Neurotherapeutics最新文献

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.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, with a 5-year mortality of up to 70 %. Disease-modifying treatments to improve neurological outcomes in ICH survivors represent a critical unmet need. Neuroinflammation contributes significantly to ongoing secondary brain injury and long-term morbidity in ICH. We and others have shown that B cells are potent modulators of the inflammatory response, capable of acquiring a regulatory phenotype within injured microenvironments. Here, we investigated the effects of a single intraparenchymal application of mature naïve splenic B lymphocytes in a murine model of collagenase-induced ICH. In vivo tracking of luciferase-expressing B cells showed that the exogenous cells remained localized at the delivery site for up to 2 weeks. Delayed intraparenchymal B cell application at 24 h post-ICH was associated with acute neuroprotection of motor function in wire grip and rotarod assays and significant cognitive neuroprotection at 30 days post-injury in a Y maze paradigm. B cell administration was associated with reduced inflammasome activation at the injury site, diminished infiltration of CD8⁺ cytotoxic T cells in the injured hemisphere, and a regulatory shift in cytokine production in infiltrating monocytes/macrophages and natural killer cells. Systemically, modest increases in inflammatory cytokines and in regulatory markers were observed in myeloid cells in the spleen of animals treated with B cells intraparenchymally. These findings support intraparenchymal delivery of naïve B lymphocytes as a promising cell-based therapy for ICH, capable of facilitating functional neuroprotection via dynamic immunomodulation of adjacent immune populations.

Acute ischemic stroke (AIS) treatment relies on early restoration of blood flow; however, ischemia/reperfusion (I/R) may lead to secondary brain injury. Supramolecular peptide assemblies in which many molecules move collectively by design can activate key cellular pathways by displaying bioactive molecules on their surfaces. In this study, we hypothesized that a highly dynamic assembly formed by a peptide amphiphile (PA) that displays the laminin-mimetic sequence IKVAV (IKVAV-PA), known to promote neuron survival, could be delivered systemically, reach the ischemic brain, and exert therapeutic effects following AIS. C57BL/6 heterozygous CX3CR1^GFP mice underwent 60-min of transient middle cerebral artery occlusion and were administered IKVAV-PA or saline (control) immediately after reperfusion. IKVAV-PA presence and distribution was evaluated by intracranial intravital and wide-field imaging. Cresyl violet staining was performed to quantitate final brain infarct volume at 7 days post stroke. IKVAV-PA formed scaffolds that contain both nanoscale filaments in equilibrium with small micellar aggregates, which is a signature of enhanced epitope dynamicity. Systemically administered IKVAV-PA crossed the blood-brain barrier and was primarily detected within the ischemic hemisphere. Cresyl violet staining demonstrated IKVAV-PA treatment significantly reduced infarct size when compared to saline treated animals. Histological screening of systemic organs suggested good biocompatibility of IKVAV-PAs at 7 days post stroke. We demonstrated the therapeutic potential of systemically delivering IKVAV-PA in a pre-clinical model of ischemic stroke. This work lays the foundation for further studies utilizing supramolecular PA assemblies as an adjunct therapy to reperfusion therapies in order to enhance long-term tissue-level neural regeneration post stroke.

Spinal cord injury (SCI) triggers reactive astrogliosis, leading to the formation of an astrocyte scar around the lesion. Regulatory T cells (Tregs), a subset of immune cells, infiltrate the peri-lesional area through the compromised blood-spinal cord barrier. However, the regulatory role of Tregs in post-SCI astrogliosis and its underlying mechanisms remain unclear. Here, we demonstrated that Tregs attenuate astrogliosis and promote neurological recovery after SCI. Treg-depleted mice exhibited exacerbated astrocyte activation, increased chondroitin sulfate proteoglycan (CSPG) deposition, and impaired axonal remodeling post-SCI. Through transcriptomic profiling, we identified vimentin (Vim) as a key gene in astrocytes upregulated by Treg depletion following SCI. In vitro Treg co-culture attenuated oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocyte activation, CSPG secretion, and vimentin high expression. Virus-mediated vimentin knockdown recapitulated Treg-mediated suppression of in vitro astrocyte activation and in vivo astrogliosis, and further ameliorated Treg depletion-induced pathological outcomes. In vitro pharmacological studies in astrocytes reveal that vimentin expression is modulated by exogenous IL-10 signaling and downstream STAT3/PKC phosphorylation. These findings demonstrate that Tregs attenuate post-SCI astrogliosis via the IL-10/STAT3/PKC/vimentin signaling axis, thereby facilitating axonal remodeling and promoting neurological recovery. Our study provides novel insights into the Treg-mediated neuroimmune repair mechanisms and establishes promising therapeutic targets for SCI treatment.

Parkinson's disease (PD) remains without effective disease-modifying therapies, primarily due to limited understanding of its underlying mechanisms. Emerging evidence suggests that dipeptidyl peptidase-4 inhibitors (DPP-4Is), commonly used as anti-diabetics, may offer neuroprotective effects. We aimed to evaluate the potential of repurposing DPP-4Is for reducing the PD risk, using a drug-target Mendelian randomization (MR) approach, with specific attention to sex. We performed two-sample MR analyses using instrumental variables (IVs) for DPP-4Is derived from gene expression quantitative trait loci (IV_eQTL) and protein QTL (IV_pQTL) data sourced from the eQTLGen consortium and UK Biobank, respectively. Associations were tested using the largest PD genome-wide association studies (GWAS) dataset from the International Parkinson's Disease Genomics Consortium, including sex-stratified analyses. Primary analyses used inverse variance weighted MR, with additional sensitivity analyses (alternative MR methods, varying IV selection thresholds, and tissue-specific eQTL), mediation analysis through diabetes and colocalization analysis. Genetically proxied DPP-4 inhibition was associated with reduced PD risk: OR (95% CI) ​= ​1.78 (1.21-2.61) for IV_eQTL and 1.21 (1.02-1.45) for IV_pQTL. This beneficial effect was more pronounced in men-IV_eQTL: 2.25 (1.55-3.28); IV_pQTL 1.35 (1.15-1.57)-but not significant in women, suggesting sex-specific effects. Findings were robust across sensitivity analyses and replicated in an independent PD GWAS. Diabetes did not mediate this relationship, and colocalization provided partial evidence for a shared causal variant only in men. This multi-omics drug-target MR study suggests that DPP-4Is may reduce PD risk, supporting their potential for repurposing, particularly in male patients.