Neurotherapeutics最新文献

{"title":"A double-blind, controlled trial of circadian effective light therapy in patients with Parkinson's disease.","authors":"Bradley T Wyman, Dan Adams, Suzanne Hendrix, Jeffrey Groves, Wayne Croft, Noel Ellison, C Warren Olanow, Karl Kieburtz","doi":"10.1016/j.neurot.2025.e00728","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00728","url":null,"abstract":"<p><p>Despite current medical therapy for Parkinson's Disease (PD), many experience persistent motor symptoms and significant unmanaged non-motor issues. Previous studies suggest that light therapy (LT) provides benefits for motor and non-motor features of PD. This study evaluated Circadian Effective LT (CELT) with a spectral band between 460 and 545 ​nm for the motor and non-motor features of PD. We conducted a multi-center, randomized, double-blind, controlled clinical trial of CELT in people with Parkinson's disease on standard-of-care therapy. Ninety-two participants (45 active, 47 control) were randomized 1:1 to active or control CELT for 1 ​h each evening for 6 months. Patients were evaluated in their 'ON state'. The mean (SE) change on the primary endpoint of the MDS-UPDRS parts 1-3 was -17.7(2.8) active vs -9.7(3.5) control, for a LSM difference of -8.0 (4.4) (p ​= ​0.074, 95% Confidence Interval: -16.7, 0.8), reflecting a trend toward improvement over control. Key secondary endpoints included PDQ-39 and CGI which favored active treatment (-5.7 ​± ​2.7; p ​= ​0.038, and -0.4 ​± ​0.2; p ​= ​0.066 respectively), while PDSS-2 Disturbed Sleep showed no difference between groups. Other secondary endpoints that supported the overall treatment effect of CELT included ESS (-1.52 ​± ​0.78; p ​= ​0.054) and CGI-E (-0.3 ​± ​0.2; p ​= ​0.088). Daily LT, with a circadian effective targeted spectrum of light, was well tolerated by PD patients, had no serious adverse effects and showed improvement in both motor and non-motor MDS-UPDRS and other scores. Larger double-blind studies are warranted to further assess the effectiveness of CELT in PD. CLINICALTRIALS.GOV REGISTRATION: NCT02175472.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00728"},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993033","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":"Stress-induced nuclear GAPDH: Scientific update and clinical application.","authors":"Parimala Vedula, Koko Ishizuka, Arisa Hayashida, Kota Sueo, Akira Sawa","doi":"10.1016/j.neurot.2025.e00725","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00725","url":null,"abstract":"<p><p>Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known as a moonlighting protein beyond its original glycolytic function. Stress-induced nuclear translocation of GAPDH has been reproducibly reported, which results in variety types of cellular responses, including cell death and dysfunction. Blocking this stress-induced cascade has been regarded as a target of drug discovery and development for human disease conditions, particularly for neurological and psychiatric diseases. There are promising small compounds that can block this cascade in cell and animal models. Nevertheless, the clinical trials for Parkinson's disease and amyotrophic lateral sclerosis with one of these compounds Omigapil were unsuccessful. Including these failure cases, this review article discussed the scientific frontline of GAPDH, particularly stress-induced nuclear GAPDH, and its potential for clinical applications.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00725"},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992987","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":"Gut microbiota mediates semaglutide attenuation of diabetes-associated cognitive decline","authors":"Liqin Qi ,&nbsp;Huimin Kang ,&nbsp;Feihui Zeng ,&nbsp;Menglan Zhan ,&nbsp;Cuihua Huang ,&nbsp;Qintao Huang ,&nbsp;Lijing Lin ,&nbsp;Guanlian He ,&nbsp;Xiaoying Liu ,&nbsp;Xiaohong Liu ,&nbsp;Libin Liu","doi":"10.1016/j.neurot.2025.e00615","DOIUrl":"10.1016/j.neurot.2025.e00615","url":null,"abstract":"<div><div>Diabetes-associated cognitive decline (DACD), characterized by cognitive impairment, is a serious complication of diabetes mellitus (DM). Research has shown that semaglutide, a novel glucagon-like peptide-1 receptor agonist, has neurotrophic and neuroprotective properties. However, a comprehensive understanding of the specific effects and underlying mechanisms of semaglutide treatment in patients with DACD remains lacking. In this study, we evaluated the potential of semaglutide to alleviate DACD in mice with DM. Eight-week-old mice fed a high-fat diet with streptozotocin-induced DM were subcutaneously injected with semaglutide (30 ​nmol/kg qd) for 12 weeks. Semaglutide administration significantly alleviated cognitive impairment, inhibited hippocampal neuron loss, improved the hippocampal synaptic ultrastructure, and effectively mitigated neuroinflammation. Furthermore, semaglutide treatment increased the relative abundances of <em>g_Alistipes, g_norank_f_Eubacterium_coprostanoligenes, g_Bacteroides,</em> and <em>g_Parabacteroides</em>, while decreasing the relative abundances of <em>g_ faecalibaculum, g_Colodertribacter, g_GCA-900066575, g_Erysipelatoclostridium,</em> and <em>g_norank_f_Lachnospiraceae</em>. Semaglutide also induced alterations in fecal and serum metabolites, as well as transcriptomic changes in brain tissue, with significant common enrichment in neuroactive ligand-receptor interactions. Furthermore, strong correlations were observed among semaglutide-affected genes, metabolites, and microbiota, as assessed by correlation analysis and integrative modeling. In conclusion, these findings suggest a correlation between the protective effects of semaglutide against DACD and the microbiota-gut-brain axis.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00615"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142773","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":"Systemic nimodipine affects pericyte calcium signaling, resting hemodynamics and neurovascular coupling in healthy mouse brain","authors":"Jessica Meza-Resillas ,&nbsp;Finnegan O'Hara ,&nbsp;Syed Kaushik ,&nbsp;Michael J. Stobart ,&nbsp;Noushin Ahmadpour ,&nbsp;Meher Kantroo ,&nbsp;John Del Rosario ,&nbsp;Megan C. Rodriguez ,&nbsp;Dmytro Koval ,&nbsp;Chaim Glück ,&nbsp;Bruno Weber ,&nbsp;Jillian L. Stobart","doi":"10.1016/j.neurot.2025.e00614","DOIUrl":"10.1016/j.neurot.2025.e00614","url":null,"abstract":"<div><div>Nimodipine is a L-type voltage gated calcium channel blocker commonly given to patients after a sub-arachnoid hemorrhage. It is known to dilate cerebral arteries and affect brain pericytes that express voltage gated calcium channels. Here, we systemically administered nimodipine (1 ​mg/kg; i.p.) and measured brain pericyte calcium transients and single-vessel hemodynamics in the brains of mice by two-photon microscopy. We find that nimodipine reduces calcium transients in all types of pericytes, from ensheathing to thin-strand cells, at different locations in the vascular network. This induces local vasodilation of vessels closer to penetrating arterioles but decreases blood cell velocity. These vascular consequences are due to systemic nimodipine effects because direct brain application of nimodipine caused blood cell velocity to increase. Nimodipine treatment also reduced further dilation during neurovascular coupling throughout the vascular network. Overall, this suggests that nimodipine can change cerebrovascular hemodynamics by altering pericyte physiology and these are important considerations for the clinical use of this drug.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00614"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127679","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":"Deep brain stimulation improves symptoms across all dimensions in treatment-resistant depression","authors":"N. Runia ,&nbsp;G.J.J. Mol ,&nbsp;D.A.J.P. Denys ,&nbsp;H. Ardon ,&nbsp;G. Beute ,&nbsp;M. Bot ,&nbsp;D.A. de Waardt ,&nbsp;D.W.W. de Knijff ,&nbsp;R.J.T. Mocking ,&nbsp;P. Notten ,&nbsp;G.J.M. Rutten ,&nbsp;P.R. Schuurman ,&nbsp;P. van den Munckhof ,&nbsp;J. van Laarhoven ,&nbsp;G.A. van Wingen ,&nbsp;I.O. Bergfeld","doi":"10.1016/j.neurot.2025.e00623","DOIUrl":"10.1016/j.neurot.2025.e00623","url":null,"abstract":"<div><div>Deep brain stimulation (DBS) reduces depressive symptom scores in many patients with treatment-resistant depression (TRD). However, it is unclear whether the observed improvement is similar across various symptom dimensions (e.g., anhedonia, anxiety, insomnia) or if some require additional clinical attention. Using a retrospective chart review, we assessed the trajectory of HAM-D-17 and MADRS scores during vALIC or slMFB DBS treatment within different symptom dimensions (HAM-D-17: 1) affective/anhedonia, 2) somatic/anxiety, 3) insomnia; MADRS: 1) affective/anhedonia, 2) anxiety/vegetative, 3) hopelessness) after at least a 25 ​% symptom reduction (partial response) at any time during their treatment course (n ​= ​34 for HAM-D-17, n ​= ​25 for MADRS). Results showed that each of the assessed symptom dimensions was significantly reduced compared to baseline at each of the assessed time periods (last follow-up: 2–15 years) after (partial) DBS response onset, which occurred at a median of approximately 2.5 months. Additionally, there was a significant interaction effect between symptom dimension and time period (HAM-D-17: F (12,1655.46) ​= ​5.46, p ​&lt; ​0.001; MADRS: F (12,938.73) ​= ​2.40, p ​&lt; ​0.01). Model coefficients indicated that insomnia symptoms (HAM-D-17) and anxiety/vegetative symptoms (MADRS) improved at a slower rate than the other symptom dimensions. Additionally, higher baseline scores in the HAM-D-17 somatic/anxiety dimension were significantly associated with a larger percentage reduction in overall symptoms after DBS (n ​= ​39, F (1,32) ​= ​12.371, p ​&lt; ​0.01). Our findings demonstrate that DBS for TRD effectively treats depressive symptoms in all dimensions, although insomnia symptoms may improve at a slower rate, and that patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00623"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275456","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":"Alterations of pro- and anti-inflammatory cytokines balance and superoxide dismutase in the dorsolateral prefrontal cortex of suicide decedents","authors":"María S. García-Gutiérrez ,&nbsp;Esther Caparros ,&nbsp;Abraham B. Torregrosa ,&nbsp;Sebastián Martínez-López ,&nbsp;Ani Gasparyan ,&nbsp;Salvador Giner ,&nbsp;Jorge Manzanares","doi":"10.1016/j.neurot.2025.e00634","DOIUrl":"10.1016/j.neurot.2025.e00634","url":null,"abstract":"<div><div>Recent studies have suggested that the immune system may be a key player in the pathophysiology of suicide. In this context, access to brain samples from individuals who died by suicide is of particular importance. Our study is designed to thoroughly investigate the link between suicide and brain immune system alterations. We analyzed changes in gene and protein expression of proinflammatory cytokines, IL-6 and TGF-β, and anti-inflammatory cytokine, IL-10, in the dorsolateral prefrontal cortex (DLPFC) of 33 suicide decedents (S) (with no clinical psychiatric history or treatment with anxiolytics or antidepressants) and 29 controls (C) using qPCR and ELISAs, respectively. Additionally, we evaluated superoxide dismutase 1 (SOD1) activity using ELISAs. S and C were matched for age and postmortem interval. Our results revealed an inverse correlation between pro- and anti-inflammatory cytokine levels in the DLPFC of S compared to C, with IL-6 and TGF-β increased and IL-10 reduced. Interestingly, contrasting changes were noted in gene expression across all analyzed targets, suggesting a potential homeostatic compensatory mechanism that warrants further analysis in large-scale studies. These alterations were accompanied by lower SOD1 activity in the DLPFC of S compared to C. These findings indicate an association between an inflammatory brain state and increased oxidative stress with suicide.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00634"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564943","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":"Efficacy and safety of efavirenz in Niemann-Pick disease type C","authors":"Jordi Gascón-Bayarri ,&nbsp;Inmaculada Rico ,&nbsp;Cristina Sánchez-Castañeda ,&nbsp;María Dolores Ledesma ,&nbsp;Thiago Carnaval ,&nbsp;Helena Bejr-Kasem ,&nbsp;Jaume Campdelacreu ,&nbsp;Anna Ferrer ,&nbsp;Laura Rodríguez-Bel ,&nbsp;Mónica Cos ,&nbsp;Eugenia de Lama ,&nbsp;Adolfo López de Munain ,&nbsp;Idoia Rouco ,&nbsp;Celia Pérez-Sousa ,&nbsp;María Cerdán ,&nbsp;Nuria Muelas ,&nbsp;María Dolores Sevillano ,&nbsp;Pablo Mir ,&nbsp;Jesús Villoria ,&nbsp;Sebastián Videla","doi":"10.1016/j.neurot.2025.e00706","DOIUrl":"10.1016/j.neurot.2025.e00706","url":null,"abstract":"<div><h3>Introduction</h3><div>In search of disease-modifying treatments for the Niemann-Pick disease type C (NPC), this Phase II single-arm clinical trial evaluated the safety and efficacy of efavirenz, a reverse transcriptase inhibitor that potentially ameliorates neuronal cholesterol turnover, typically impaired in this rare lysosomal storage disorder.</div></div><div><h3>Material and methods</h3><div>Patients 14 years of age or older with genetically confirmed NPC received efavirenz 25 mg/day (Weeks 1–26) or 100 mg/day (Weeks 27–52) orally on top of standard care including miglustat. The primary endpoint was the proportion of response, defined as lack of deterioration in a composite outcome of cognitive performance. Secondary endpoints included the quantitative scores of several clinical neuropsychological assessment tools, some relevant neurological signs and symptoms, and imaging and biological specimen-based biomarkers. Measures were taken repeatedly over time and were analyzed using generalized linear mixed models.</div></div><div><h3>Results</h3><div>Sixteen patients 15–60 years of age were enrolled. All (100.0 %, 95 % exact confidence interval: 79.4–100.0 %) met the primary endpoint response criterion at Week 52. Quantitative neuropsychological assessments yielded more nuanced results, with relative preservation of learning, memory and executive control, and subtle impairments of verbal fluency, selective and divided attention, and cognitive inhibition. Some patients had better responses than others, allowing us to set two well-differentiated subgroups that differed essentially in the time since symptoms onset. No efavirenz-related or serious adverse events were reported.</div></div><div><h3>Conclusion</h3><div>Efavirenz appears to be a safe, easy-to-use, new targeted therapeutic option which slows the rate of NPC progression. The benefits of efavirenz are greater if started earlier.</div></div><div><h3>Trial Registration</h3><div>Registered on the European Union Clinical Trials Register (EurdraCT) on December 20th, 2019 under the number: 2019-004498-18 (<span><span>https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004498-18/ES/</span><svg><path></path></svg></span>). The first patient was enrolled on May 25th, 2022.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00706"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699118","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":"Hydrogen inhalation and intrathecal magnesium sulfate ameliorate ischemia by suppressing cortical spreading depolarization in a rat subarachnoid hemorrhage model","authors":"Toru Yoshiura ,&nbsp;Satoko Kawauchi ,&nbsp;Sho Nishida ,&nbsp;Sho Sato ,&nbsp;Daichi Hagita ,&nbsp;Arumu Endo ,&nbsp;Masaya Nakagawa ,&nbsp;Takashi Fujii ,&nbsp;Yohei Otsuka ,&nbsp;Yumiko Mishima ,&nbsp;Kazuya Fujii ,&nbsp;Satoru Takeuchi ,&nbsp;Arata Tomiyama ,&nbsp;Terushige Toyooka ,&nbsp;Shunichi Sato ,&nbsp;Kojiro Wada","doi":"10.1016/j.neurot.2025.e00617","DOIUrl":"10.1016/j.neurot.2025.e00617","url":null,"abstract":"<div><div>This study investigated whether inhaled hydrogen and intrathecal magnesium could mitigate cortical spreading depolarization and delayed cerebral ischemia in a rat model of subarachnoid hemorrhage. Adult male rats underwent subarachnoid hemorrhage induction with nitric oxide synthase inhibition and high-potassium application to elicit cortical spreading depolarization. Animals were assigned to sham, control, H₂, Mg, or combined H₂ and Mg treatment groups. We measured direct current potentials, cerebral blood flow, brain water content, bodyweight changes, and neurological outcomes. Compared with controls, the H₂ and Mg groups had significantly reduced total depolarization and hypoperfusion times. The combined treatment produced similar benefits. H₂ alone rapidly shortened depolarization duration, suggesting that it may offer neuroprotection until Mg effects fully manifest. Neither treatment altered physiological parameters, brain water content, bodyweight, or neurological deficits. These findings indicate that H₂ and Mg reduce key pathophysiological processes related to early brain injury and delayed cerebral ischemia following subarachnoid hemorrhage, potentially improving outcomes by minimizing depolarization events and associated ischemia. H₂ therapy may provide early protective effects before Mg exertion.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00617"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182855","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":"Neuroprotective effects of G9a inhibition and cannabinoid receptor activation in Alzheimer's disease through a pharmacological approach","authors":"Aina Bellver-Sanchis ,&nbsp;Marta Ribalta-Vilella ,&nbsp;Jaume Lillo ,&nbsp;Daniel Ortuño-Sahagún ,&nbsp;Rafael Franco ,&nbsp;Mercè Pallàs ,&nbsp;Gemma Navarro ,&nbsp;Christian Griñán-Ferré","doi":"10.1016/j.neurot.2025.e00616","DOIUrl":"10.1016/j.neurot.2025.e00616","url":null,"abstract":"<div><div>Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling. In SAMP8 mice (sporadic AD model), we evaluated the effects of pharmacological inhibition of G9a (UNC0642), combined with CB₁R agonism (ACEA) and/or CB₂R agonism (JWH133), on cognitive recovery, neuronal morphology, and neuroinflammation. Our results demonstrated that SAMP8 mice treated with UNC0642 and ACEA exhibited significant recovery in short-term memory, as assessed by the Novel Object Recognition Test (NORT), and complete recovery of spatial memory in the Object Location Test (OLT). These improvements were accompanied by enhanced neuronal morphology (increased dendritic length and density) and reduced neuroinflammation markers, suggesting a synergistic effect of G9a inhibition and CB₁R activation. Importantly, JWH133 treatment, both alone and in combination with UNC0642, resulted in a pronounced reduction of neuroinflammatory markers (<em>Trem2, Cd33, iNOS</em>) and a significant restoration of dendritic spine density and branching length, with the dual treatment showing the most robust effects. JWH133 alone produced moderate cognitive improvement, but its combination with G9a inhibition led to outcomes comparable to those of control animals. Thus, the results underscore G9a inhibition's potential to amplify cannabinoid receptor-mediated neuroprotection while mitigating psychoactive risks, offering a promising multi-target approach for neurodegenerative diseases.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00616"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225997","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":"Deep brain stimulation is well tolerated and effective following ProSavin® gene therapy for Parkinson's disease","authors":"S. Senova ,&nbsp;K. Edakawa ,&nbsp;G. Gouello ,&nbsp;M. Faillot ,&nbsp;M. Derosin ,&nbsp;H. Lepetit ,&nbsp;G.S. Ralph ,&nbsp;P.C. Buttery ,&nbsp;R.A. Barker ,&nbsp;K.A. Mitrophanous ,&nbsp;J.M. Gurruchaga ,&nbsp;S. Palfi","doi":"10.1016/j.neurot.2025.e00629","DOIUrl":"10.1016/j.neurot.2025.e00629","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder initially treated with oral dopaminergic medications. When motor fluctuations and side effects develop on these treatments, Deep Brain stimulation (DBS) of the subthalamic nucleus (STN) is used. Striatal dopamine replacement, using a lentiviral vector-based gene therapy (GT), was previously shown to be well-tolerated, leading to clinical improvement in motor function. Later, some of these patients showed evidence of disease progression and were proposed DBS since new GT injection was not yet authorized by regulatory authorities. The tolerance and motor efficacy of DBS in this cohort is reported. Eight patients who had previously received GT (GT/DBS group), were evaluated pre- and 12 months-post DBS. A control group of 84 PD patients who had received DBS, were used for comparison (DBS group). Patients in the GT/DBS group were administered DBS significantly later after PD diagnosis than the DBS group (19.6 vs 12.1 years). Similar rate of serious adverse events, UPDRS III MEDSOFF scores 12 months post-DBS and reduction in LEDD between baseline DBS and 12 months post DBS were reported in both groups. The decrease in axial scores from UPDRS III MEDSOFF/STIMON at 12 months post-DBS compared with baseline DBS was significantly greater in the GT/DBS group than in the DBS group. DBS of the STN was as effective and well-tolerated in GT/DBS PD patients as in the DBS group, even when administered later in their disease course.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00629"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554024","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}