title: Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Trophos, Parc Scientifique de Luminy, Marseille Cedex , France. tbordet@trophos.com
authors.forename: Thierry
authors.initials: T
authors.lastname: Bordet
authors.forename: Bruno
authors.initials: B
authors.lastname: Buisson
authors.forename: Magali
authors.initials: M
authors.lastname: Michaud
authors.forename: Cyrille
authors.initials: C
authors.lastname: Drouot
authors.forename: Pascale
authors.initials: P
authors.lastname: Galéa
authors.forename: Pierre
authors.initials: P
authors.lastname: Delaage
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Akentieva
authors.forename: Alex S
authors.initials: AS
authors.lastname: Evers
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Ostuni
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lacapère
authors.forename: Charbel
authors.initials: C
authors.lastname: Massaad
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Esther-Marie
authors.initials: EM
authors.lastname: Steidl
authors.forename: Delphine
authors.initials: D
authors.lastname: Maux
authors.forename: Michel
authors.initials: M
authors.lastname: Delaage
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D049108:Cell Enlargement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002783:Cholestenones / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: C463819:Bzrp protein, mouse; D002783:Cholestenones; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D018079:Receptors, GABA; D050994:Voltage-Dependent Anion Channels; D045304:Cytochromes c; C522838:olesoxime; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1