Neurotherapeutics最新文献

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.

Migraine is one of the leading causes of disability globally. Despite advances in the available pharmacological options for its management, many patients still show a lack of response to these current therapeutics. As a consequence, it is important to explore new targets for the management of migraine and related headache disorders. In this review, we discuss evidence related to various novel targets that are in different stages of development as part of the current therapeutic pipeline in migraine management. These include recent studies that report the role of specific ion channels in migraine pathophysiology, including ATP-sensitive potassium channels (K_ATP), large conductance calcium- and voltage-activated potassium channels (BK_Ca), and transient receptor potential melastatin (TRPM) channels, specifically TRPM3 and TRPM8. Additionally, peptides secreted endogenously by hypothalamic nuclei have drawn attention, for example, oxytocin, orexins and prolactin have been signaled as possible systems for modulation with therapeutics. Here, we will assess preclinical validation studies, as well as clinical experimental and clinical trial data, and we will discuss some of the potential challenges with these targets and the future perspectives of these pipeline targets.

Biomarkers are essential to guide decision making in Alzheimer's disease (AD) clinical trials where they have a variety of contexts of use (COUs) including diagnosis, risk, pharmacodynamic response, prognosis, prediction, monitoring, and safety. The COU of biomarkers may differ by phase of drug development with Phase 1, 2, and 3 emphasizing different types of information for decision making. A variety of biomarkers are currently serving as pharmacodynamic outcomes in clinical trials including amyloid and tau PET and fluid measures of amyloid, tau, neurodegeneration, inflammation, and synaptic plasticity. Biomarker strategies are integrated throughout drug development programs from collection and assay performance to statistical analysis and data interpretation. Data interrogation approaches using artificial intelligence and machine learning may enhance the value of biomarker observations through integration of multimodal data. Emerging biomarkers that may play a role in future AD trials include proteomics, exosome assays of co-pathology occurring in AD, EEG, ocular measures, and digital biomarkers. Biomarkers inform drug development decision-making including termination of candidate agents without sufficient biomarker effects, resourcing of promising therapies impacting the fundamental features of AD, and accelerating the development of new therapies for those with or at risk for AD.

Migraine is among the most dynamic and disabling neurological disorders, affecting over one billion people globally. Attacks demonstrate rhythmic patterns of onset across the day and seasonally, highlighting that attack onset is influenced by an individual's biological rhythms. Indeed, an individual's chronotype (their endogenous circadian clock rhythm) predicts when they are most likely to have an attack. These biological rhythms are regulated by an endogenous master biological clock in the hypothalamus that coordinates the function of peripheral clocks, aligning biological processes and behaviours to environmental cues (e.g. daily rhythms in light-dark cycles). As such, circadian rhythms are essential to maintain normal neurological function and health, regulating the expression of approximately 50 % of all protein coding genes in mammals. Importantly, the majority of the World Health Organisations essential medicines and several migraine-related therapeutics directly target the products of these rhythmic genes or influence circadian-related genes directly. Therefore, the current review will focus on the potential for chronotherapy in migraine. Highlighting its potential to optimise the chronopharmacokinetic profile, therapeutic efficacy and reduce potential side effects of anti-migraine therapies. A greater understanding of which has the potential for significant impact, representing a low cost, scalable method to improve therapeutic response and inform a personalized therapeutic strategy.

α-Synuclein is a small presynaptic protein whose aggregation is one of the hallmarks of Parkinson's disease (PD). In our quest to identify novel preventive or therapeutic treatments for PD, we collected 60 Italian plant species, representative of part of the Mediterranean flora, which were screened by a phylogenetic analysis in conjunction with a high-throughput screening in a yeast model of PD expressing human α-synuclein. The integration of these approaches led to the identification of four plants, Allium lusitanicum, Salvia pratensis, Verbascum thapsus and Glaucium flavum, whose extracts, characterized by a metabolomic analysis, exhibit robust inhibitory activity against the amyloid aggregation of α-synuclein in vitro, as well as in neuroblastoma cells overexpressing the protein. By employing a size exclusion chromatography affinity approach coupled to mass spectrometry, we identified the phenylpropanoid glycoside acteoside from the extract of the edible plant V. thapsus as the metabolite that directly binds α-synuclein and effectively inhibits its fibril formation. In addition, acteoside reduces oxidative stress in neuroblastoma cells exposed to α-synuclein fibrils and activates the NRF2 pathway. Notably, acteoside improves motor performance in a Drosophila model of PD and exhibits a significant reduction of protein carbonyl groups, suggesting that this compound may mitigate oxidative stress-induced protein damage. Our findings could pave the way for the development of new strategies aimed at discovering novel neuroprotective agents targeting PD-related diseases.