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1دورية أكاديمية
المؤلفون: JingSi Jiang, Yan Wang, Min Deng
المصدر: Frontiers in Pharmacology, Vol 13 (2022)
مصطلحات موضوعية: amyotrophic lateral sclerosis, amyotrophic lateral sclerosis∗/drug therapy, amyotrophic lateral sclerosis∗/genetics, clinical trials as topic, drug development, Therapeutics. Pharmacology, RM1-950
الوصف: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. In the recent past, there have been just two drugs approved for treatment, riluzole and edaravone, which only prolong survival by a few months. However, there are many novel experimental drugs in development. In this review, we summarize 53 new drugs that have been evaluated in clinical trials from 2020 to 2022, which we have classified into eight mechanistic groups (anti-apoptotic, anti-inflammatory, anti-excitotoxicity, regulated integrated stress response, neurotrophic factors and neuroprotection, anti-aggregation, gene therapy and other). Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone.
وصف الملف: electronic resource
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المؤلفون: Fay Probert, Anna Gorlova, Alexei Deikin, Lucien Bettendorff, Ekaterina Veniaminova, Andrey Nedorubov, Kirill D. Chaprov, Tamara A. Ivanova, Daniel C. Anthony, Tatyana Strekalova
المساهمون: Basic Neuroscience 1, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie
المصدر: Biomedicine & Pharmacotherapy, 156:113986. Elsevier Masson
مصطلحات موضوعية: Pharmacology, Thiamine/pharmacology, Glycogen Synthase Kinase 3 beta, Amyotrophic Lateral Sclerosis, RNA, Messenger/metabolism, Mice, Transgenic, Messenger/metabolism, General Medicine, Glycogen Synthase Kinase 3 beta/metabolism, Transgenic, Amyotrophic Lateral Sclerosis/drug therapy, Mice, Muscular Atrophy, Metabolome, RNA-Binding Protein FUS, Animals, RNA, Thiamine, RNA, Messenger, RNA-Binding Protein FUS/genetics
الوصف: Mutations in the gene encoding the RNA/DNA-binding protein Fused in Sarcoma (FUS) have been detected in familial amyotrophic lateral sclerosis (ALS) patients. FUS has been found to be a critical component of the oxidative damage repair complex that might explain its role in neurodegeneration. Here, we examined what impact antioxidant treatment with thiamine (vitamine B1), or its more bioavailable derivative O,S-dibenzoylthiamine (DBT), would have on the hallmarks of pathology in the FUS[1-359]-transgenic mouse model of ALS. From 8-weeks old, in the pre-symptomatic phase of disease, animals received either thiamine, DBT (200 mg/kg/day), or vehicle for 6 weeks. We examined physiological, behavioral, molecular and histological outcomes, as well as the serum metabolome using nuclear magnetic resonance (NMR). The DBT-treated mice displayed improvements in physiological outcomes, motor function and muscle atrophy compared to vehicle, and the treatment normalized levels of brain glycogen synthase kinase-3β (GSK-3β), GSK-3β mRNA and IL-1β mRNA in the spinal cord. Analysis of the metabolome revealed an increase in the levels of choline and lactate in the vehicle-treated FUS mutants alone, which is also elevated in the cerebrospinal fluid of ALS patients, and reduced glucose and lipoprotein concentrations in the FUS[1-359]-tg mice, which were not the case in the DBT-treated mutants. The administration of thiamine had little impact on the outcome measures, but it did normalize circulating HDL levels. Thus, our study shows that DBT therapy in FUS mutants is more effective than thiamine and highlights how metabolomics may be used to evaluate therapy in this model.
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المصدر: Chemico-Biological Interactions. 352
مصطلحات موضوعية: Noscapine, Bradykinin/metabolism, NF-KAPPA-B, Oligodendroglia/drug effects, MECHANISMS, Multiple sclerosis, CEREBROSPINAL-FLUID, Signal Transduction/drug effects, Neurodegenerative Diseases/drug therapy, Receptors, Histamine Antagonists/pharmacology, Ion Channels/drug effects, INJURY, Animals, Humans, Immunomodulating Agents/pharmacology, Alzheimer 's disease, CA2+-ACTIVATED K+ CHANNELS, NF-KappaB, G-Protein-Coupled/metabolism, Alzheimer Disease/drug therapy, RECEPTOR, Amyotrophic lateral sclerosis, Mental Disorders/drug therapy, Parkinson 's disease, Amyotrophic Lateral Sclerosis/drug therapy, Multiple Sclerosis/drug therapy, Parkinsonian Disorders/drug therapy, INHIBITORS, Neuroprotective Agents/pharmacology, Stroke/drug therapy, Noscapine/administration & dosage
الوصف: Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.
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المؤلفون: Meric A. Altinoz, Sinan Guloksuz, Aysel Ozpinar
المصدر: Chemico-biological interactions. 352
مصطلحات موضوعية: Noscapine, Bradykinin/metabolism, Multiple Sclerosis, NF-KAPPA-B, Histamine Antagonists, Oligodendroglia/drug effects, Toxicology, Bradykinin, Ion Channels, MECHANISMS, Receptors, G-Protein-Coupled, Immunomodulating Agents, CEREBROSPINAL-FLUID, Parkinsonian Disorders, Alzheimer Disease, Signal Transduction/drug effects, Neurodegenerative Diseases/drug therapy, Receptors, Histamine Antagonists/pharmacology, Ion Channels/drug effects, INJURY, Animals, Humans, Immunomodulating Agents/pharmacology, Alzheimer 's disease, CA2+-ACTIVATED K+ CHANNELS, NF-KappaB, G-Protein-Coupled/metabolism, Alzheimer Disease/drug therapy, RECEPTOR, Mental Disorders, Amyotrophic Lateral Sclerosis, Neurodegenerative Diseases, General Medicine, Mental Disorders/drug therapy, Parkinson 's disease, Amyotrophic Lateral Sclerosis/drug therapy, Stroke, Oligodendroglia, Neuroprotective Agents, Multiple Sclerosis/drug therapy, Parkinsonian Disorders/drug therapy, INHIBITORS, Neuroprotective Agents/pharmacology, Stroke/drug therapy, Noscapine/administration & dosage, Signal Transduction
الوصف: Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.
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5دورية أكاديمية
المصدر: Neurology, 57 (5), 897-9 (2001)
مصطلحات موضوعية: Action Potentials/physiology, Adult, Aged, Amyotrophic Lateral Sclerosis/drug therapy/physiopathology, Humans, Median Nerve/physiology, Middle Aged, Muscular Atrophy/physiopathology, Neuroprotective Agents/therapeutic use, Prognosis, Prospective Studies, Riluzole/therapeutic use, Transcutaneous Electric Nerve Stimulation/methods, Human health sciences, Neurology, Sciences de la santé humaine, Neurologie
الوصف: Decrement of the thenar compound muscle action potentials (CMAP), after repetitive nerve stimulation (RNS) of the median nerve at 3 Hz, was evaluated in patients with ALS before riluzole therapy. CMAP size as well as motor unit number and size estimates were evaluated twice before and after 1 year of riluzole therapy. The correlation between decrement and CMAP size reduction per year was highly significant (r = 0.77), but no relationship could be demonstrated between decrement and other variables. The authors thus propose that decrement after RNS may be used as a predictor of further drop in CMAP size.
Relation: urn:issn:0028-3878; urn:issn:1526-632X
URL الوصول: https://orbi.uliege.be/handle/2268/116773
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6دورية أكاديمية
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المؤلفون: Aebischer, P., Schluep, M., Deglon, N., Joseph, J. M., Hirt, L., Heyd, B., Goddard, M., Hammang, J. P., Zurn, A. D., Kato, A. C., Regli, F., Baetge, E. E.
مصطلحات موضوعية: Amyotrophic Lateral Sclerosis/ drug therapy/ genetics/therapy, Cell Transplantation/methods, Spinal, Lumbar Vertebrae/surgery, Kidney/cytology/physiology, fluid/ therapeutic use, Injections, Genetic Vectors/chemistry/genetics, Drug Implants/administration & dosage/ chemistry, Gene Therapy/methods, Recombinant Proteins/administration & dosage/biosynthesis/therapeutic use, Cricetinae, Animals, Humans, Ciliary Neurotrophic Factor, Nerve Tissue Proteins/ administration & dosage/cerebrospinal
الوصف: Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=od_______185::683f5dc6d3b3a7f334132c9609f6d913
https://infoscience.epfl.ch/record/101228 -
8دورية أكاديمية
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9دورية أكاديمية
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10دورية أكاديمية
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