Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics

Despite advances in intravenous thrombolysis and endovascular thrombectomy, numerous acute ischemic stroke survivors continue to experience various disability levels. The nitric oxide (NO) donor, Glyceryl Trinitrate (GTN), has been identified as a potential neuroprotective agent against ischemic damage. We evaluated the safety and feasibility of intravenous GTN in AIS patients. Subsequently, we conducted a secondary analysis to assess for possible efficacy of GTN as a neuroprotectant. We conducted a prospective, double-blind, randomized controlled trial in the Stroke Intervention & Translational Center (SITC) in Beijing Luhe Hospital, Capital Medical University (ChiCTR2100046271)...

No abstract text is available yet for this article.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors...

Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role of lysosomal dysfunction in epilepsy, which can lead to the accumulation of toxic substrates and impaired autophagy in neurons. Our focus is on phosphodiesterase-4 (PDE4), an enzyme that plays a crucial role in regulating intracellular cyclic adenosine monophosphate (cAMP) levels by converting it into adenosine monophosphate (AMP). In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses...

Deep brain stimulation (DBS) is an established therapeutic tool for the treatment of Parkinson's disease (PD). The mechanisms of DBS for PD are likely rooted in modulation of the subthalamo-pallidal network. However, it can be difficult to electrophysiologically interrogate that network in human patients. The recent identification of large amplitude evoked potential (EP) oscillations from DBS in the subthalamic nucleus (STN) or globus pallidus internus (GPi) are providing new scientific opportunities to expand understanding of human basal ganglia network activity...

Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action...

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction...

Recently, we showed that high-definition transcranial direct current stimulation (hd-tDCS) can acutely reduce epileptic spike rates during and after stimulation in refractory status epilepticus (RSE), with a greater likelihood of patient discharge from the intensive care unit compared to historical controls. We investigate whether electroencephalographic (EEG) desynchronization during hd-tDCS can help account for observed anti-epileptic effects. Defining desynchronization as greater power in higher frequencies such as above 30 ​Hz ("gamma") and lesser power in frequency bands lower than 30 ​Hz, we analyzed 27 EEG sessions from 10 RSE patients who had received 20-minute session(s) of 2-milliamperes of transcranial direct current custom-targeted at the epileptic focus as previously determined by a clinical EEGer monitoring the EEG in real-time...

Deep Brain Stimulation (DBS) has become a pivotal therapeutic approach for Parkinson's Disease (PD) and various neuropsychiatric conditions, impacting over 200,000 patients. Despite its widespread application, the intricate mechanisms behind DBS remain a subject of ongoing investigation. This article provides an overview of the current knowledge surrounding the local, circuit, and neurobiochemical effects of DBS, focusing on the subthalamic nucleus (STN) as a key target in PD management. The local effects of DBS, once thought to mimic a reversible lesion, now reveal a more nuanced interplay with myelinated axons, neurotransmitter release, and the surrounding microenvironment...

Postural instability is a detrimental and often treatment-refractory symptom of Parkinson's disease. While many existing studies quantify the biomechanical deficits among various postural domains (static, anticipatory, and reactive) in this population, less is known regarding the neural network dysfunctions underlying these phenomena. This review will summarize current studies on the cortical and subcortical neural activities during postural responses in healthy subjects and those with Parkinson's disease...

Driven by the scarcity of effective treatment options in clinical settings, the present study aimed to identify a new potential target for Alzheimer's disease (AD) treatment. We focused on Lars2, an enzyme synthesizing mitochondrial leucyl-tRNA, and its role in maintaining mitochondrial function. Bioinformatics analysis of human brain transcriptome data revealed downregulation of Lars2 in AD patients compared to healthy controls. During in vitro experiments, the knockdown of Lars2 in mouse neuroblastoma cells (neuro-2a cells) and primary cortical neurons led to morphological changes and decreased density in mouse hippocampal neurons...

Berberine (BBR) has demonstrated potent anti-inflammatory effects by modulating macrophage polarization. Nevertheless, the precise mechanisms through which berberine regulates post-injury inflammation within the peripheral nerve system remain elusive. This study seeks to elucidate the role of BBR and its underlying mechanisms in inflammation following peripheral nerve injury (PNI). Adult male C57BL/6J mice subjected to PNI were administered daily doses of berberine (0, 60, 120, 180, 240 ​mg/kg) via gavage from day 1 through day 28...

No abstract text is available yet for this article.

In the landscape of paediatric epilepsy treatment, over 20 anti-seizure medications (ASMs) have gained approval from Drug Regulatory Agencies, each delineating clear indications. However, the complexity of managing drug-resistant epilepsy often necessitates the concurrent use of multiple medications. This therapeutic challenge highlights a notable gap: the absence of standardized guidelines, compelling clinicians to rely on empirical clinical experience when selecting combination therapies. This comprehensive review aims to explore current evidence elucidating the preferential utilization of specific ASMs or their combinations, with a primary emphasis on pharmacodynamic considerations...

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties...

Novel therapeutics for the treatment of ischemic stroke remains to be the unmet clinical needs. Previous studies have indicated that salvianolic acid A (SAA) is a promising candidate for the treatment of the brain diseases. However, SAA has poor absolute bioavailability and does not efficiently cross the intact blood-brain barrier (BBB), which limit its efficacy. To this end we developed a brain-targeted liposomes for transporting SAA via the BBB by incorporating the liposomes to a transport receptor, insulin-like growth factor-1 receptor (IGF1R)...

Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022...

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration...

Therapeutic hypothermia is the standard of care for hypoxic-ischemic (HI) encephalopathy. Inter-alpha Inhibitor Proteins (IAIPs) attenuate brain injury after HI in neonatal rats. Human (h) IAIPs (60 ​mg/kg) or placebo (PL) were given 15 ​min, 24 and 48 ​h to postnatal (P) day-7 rats after carotid ligation and 8% oxygen for 90 ​min with (30 ​°C) and without (36 ​°C) exposure to hypothermia 1.5 ​h after HI for 3 ​h...

Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS...