Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis

Thierry Bordet, Bruno Buisson, Magali Michaud, Cyrille Drouot, Pascale Galéa, Pierre Delaage, Natalia P. Akentieva, Alex S. Evers, Douglas F. Covey, Mariano A. Ostuni, Jean Jacques Lacapère, Charbel Massaad, Michael Schumacher, Esther Marie Steidl, Delphine Maux, Michel Delaage, Christopher E. Henderson, Rebecca M. Pruss

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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 SOD1G93A 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.

Original languageEnglish
Pages (from-to)709-720
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number2
DOIs
StatePublished - Aug 2007

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    Bordet, T., Buisson, B., Michaud, M., Drouot, C., Galéa, P., Delaage, P., Akentieva, N. P., Evers, A. S., Covey, D. F., Ostuni, M. A., Lacapère, J. J., Massaad, C., Schumacher, M., Steidl, E. M., Maux, D., Delaage, M., Henderson, C. E., & Pruss, R. M. (2007). Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. Journal of Pharmacology and Experimental Therapeutics, 322(2), 709-720. https://doi.org/10.1124/jpet.107.123000