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NEUROPHARMACOLOGY

Identification and Characterization of Cholest-4-en-3-one, Oxime (TRO19622), a Novel Drug Candidate for Amyotrophic Lateral Sclerosis

Trophos, Parc Scientifique de Luminy case 931, Marseille, France (T.B., B.B., M.M., C.D., P.G., P.D., E.-M.S., D.M., M.D., R.M.P.); Washington University School of Medicine, St. Louis, Missouri (N.P.A., A.S.E., D.F.C.); U773 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Biologique Bichat Beaujeon (CRB3), Université Paris 7, Facultéde Médecine Bichat, Paris, France (M.A.O., J.-J.L.); Unité Mixte de Recherche 788, Institut National de la Santé etdela Recherche Médicale, Université Paris 11, Le Kremlin-Bicêtre, France (C.M., M.S.); and Unité Mixte de Recherche 623, Institut National de la Santé et de la Recherche Médicale, Parc Scientifique de Luminy, Marseille, France (C.E.H.)

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.

Address correspondence to: Dr. Thierry Bordet, Trophos, Parc Scientifique de Luminy, Case 931, 13288 Marseille Cedex 9, France. E-mail: tbordet{at}trophos.com

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				T. Bordet, B. Buisson, M. Michaud, J.-L. Abitbol, F. Marchand, J. Grist, E. Andriambeloson, M. Malcangio, and R. M. Pruss Specific Antinociceptive Activity of Cholest-4-en-3-one, Oxime (TRO19622) in Experimental Models of Painful Diabetic and Chemotherapy-Induced Neuropathy J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 623 - 632. [Abstract] [Full Text] [PDF]