Neurotherapeutics最新文献

Trigeminal nerve stimulation (TNS) is a minimal-risk, noninvasive neuromodulation method with growing evidence of efficacy across psychiatric conditions. However, its safety and potential effects in autism spectrum disorder (ASD) remain underexplored. This exploratory pilot study aimed primarily to evaluate the safety and tolerability, and secondarily to explore changes in ASD-related symptoms - including impairments in social communication and reciprocity, attention, executive functioning, emotional regulation, sleep, and sensory processing - in children with ASD, and to examine associated changes using quantitative electroencephalography (qEEG). This double-blind, sham-controlled, randomized exploratory pilot trial enrolled 29 children aged 7-12 years with ASD. The participants were randomized to receive 28 nightly sessions of active or sham TNS over 4 weeks. At baseline and week 4, we assessed safety, clinical outcomes and Clinical Global Impression scales, in addition to analyzing qEEG band power. No serious adverse events were observed, and TNS was well tolerated. Exploratory analyses showed nominal between-group differences (unadjusted) favoring the TNS group in maladaptive behavior (Vineland-II: 1.38 vs 0.08; p = .017) and social reciprocity (Social Responsiveness Scale-2: 12.07 vs -1.43; p = .025). Exploratory qEEG analyses revealed decreased gamma/high-frequency and increased alpha power in the left frontal and parietal regions, changes that significantly correlated with improvements in social (r = -0.917; p = .001) and overall (r = -0.680; p = .030) functioning. TNS was safe and showed preliminary evidence of potential benefits in improving behavioral and social functioning in children with ASD. Larger trials are required to confirm these findings. Clinical trial registration information: http://clinicaltrials.gov/; NCT06233279.

We aim to evaluate sleep disruption in people with multiple sclerosis (MS) compared to an age- and gender-matched control cohort using patient-reported outcome measures and formal polysomnography (PSG) scoring, and testing the effect of Nabiximols on these measures in people with MS. We enrolled adult individuals with MS who were eligible to receive nabiximols. Clinical variables and self-reported items like Pittsburgh Sleep Quality Index (PSQI) score were collected. Individuals underwent two full-night PSG recordings: baseline and after a 6-week nabiximols trial. Additionally, 24 healthy individuals (18 females; mean age:55.7 ± 9.5 years) were recruited as control cohort. Linear mixed-effects models (LMMs) using clinical and PSG parameters were used. Our cohort of 19 people with MS (16 females; mean age of 50.8 ± 10.2 years) with elevated PSQI (11.7 ± 2.8) exhibited: reduced sleep efficiency (SE)[P < 0.001,q-value = 0.003], reduced total sleep time (TST)[P = 0.0021,q-value = 0.005], higher number of awakenings [P < 0.001,q-value = 0.003], increased arousal-index (AI) [P < 0.001,q-value = 0.003], a greater periodic limb movement index (PLMI) [P < 0.001,q-value = 0.003] and a reduced proportion of REM [P < 0.001,q-value = 0.003] compared with the controls. The 6-weeks nabiximols trial resulted in a significant improvement in the PSQI [β 95%CI = -1.28 (-1.67, -0.88)] and in the following PSG measures: SE [β 95%CI = 1.57 (1.18, 1.95)], TST [β 95%CI = 0.93 (0.46, 1.40)], AI [β 95%CI = -1.41 (-1.79, -1.30)], PLMI [β 95%CI = -1.73 (-2.03, -1.43)] and REM sleep [β 95%CI = 1.44 (1.00, 1.87)]. Our prospective study reported a significant sleep disruption in MS and a great improvement in sleep parameters following a 6-week trial of Nabiximols, as indicated by LMMs using PSQI score and PSG measures. We suggest broadening the therapeutic indications of nabiximols to also include individuals with MS who experience significant sleep disruption.

Efgartigimod is an established therapy for acetylcholine receptor antibody-positive generalized myasthenia gravis, yet real-world data on long-term overall responsiveness, response patterns, steroid-sparing effects, bridging therapy use, and predictors of benefit remain limited. In this multicenter retrospective study, we evaluated 46 patients treated across seven tertiary centers between April 2022 and March 2025, collecting demographic, clinical, therapeutic, and outcome data. Patients received 193 treatment cycles (mean 4.3 per patient) with a mean inter-cycle interval of 9.8 weeks. Following the first cycle, 86.9 % achieved a ≥2-point improvement in the Myasthenia Gravis Activities of Daily Living scale and 43.5 % reached minimal symptom expression (MSE); overall, 52.2 % achieved MSE at least once during follow-up. Nonetheless, 35.9 % discontinued efgartigimod due to insufficient efficacy, underscoring heterogeneous and often non-durable responses. Among 29 patients on prednisone, 58.6 % achieved a significant dose reduction (30.9-16.8 mg/day, p = 0.001), with shorter disease duration predicting successful tapering. Bridging therapy was successful in 5 patients, particularly those receiving azathioprine or mycophenolate (p = 0.040), supporting its utility during transitions to slower-acting immunosuppressants. Adverse events occurred in 21.7 % of patients, were generally mild, and led to discontinuation in only one case. Overall, efgartigimod was effective and well tolerated, but treatment responses varied, and cycle-based regimens frequently failed to sustain benefit. The observed steroid-sparing effect and predictors of response highlight the need for personalized treatment strategies and prospective studies to refine long-term use and optimize patient selection.

The response to neurostimulation can be modulated based on the state of neural network activation prior to stimulation, a mechanism termed metaplasticity. In the swallowing system, preconditioning the pharyngeal motor cortex with non-invasive brain stimulation (NIBS) can induce metaplasticity. However, the effects of cross-modal neurostimulation, i.e. combined peripheral (pharyngeal electrical stimulation; PES) and central (transcranial direct current stimulation; tDCS) approaches, remain unknown. This study investigated the effects of PES preconditioned by tDCS on cortical activation of swallow-related network and swallowing behaviour. Twenty-one healthy volunteers (8 males, 13 females; mean age = 27.0 ± 4.8 years) participated in the study. They received, in randomized order across three separate visits, three experimental conditions in which PES (5Hz, 10 min) was preconditioned by (1) anodal tDCS (1 mA, 20 min), (2) cathodal tDCS (1.5 mA, 10 min), and (3) sham tDCS. Cortical activation of swallow-related network during "volitional" and "challenged" swallow tasks was measured using magnetoencephalography (MEG) at baseline and immediately post-intervention. Swallowing behaviour was assessed by submental electromyographic (EMG) measurements and timed water swallow test. Significant bilateral enhancement of cortical activation of swallow-related network during challenged swallow task was observed in the theta frequency following cathodal preconditioning (p = 0.042) and PES alone (p < 0.001). By contrast, anodal preconditioning significantly reduced swallow-related network activation in the alpha frequency (p = 0.037). There were no significant changes in swallowing behaviour across conditions. This is the first evidence of metaplasticity induced by cross-modal neurostimulation in the swallowing system. Future studies may focus on its clinical application in patients with neurogenic dysphagia.

Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling. The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes. This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models. We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology. Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.

Neuronal cytoplasmic aggregation and nuclear depletion of the TAR DNA-binding protein 43 (TDP-43) is the most characteristic pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing toxicity through cytoplasmic gain and nuclear loss of function mechanisms. In addition to its canonical role in nuclear cytoplasmic transport (NCT), the nuclear import receptor, importin-β1 (KPNB1) also acts as a molecular chaperone capable of preventing and reversing aberrant protein aggregation. Previous studies have demonstrated that increased expression of KPNB1 solubilizes TDP-43 aggregates and restores its nuclear localization. Here, we identify JRMS, a small molecule that enhances the chaperone activity of KPNB1 by increasing its cytoplasmic availability. JRMS treatment reduced cytoplasmic aggregation and promoted nuclear localization of full-length and pathological truncated TDP-43 variants across multiple experimental systems, including cell lines, primary neurons, iPSC-derived cortical neurons, organotypic brain slices and in vivo model. The effects of JRMS were KPNB1 dependent and occurred without inducing cytotoxicity or perturbing basal NCT. These findings identify JRMS as a promising therapeutic strategy for targeting TDP-43 pathology in ALS/FTD and other related TDP-43 proteinopathies.

Home-based transcutaneous auricular vagus nerve stimulation (taVNS) holds therapeutic potential for neurological disorders, yet its application in Parkinson's disease (PD) remains underexplored. In this single-blinded, placebo-controlled randomized clinical trial, PD patients received either home-based taVNS with specific stimulation parameters or sham stimulation for three weeks. TaVNS significantly improved motor symptoms, reflected as reduced MDS-UPDRS Ⅲ scores, and alleviated non-motor symptoms including quality of life and sleep disturbances compared with sham stimulation. Neuroimaging revealed that taVNS decreased glutamate levels in the striatum and thalamus, increased Regional Homogeneity values in the rolandic operculum, and enhanced fractional anisotropy in the left hippocampal cingulum and right inferior longitudinal fasciculus. Serum acetylcholine levels were elevated following taVNS and correlated with motor improvement. No serious adverse events occurred. These findings suggest that taVNS with specific parameters effectively alleviates motor and non-motor symptoms in PD, possibly through modulation of brain networks and vagal activity. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR230007082.

There remains a critical unmet need for effective, accessible, and well-tolerated therapies for myasthenia gravis (MG) who are refractory to current immunotherapies. The janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a pivotal role in maintaining immune homeostasis by regulating cytokine-mediated responses. However, insights into the involvement of the JAK-STAT signaling in MG pathogenesis are still preliminary. In this study, we observed elevated levels of JAK2 in MG and further assessed the clinical efficacy of the pan-JAK inhibitor, tofacitinib, administered over 24 weeks in a cohort of 19 patients with refractory MG (NCT04431895). Tofacitinib significantly reduces the glucocorticoid dose and improves MG-relevant clinical scores and quality of life. The immunomodulatory effects of tofacitinib were mediated through downregulation of p-STAT3, IL-6, and IL-23, resulting in suppression of pathogenic Th17.1 cells in MG. Collectively, our results suggest that a novel approach to suppress pathogenic Th17.1 cells via the JAK-STAT3 signalling pathway with tofacitinib is effective and well-tolerated for treating patients with refractory MG.

Exogenous plasma kallikrein 1 (KLK1) supplementation is hypothesized to have both immediate and long-lasting actions that may improve outcomes following acute ischemic stroke. ZHB103, a polyethylene glycol (PEG)-modified long-acting recombinant human KLK1 (LA-rhKLK1), has been developed as a candidate for exogenous KLK1 supplementation in stroke patients and for the prevention of stroke. In pharmacokinetic and toxicokinetic studies, ZHB103 exhibited high bioavailability, a prolonged half-life (T_1/2) and no treatment-related adverse effects after intramuscular injection in Sprague-Dawley rats and cynomolgus monkeys. Single-dose or once-weekly administration of ZHB103 demonstrated both short-term and long-term protective effects against ischemic stroke in oxygen-glucose deprivation/reoxygenation models, H₂O₂-induced oxidative stress models and experimental stroke models. Compared with rKLK1 (the proprotein of ZHB103, a short-acting non-PEGylated recombinant KLK1), Sanbexin (Edaravone and Dexborneol concentrated solution for injection) or HUK (human urinary kallidinogenase, a form of tissue kallikrein 1 from urine), ZHB103 promoted cell proliferation, inhibited apoptosis, reduced inflammatory factor levels in the acute stage of stroke models and improved cognitive function recovery during the later recovery stage via a significantly prolonged duration of B2 receptor (B2R)-mediated signaling pathway (eNOS-Akt-ERK1/2-CREB-Bcl-2) activation. The introduction of B2R inhibitor HOE-140 further confirmed, both in vitro and in vivo that ZHB103 exerts its efficacy in stroke treatment through upregulation of B2R and activation of its downstream eNOS signaling pathway. These results suggest that the administration frequency of ZHB103 may be reduced to once weekly, demonstrating the advantages of PEG-conjugation strategy in improving patient compliance among stroke patients in clinical practice.

Paediatric acute-onset neuropsychiatric syndrome (PANS) is a syndrome of infection-provoked abrupt-onset obsessive-compulsive disorder (OCD) or eating restriction. Based on the hypothesis that PANS is an epigenetic disorder of immune and brain function, a full-spectrum medicinal cannabinoid-rich low-THC cannabis (NTI164) was selected for its known epigenetic and immunomodulatory properties. This open-label trial of 14 children with chronic-relapsing PANS (mean age 12·1 years; range 4-17; 71 % male) investigated the safety and efficacy of 20 mg/kg/day NTI164 over 12 weeks. Clinical outcomes were assessed using gold standard tools. To define the biological effects of NTI164, blood samples were collected pre- and post-treatment for bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation. NTI164 was well-tolerated, and 12 weeks of treatment decreased the mean Clinical Global Impression-Severity (CGI-S) score from 4·8 to 3·3 (p = 0·002). Significant improvements were observed in emotional regulation (RCADS-P, p < 0·0001), obsessive-compulsive disorder (CYBOCS-II, p = 0·0001), tics (YGTSS, p < 0·0001), attention-deficit hyperactivity disorder (Conner's, p = 0·028), and overall quality of life (EQ-5D-Y, p = 0·011). At baseline, the multi-omic approach revealed that leucocytes from patients with PANS had dysregulated epigenetic (chromatin structure, DNA methylation, histone modifications, transcription factors), ribosomal, mRNA processing, immune, and signalling pathways. These pathways were significantly modulated by NTI164 treatment. NTI164 shows promise as a disease-modifying therapeutic for PANS. Multi-omics reveal broad epigenetic and immune dysregulation in patients, which was modified by NTI164, presenting epigenetic machinery as a therapeutic target in PANS.