Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis.
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.
Bordet
Thierry
T
Trophos, Parc Scientifique de Luminy, Marseille Cedex , France. tbordet@trophos.com
Buisson
Bruno
B
Michaud
Magali
M
Drouot
Cyrille
C
Galéa
Pascale
P
Delaage
Pierre
P
Akentieva
Natalia P
NP
Evers
Alex S
AS
Covey
Douglas F
DF
Ostuni
Mariano A
MA
Lacapère
Jean-Jacques
JJ
Massaad
Charbel
C
Schumacher
Michael
M
Steidl
Esther-Marie
EM
Maux
Delphine
D
Delaage
Michel
M
Henderson
Christopher E
CE
Pruss
Rebecca M
RM
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
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