesh B. Patel, Anil K. Chauhan","doi":"10.1016/j.neurot.2024.e00461","DOIUrl":"10.1016/j.neurot.2024.e00461","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00461"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365919","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":"An emerging role for the gut microbiome in tauopathy","authors":"Yiyang Zhu,&nbsp;Wade K. Self,&nbsp;David M. Holtzman","doi":"10.1016/j.neurot.2024.e00423","DOIUrl":"10.1016/j.neurot.2024.e00423","url":null,"abstract":"<div><div>Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota. We explore both animal and human studies that define causative relationships between the gut microbiome and tauopathy by directly manipulating or transferring gut microbiota. This review highlights future directions into identifying and mechanistically elucidating microbial species causally linked to tauopathies, with an ultimate goal of devising therapeutic targets towards the gut microbiome to treat tauopathies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00423"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534917","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":"Application of multimodal deep learning and multi-instance learning fusion techniques in predicting STN-DBS outcomes for Parkinson's disease patients","authors":"Bowen Chang ,&nbsp;Zhi Geng ,&nbsp;Jiaming Mei ,&nbsp;Zhengyu Wang ,&nbsp;Peng Chen ,&nbsp;Yuge Jiang ,&nbsp;Chaoshi Niu","doi":"10.1016/j.neurot.2024.e00471","DOIUrl":"10.1016/j.neurot.2024.e00471","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00471"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470919","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":"Neurological glycogen storage diseases and emerging therapeutics","authors":"Matthieu Colpaert ,&nbsp;Pankaj K. Singh ,&nbsp;Katherine J. Donohue ,&nbsp;Natacha T. Pires ,&nbsp;David D. Fuller ,&nbsp;Manuela Corti ,&nbsp;Barry J. Byrne ,&nbsp;Ramon C. Sun ,&nbsp;Craig W. Vander Kooi ,&nbsp;Matthew S. Gentry","doi":"10.1016/j.neurot.2024.e00446","DOIUrl":"10.1016/j.neurot.2024.e00446","url":null,"abstract":"<div><div>Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00446"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292176","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":"The relationship between ischemic penumbra progression and the oxygen content of cortex microcirculation in acute ischemic stroke","authors":"","doi":"10.1016/j.neurot.2024.e00387","DOIUrl":"10.1016/j.neurot.2024.e00387","url":null,"abstract":"<div><div>The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA₃-Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 ​h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 ​h. Within 6 ​h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00387"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450998","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":"Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction","authors":"","doi":"10.1016/j.neurot.2024.e00388","DOIUrl":"10.1016/j.neurot.2024.e00388","url":null,"abstract":"<div><div>Protein misfolding and mislocalization are common to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Maintaining proteostasis through induction of heat shock proteins (HSP) to increase chaperoning capacity is a rational therapeutic strategy in the treatment of ALS. However, the threshold for upregulating stress-inducible HSPs remains high in neurons, presenting a therapeutic obstacle. This study used mouse models expressing the ALS variants FUS^R521G or SOD1^G93A to follow up on previous work in cultured motor neurons showing varied effects of the HSP co-inducer, arimoclomol, and class I histone deacetylase (HDAC) inhibitors on HSP expression depending on the ALS variant being expressed. As in cultured neurons, neither expression of the transgene nor drug treatments induced expression of HSPs in cortex, spinal cord or muscle of FUS^R521G mice, indicating suppression of the heat shock response. Nonetheless, arimoclomol, and RGFP963, restored performance on cognitive tests and improved cortical dendritic spine densities. In SOD1^G93A mice, multiple HSPs were upregulated in hindlimb skeletal muscle, but not in lumbar spinal cord with the exception of HSPB1 associated with astrocytosis. Drug treatments improved contractile force but reduced the increase in HSPs in muscle rather than facilitating their expression. The data point to mechanisms other than amplification of the heat shock response underlying recovery of cognitive function in ALS-FUS mice by arimoclomol and class I HDAC inhibition and suggest potential benefits in counteracting cognitive impairment in ALS, frontotemporal dementia and related disorders.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00388"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555285","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":"LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner","authors":"Yanhui Duan ,&nbsp;Chenyuan Ye ,&nbsp;Jingyi Liao ,&nbsp;Xin Xie","doi":"10.1016/j.neurot.2024.e00424","DOIUrl":"10.1016/j.neurot.2024.e00424","url":null,"abstract":"<div><div>The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00424"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616890","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":"Corrigendum to “Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial” [Neurotherapeutics 21 (3) (2024) e00331]","authors":"Zahra Moussavi ,&nbsp;Maria Uehara ,&nbsp;Grant Rutherford ,&nbsp;Brian Lithgow ,&nbsp;Colleen Millikin ,&nbsp;Xikui Wang ,&nbsp;Chandan Saha ,&nbsp;Behzad Mansouri ,&nbsp;Craig Omelan ,&nbsp;Lesley Fellows ,&nbsp;Paul B. Fitzgerald ,&nbsp;Lisa Koski","doi":"10.1016/j.neurot.2024.100438","DOIUrl":"10.1016/j.neurot.2024.100438","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article 100438"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109951","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":"Butylphthalide inhibits ferroptosis and ameliorates cerebral Ischaemia–Reperfusion injury in rats by activating the Nrf2/HO-1 signalling pathway","authors":"Meilin Sun ,&nbsp;Junmin Chen ,&nbsp;Fan Liu ,&nbsp;Pei Li ,&nbsp;Jundong Lu ,&nbsp;Shihao Ge ,&nbsp;Lele Wang ,&nbsp;Xin Zhang ,&nbsp;Xiaopeng Wang","doi":"10.1016/j.neurot.2024.e00444","DOIUrl":"10.1016/j.neurot.2024.e00444","url":null,"abstract":"<div><div>This study aims to investigate whether butylphthalide can inhibit ferroptosis and ameliorate cerebral ischaemia–reperfusion (I/R) injury in rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) signalling pathway, known for its antioxidative and cytoprotective properties. Middle cerebral artery occlusion reperfusion (MCAO/R) rat models were established. Male rats were randomly divided into five groups: a sham-operated group (sham), MCAO/R group, MCAO/R ​+ ​ML385 (Nrf2-specific inhibitor) group, MCAO/R ​+ ​NBP (butylphthalide) group and MCAO/R ​+ ​ML385 ​+ ​NBP group. The effect of butylphthalide on cerebral I/R injury was evaluated using neurological deficit scores. The expression levels of Nrf2, HO-1, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and transferrin receptor 1 (TfR1) protein were detected using Western blot. Moreover, the expression levels of GPX4, HO-1 and TfR1 mRNA were determined through real-time fluorescence quantitative reverse transcription polymerase chain reaction. The distribution of Nrf2, HO-1, GPX4 and TfR1 was detected using immunohistochemical staining. The levels of iron and related lipid peroxidation indexes, such as reduced glutathione, reactive oxygen species, malondialdehyde and nitric oxide, were measured using a kit. The changes in mitochondria were observed through transmission electron microscopy. Butylphthalide treatment significantly improved neurological dysfunction, reduced cerebral infarction volume and mitigated histopathological damage in MCAO/R rats. It induced the nuclear translocation of Nrf2 and upregulated HO-1 expression, which was attenuated by ML385. Butylphthalide also attenuated lipid peroxidation, iron accumulation and mitochondrial damage induced by MCAO/R. The expression of GPX4, ACSL4 and TfR1 proteins, as well as their mRNA levels, was modulated through butylphthalide treatment, with improvements observed in mitochondrial morphology. Butylphthalide exerts neuroprotective effects by attenuating neurological dysfunction and ferroptosis in MCAO/R rats through the activation of the Nrf2/HO-1 pathway and inhibition of lipid peroxidation and iron accumulation.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00444"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365918","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":"Early efficacy of rTMS intervention at week 2 predicts subsequent responses at week 24 in schizophrenia in a randomized controlled trial","authors":"","doi":"10.1016/j.neurot.2024.e00392","DOIUrl":"10.1016/j.neurot.2024.e00392","url":null,"abstract":"<div><div>Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique for modulating cortical activities and improving neural plasticity. Several studies investigated the effects of rTMS, etc., but the results are inconsistent. This study was designed to examine whether rTMS applied on the left dorsolateral prefrontal cortex (l-DLPFC) showed an effect on improving cognitive deficits in SZ and whether the early efficacy could predict efficacy at subsequent follow-ups. Cognitive ability was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale at baseline, weeks 2, 6, and 24. We found a significant interaction between time (weeks 0, 2, 6, and 24) and intervention on immediate memory and RBANS total scores (p ​= ​0.02 and p ​= ​0.04), indicating that both 10-Hz and 20-Hz rTMS stimulations had a delayed beneficial effect on immediate memory in SZ. Moreover, we found that 20-Hz rTMS stimulation, but not 10-Hz rTMS improved immediate memory at week 6 compared to the sham group (p ​= ​0.029). More importantly, improvements in immediate memory at week 2 were positively correlated with improvements at week 24 (β ​= ​0.461, t ​= ​3.322, p ​= ​0.002). Our study suggests that active rTMS was beneficial for cognitive deficits in patients with SZ. Furthermore, efficacy at week 2 could predict the subsequent efficacy at 24-week follow-up.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00392"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469692","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}