Neurotherapeutics最新文献

Generalized Convulsive status epilepticus (SE) is a neurological emergency because prolonged convulsions can cause respiratory compromise and neuronal injury. Compromised GABA-mediated inhibition is a defining feature of SE, and many current therapies are benzodiazepines, which are allosteric modulators of GABA-A receptors. Many patients with medically refractory epilepsy are at risk for SE. Newly available nasally delivered benzodiazepines: midazolam and diazepam given for seizure clusters may prevent SE. Although three different benzodiazepines, diazepam, lorazepam and midazolam terminate early SE, midazolam is preferred. It is administered via the intramuscular route, which saves time and is at least as practical or more effective than intravenous lorazepam. Unfortunately, many early SE patients are receiving inadequate doses of benzodiazepines. Patients who fail to respond to adequate doses of benzodiazepines are considered to be in established SE. Levetiracetam, fosphenytoin, and valproic acid are equally safe and effective in treating established SE. The rate of cardiovascular complications: cardiac arrhythmias and hypotension were low in patients treated with phenytoin, levetiracetam, or valproic acid. In contrast, overall, 25 ​% of patients in established SE were intubated, and this was in response to respiratory compromise in many patients. Interestingly, children treated with fosphenytoin were more likely to require intubation than those treated with valproic acid or levetiracetam. Better therapies are needed for the treatment established SE, because all three drugs were effective in less than 50 ​% of the patients.

Tetrahydrobiopterin (BH4) expression is normally strictly controlled; however, its intracellular levels increase considerably following nerve damage. GTP cyclohydrolase I (GCH1) plays a crucial role in regulating BH4 concentration, with an upregulation observed in the dorsal root ganglion in cases of neuropathic pain. In this study, we aimed to develop and evaluate the clinical potential of an RNA interference-based adeno-associated virus (AAV) targeting GCH1 across various species to decrease BH4 levels and, consequently, alleviate neuropathic pain symptoms. We identified universal small-interfering RNA sequences effective across species and developed an AAV-u-shRNA that successfully suppressed GCH1 expression with minimal off-target effects. Male Sprague Dawley rats were divided into four groups: normal, spared nerve injury, AAV-shCON, and AAV-u-shGCH1. The rats were sacrificed on post-injection day 28 to collect blood for BH4 level assessment. The AAV-u-shGCH1 group demonstrated remarkable improvement in the mechanical withdrawal threshold by PID 28, significantly outperforming the normal, spared nerve injury, and AAV-shCON groups. Plasma BH4 levels confirmed that AAV-u-shGCH1 effectively reduced neuropathic pain by inhibiting BH4 synthesis in vivo, introducing a novel, multispecies-compatible therapeutic strategy. Our results suggest that a single application of AAV-u-shGCH1 could offer a viable solution for neuropathic pain relief.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. In vivo, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3-4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies.

Positron emission tomography (PET) is a highly sensitive, quantitative imaging technique that can track sub-nanomolar quantities of positron-emitting radionuclides throughout the body. By incorporating such radionuclides into molecules of interest, we can directly assess their pharmacokinetic and pharmacodynamic (PK/PD) characteristics in vivo without changing their physicochemical characteristics or eliciting a pharmacological response. As such, PET imaging has long been used as a tool to aid drug discovery programs from preclinical biomarker validation all the way through to clinical trials. In this perspective we discuss the use of PET radioligands in central nervous system (CNS) drug discovery and development, with a focus on recent applications in psychiatry (e.g. 5-HT₂A, 11β-HSD1), neuro-oncology (e.g. KRAS^G12C, ATM, ALK2), and neurodegeneration (e.g. amyloid beta plaques, MAPK p38), while exploring the intricacies associated with developing novel radiotracers for CNS targets. Examples highlight the preclinical and clinical uses of PET for studying biomarker function, drug candidate PK/PD, target occupancy/engagement, dosing regimen determination, clinical trial patient selection, and quantifying biomarker changes in response to treatments.

In the neurological intensive care unit (neuroICU), patients with severe acute brain injury (SABI) are rendered unable to make their own healthcare decisions. The responsibility of making life-or-death decisions, such as goals of care, is carried by surrogate decision-makers, usually families. In addition to the burden of decision-making, the emotional burden on families is further compounded by prognostication uncertainty, time-pressure for decision-making, and difficulties in understanding and interpreting the patient's values and preferences, ultimately resulting in potential clinician-family communication breakdown. Despite these challenges, there is currently no guidance on how to best approach these difficult decisions. Shared decision-making (SDM) has emerged as the recommended approach to improve clinician-family communication, empowering surrogates to take an active role in decision-making by providing a structured framework for information exchange, deliberation, and treatment decisions. Decision aids (DAs) facilitate SDM by offering balanced, accessible, unbiased information and helping surrogates decide according to patients' values. This review highlights the potential advantage of digital over paper-based DAs, including improved accessibility, interactivity, and personalization, and the integration of emerging technologies to enhance DA effectiveness. Additionally, we review the current digital DAs developed for the neuroICU setting.

Molecules with optimized pharmacokinetic properties selectively aimed at the inhibition of STAT3 phosphorylation in brain have recently emerged as potential disease modifying therapies for epilepsy. In the current study, pharmacological inhibition of JAK1/2 with the orally available, FDA-approved drug ruxolitinib, produced nearly complete inhibition of hippocampal STAT3 phosphorylation, and reduced the expression of its downstream target Cyclin D1, when administered to rats 30 ​min and 3 ​h after onset of pilocarpine-induced status epilepticus (SE). This effect was accompanied by significantly shorter seizure duration and lower overall seizure frequency throughout the 4 weeks of EEG recording, but did not completely prevent the development of epilepsy in ruxolitinib-treated male rats. Compared to DMSO-treated animals, administration of ruxolitinib also improved memory (Y maze) but did not impact motor function (open field) following SE. Taken together with our previous findings, the results of this study provide further evidence that inhibition of the JAK/STAT pathway may be a promising disease modifying strategy to reduce severity of acquired epilepsy after brain injury, but also point to the need to better understand and optimize inhibitors of this pathway.

Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, in silico protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery.

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.

This study aims to develop a reliable predictive model for assessing intracranial aneurysm (IA) instability by utilizing four-dimensional flow magnetic resonance imaging (4D-Flow MRI) and high-resolution MRI (HR-MRI). Initially, we curated a prospective dataset, dubbed the primary cohort, by aggregating patient data that was consecutively enrolled across two centers from November 2018 to November 2021. Unstable aneurysms were defined as those with symptoms, morphological change or ruptured during follow-up periods. We introduce a specialized ensemble learning framework, termed the Hybrid Model, which synergistically combines two heterogeneous base learning algorithms: 4D-Flow logistic regression (4D-Flow-LR) and Multi-crop Attention Branch Network (MicroAB-Net). The ability of the hybrid model to predict aneurysm instability was compared with baseline models: PHASES (population, hypertension, age, size, earlier rupture, and site) LR, ELAPSS (earlier subarachnoid hemorrhage, location, age, population, size, and shape) LR, aneurysm wall enhancement (AWE) LR, and Radiomics using the area under the curve (AUC) with Delong's test. Finally, the Hybrid Model was further validated in the validation cohort (patients enrolled between December 2021 to May 2022). In the primary cohort, 189 patients (144 women [76.2 ​%]; aged 58.90 years ​± ​10.32) with 213 IAs were included. In the validation cohort, 48 patients (35 women [72.9 ​%]; aged 55.0 years ​± ​10.77) with 53 IAs were included. The Hybrid Model achieved the highest performance both in the primary cohort (AUC ​= ​0.854) and the validation cohort (AUC ​= ​0.876). The Hybrid model provided a promising prediction of aneurysm instability.