Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis
| Autor: | Esther-Marie Steidl, Christopher E. Henderson, Mariano A. Ostuni, Natalia P. Akentieva, Rebecca M. Pruss, Magali Michaud, Michel Delaage, Pascale Galéa, Bruno Buisson, Cyrille Drouot, Charbel Massaad, Jean-Jacques Lacapère, Thierry Bordet, Delphine Maux, Douglas F. Covey, Michael Schumacher, Pierre Delaage, Alex S. Evers |
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| Rok vydání: | 2007 |
| Předmět: |
Programmed cell death
Cell Survival Mice Transgenic Pharmacology Cell Enlargement Neuroprotection Binding Competitive Rats Sprague-Dawley chemistry.chemical_compound Mice Superoxide Dismutase-1 Receptors GABA In vivo medicine Translocator protein Animals Voltage-Dependent Anion Channels Nerve Growth Factors Amyotrophic lateral sclerosis Cells Cultured Cholestenones Motor Neurons biology Superoxide Dismutase Amyotrophic Lateral Sclerosis Cytochromes c Motor neuron medicine.disease Sciatic Nerve Survival Analysis Mitochondria Nerve Regeneration Rats Mice Inbred C57BL medicine.anatomical_structure Neuroprotective Agents chemistry Mitochondrial permeability transition pore Animals Newborn biology.protein Molecular Medicine Olesoxime Female Neuroscience |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 322(2) |
| ISSN: | 0022-3565 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1 G93A transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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