Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis

American Journal of Therapeutics, Journal Year: 2024, Volume and Issue: 31(3), P. e258 - e267

Published: May 1, 2024

Background: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, slurred speech. As disease progresses, difficulty breathing, swallowing, paralysis can lead death. Currently, there are no medications that cure ALS, guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved US Food Drug Administration (FDA) in 2017 as a treatment slow progression ALS. In May 2022, FDA an oral suspension (ORS) formulation edaravone. Mechanism Action: The mechanism action not well defined. However, its neuroprotective effects thought result from antioxidant properties occurring through elimination free radicals. Pharmacokinetics: Edaravone ORS (105 mg) has bioavailability 57% when compared with IV (60 mg). should be taken empty stomach morning, water food beverages, for 1 hour. bound albumin (92%), mean volume distribution 63.1 L, half-life 4.5–9 hours, total clearance 35.9 L/h after intravenous administration. metabolized into nonactive sulfate glucuronide conjugates. Clinical Trials: approval based studies pharmacokinetics, safety, tolerability, ORS. A phase III, global, multicenter, open-label safety study conducted 185 patients ALS over 48 weeks. most reported treatment-emergent adverse events were falls, muscular constipation. Serious included worsening, dysphagia, dyspnea, respiratory failure. Therapeutic advance: Oral self-administered administered caregiver, precluding need administration health care professional institutional setting.

Language: Английский

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Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases

Biomolecules, Journal Year: 2024, Volume and Issue: 14(11), P. 1366 - 1366

Published: Oct. 27, 2024

Individuals affected by neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked onset diseases known, they can explain only a small portion cases. The etiopathology underlying process in most patients is likely due interplay between predisposing environmental factors. Epigenetic mechanisms, DNA methylation, central candidates translating effects factors genome modulation, play critical role etiology AD, PD, ALS. Among main exposures that have been an increased risk accumulating evidence points heavy metals, pesticides, air pollutants. These compounds could trigger neurodegeneration through different mainly neuroinflammation induction oxidative stress. However, suggests also capable inducing epigenetic alterations neurons. In this article, we review available literature linking exposure pollutants methylation changes relevant neurodegeneration.

Language: Английский

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Decoding Neuromuscular Disorders: The Complex Role of Genetic and Epigenetic Regulators

Genes, Journal Year: 2025, Volume and Issue: 16(6), P. 622 - 622

Published: May 23, 2025

Neuromuscular disorders (NMDs), such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and dystrophies (e.g., Duchenne dystrophy, DMD), are primarily driven by genetic mutations but critically modulated epigenetic mechanisms DNA methylation, histone modifications, noncoding RNA activity. These processes contribute to phenotypic variability disease progression, emerging evidence suggests that environmental factors, particularly nutrition exercise, may further influence the molecular pathways modulate these diseases. Dietary bioactive compounds polyphenols omega-3 fatty acids) exhibit modulatory properties, which could mitigate oxidative stress, inflammation, muscle degeneration in NMDs. For example, inhibition of DNMTs HDACs curcumin ALS models promyogenic effects green tea catechins DMD suggest plausible, though still requiring investigation, therapeutic avenues. However, clinical application nutriepigenetic interventions is preliminary requires validation. This review examines interaction factors ALS, SMA, dystrophies, highlighting their combined role heterogeneity Integrative strategies combining gene therapies, modulators, lifestyle offer a multidimensional approach management NMD. A deeper understanding interactions will be essential for advancing precision medicine improving patient outcomes.

Language: Английский

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Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS

Journal of Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 28, 2024

Language: Английский

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Single-cell pan-omics, environmental neurology, and artificial intelligence: the time for holistic brain health research

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(6), P. 1703 - 1704

Published: June 26, 2024

The brain, with its trillions of neural connections, different cellular types, and molecular complexities, presents a formidable challenge for researchers aiming to comprehend the multifaceted nature health. As traditional methods have provided valuable insights, emerging technologies offer unprecedented opportunities delve deeper into underpinnings brain function. In ever-evolving landscape neuroscience, quest unravel mysteries human is bound take leap forward thanks new technological improvements bold interpretative frameworks. Indeed, as our understanding intricacies advances, so does need comprehensive integrative approaches studying health in synergistic manner, bridging gap between biology (e.g., pathways), interactions environmental influences), advanced computational analyses explainable artificial intelligence). Brain health, therefore, not just about function itself; it comprehending complex relational networks surrounding environment (represented by physiological, psychological, or external stimuli) putting this information at service personalized well-being through precision medicine. Advancements whole genome sequencing single-cell revolutionized ability scrutinize individual cells within (Bagger et al., 2024). Techniques such RNA sequencing, epigenomics, proteomics enable capture heterogeneity that exists among drastically levels detail (Zhang By examining gene expression, epigenetic modifications, protein profiles resolution, scientists can diversity (Rizzuti 2023). application omics research offers insights cell states, interactions, providing nuanced development, neurodegenerative disorders, dynamics underlying cognitive functions. Additionally, approach facilitates identification rare populations transitional states may play crucial roles (Kwok lens which was studied could often detect general outlines pathological mechanisms but lacked resolution discern finer features. With omics, we become able detail. So, decipher unique signatures diverse shedding light on also unraveling intricate relationship genes, proteins, modifications influence landscape. scenario, pan-omic applied level (i.e. study totality specific biological molecules collection cells) seem be definitive tool specificities disease, establishing paramount contribution each cell, type alterations, physiological even allowing delineation neuropsychological correlates physical structures activity changes significantly relation psychological change) (Abondio 2024; Groza exist isolation: constantly influenced surroundings operates. Polymorphic factors, ranging from pollutants toxins lifestyle socioeconomic status, contribute interplay shapes Environmental neurology recognizes brains intricately connected what happens around us, both short long term, seeks elucidate how these factors impact molecular, cellular, systemic (Reis Studying determinants requires interdisciplinary collaboration, incorporating expertise science, epidemiology, neuroscience. identifying develop targeted interventions preventive strategies. Integration pan-omics provides further dimension holistic perspective, connecting alterations exposures, paving way conservation. Given all live hyper-accelerated modernity defined rapidly changing natural, socioeconomic, industrial, digital, technological, interpersonal variables, immediate socio-environmental paramount. From air pollution choices, everything leaves an imprint brain: delving exposures neurological extreme only would frame effectors inform willful construction stable environments restorative nurture rather than causing harm (Hachinski sheer volume complexity data generated multidisciplinary necessitate analytical tools. Artificial intelligence (AI), capacity pattern recognition, machine learning, predictive modeling, emerges component analysis high-dimensional datasets (Kim Machine learning algorithms subtle patterns data, associated disease conditions. Integrating AI models enables relationships brain. AI-driven modeling holds potential anticipate individualized risk decline disorders based person's characteristics (Vodovotz Advanced architectures particular interest include deep-learning transformers, been developed primarily natural language processing computer vision context, they used integrated decision-making processes supported neuroimaging (Wang A characteristic feature implies attention mechanism, allows simultaneous input contextualizing analyzed object rest differentially weighting them, most relevant pieces will supply amplified signal throughout model. explosion studies number biopsychosocial considered variables (and merely corrective values simplified equation), responds digital structure helps making sense landscapes. spot eyes might miss; predict certain responses, offering glimpse future (Kalyakulina This, course, demote experience, expertise, clinician, support expert opinion borderline cases. integration pan-omics, neurology, (Figure 1) promise create powerful synergy transcends limitations approaches. This framework examine types response stimuli, uncovering critical underlie variations For example, neuronal subpopulations delineated level, elucidating differential vulnerability stressors. recently paradigm direction exposomics, systematically investigates cell-environment transient life-long significant (Tamiz 2022). behavioral monitoring enacted assess collect discrete continuous while -omic biomarker relay internal exposome response, favoring interpretation mitigation public wider repercussions policy One Health approach, elevating standards healthy ecosystem turn favor healthier living conditions urban rural areas and, extension, individuals (Wood then long-term consequences strategies mitigate adverse effects. Ideally, following delineated: reveal nuances identifies players influencing determines refer community. (precision) medicine stressors affect neurons, predicting risks combination genetic predispositions devising are group people shared characteristics.Figure 1: Integrative research.Schematic representation synergystically Created Adobe Illustrator 2020.While proposed great promise, several challenges must addressed fully realize potential. Technical drawbacks noise limitations, require ongoing refinement, well standardization experimental protocols pipelines, ensuring comparability across studies, repeatability. Moreover, size should analyzed, integrated, stored, managed infrastructures magnitude power. While some material obstacles easier bypass achieve goal integrating omic AI, there algorithmic computation considered. especially new, field crossroads ecology, sciences, biology, faces accurately quantifying characterizing other parameters correctors, predictive, generative models. Developing databases catalog their essential advancing field. reference intelligence, ethical concerns, interpretability models, robust validation present challenges; particular, responsible transparent use imperative foster trust results applications. conclusion, heralds promising era research. connections determinants, influences, outcomes. technology continues advance, deepen pave embracing environment, move closer ultimately contributing development therapies range It recognize potentials limitations) reshaping perceive prioritize experience benefit individual, Open peer reviewer:Shouneng Peng, Icahn School Medicine Mount Sinai, USA. Additional file:Open review report 1.P-Reviewer: Peng S; C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Language: Английский

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BV2 Microglial Cell Activation/Polarization Is Influenced by Extracellular Vesicles Released from Mutated SOD1 NSC-34 Motoneuron-like Cells

Biomedicines, Journal Year: 2024, Volume and Issue: 12(9), P. 2069 - 2069

Published: Sept. 11, 2024

Microglia-mediated neuroinflammation is a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) as it can contribute to progressive degeneration motor neurons (MNs). Here, we investigated role mSOD1 NSC-34 MN-like cell-derived extracellular vesicles (EVs) inducing activation BV2 microglial cells. NSC-34-released EVs were isolated by culture medium differential ultracentrifugation obtain two fractions, one containing small (diameter < 200 nm) and other large > nm). cells incubated with EV fractions for 12, 24, 48 h evaluate 1) state inflammation through RT-PCR IL-1β, IL-6, IL-4, IL-10 2) expression proteins involved inflammasome (IL-β caspase 1), cell death (caspase 3), glial recruitment (CXCR1), presence TGFβ cytokine receptor (TGFβ-R2). The obtained results suggest type-dependent polarization towards an early neurotoxic phenotype late neuroprotective status, appearance mixed M1 M2 microglia subpopulations. A significant driving played TGFβ/CX3CR1 axis. Therefore, targeting dysregulated response modulating could hold promise therapeutic strategy ALS.

Language: Английский

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Pyroptosis in Lung Cancer: The Emerging Role of Non-Coding RNAs

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 263, P. 155619 - 155619

Published: Sept. 28, 2024

Language: Английский

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L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 180, P. 117588 - 117588

Published: Oct. 19, 2024

Language: Английский

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Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes

Genes, Journal Year: 2024, Volume and Issue: 15(11), P. 1431 - 1431

Published: Nov. 2, 2024

Background/Objectives: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, excitotoxicity. The frontal cortex crucial for action initiation, planning, voluntary movements whereas spinal cord facilitates communication with brain, walking, reflexes. By investigating transcriptome data from cord, we aim elucidate common pathological mechanisms pathways involved in ALS understanding disease progression identifying potential therapeutic targets. Methods: In this study, quantified gene transcript expression patterns, predicted variants, assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing interaction networks, performing enrichment analysis. Results: We found novel genes upregulation immune response, downregulation metabolic-related defective degradation processes both cortex. Additionally, observed dysregulation histone regulation blood pressure-related specifically Conclusions: These results highlight distinct shared molecular disruptions ALS, emphasizing critical roles response metabolic dysfunction degeneration. Targeting these may provide new avenues combat neurodegeneration preserve health.

Language: Английский

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