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.
Footnotes
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This work was supported by the Association Française contre les Myopathies.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123000.
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ABBREVIATIONS: ALS, amyotrophic lateral sclerosis; SOD, superoxide dismutase; TRO19622, cholest-4-en-3-one, oxime; CsA, cyclosporine A; DMSO, dimethyl sulfoxide; AM, acetoxymethyl ester; PK11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline carboxamide; TSPO, translocator protein 18 kDa; VDAC, voltage-dependent anion channel; 6-AziP, 6-azi-3α-hydroxy-5β-pregnan-20-one; CGC, cerebellar granule cell; PR, progesterone receptor; CMAP, compound muscle action potential; mPTP, mitochondrial permeability transition pore; R-5020, 17α,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione; h, human; 3α5β-TH PROG, 3α-hydroxy-5β-pregnan-20-one; 3α5α-TH PROG, 3α-hydroxy-5α-pregnan-20-one.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York.
- Received March 20, 2007.
- Accepted May 10, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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