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 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.Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that selectively affects motor neurons in the spinal cord, brainstem, and cortex. ALS affects people of all races and ethnic backgrounds with an incidence approximately 2 per 100,000 individuals (McGuire and Nelson, 2006). The onset of ALS is most common in the 55 to 75 year age range, and incidence rises with advancing age; men have a higher risk of developing the disease than women (Nelson, 1995). Common clinical features of ALS include muscle weakness and fasciculations. These occur predominantly in limbs, although bulbar onset pathology can also lead to tongue atrophy and dysphagia. Failure of the respiratory muscles and cardiac complications are generally the fatal event, occurring within an average of 3 years of disease onset, with only a 5% chance of survival 5 years after diagnosis (del Aguila et al., 2003). Although 5 to 10% of ALS This work was supported by the Association Française contre les Myopathies.1 Current affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York.Article, publication date, and citation information can be found at

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…Lovastatin, a cholesterol synthesis inhibitor, decreased alpha-synuclein aggregation and pathology in the Thy1-aSyn mice [86]. Interestingly, the cholesterol-oximes TRO19622 and TRO40303, 2 drugs that target outer mitochondrial membrane proteins and are cytoprotective in several cell and animal models involving oxidative stress, trophic factor withdrawal, and Fas (TNF receptor superfamily, member 6)-induced death pathways [87][88][89], normalized a number of transcriptome anomalies observed in laser-captured nigrostriatal dopaminergic neurons of young Thy1-aSyn mice after 3 months of administration in food [90]. Finally, we have investigated whether increasing the stability, trafficking, and activity of glucocerebrosidase with the pharmacological chaperone afegostat-tartrate (AT2101) in mice that over-express human wild-type alpha-synuclein (Thy1-aSyn mice) could be a therapeutic approach for synucleinopathies.…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…131 Daily oral administration of olesoxime improved motor nerve conduction impaired in streptozotocin-induced diabetic rats and also reversed neuropathic pain behavior as early as the first administration. 133 Olesoxime also reversed tactile allodynia in chemotherapy-induced (vincristine-induced) painful peripheral neuropathy, but had had no analgesic activity per se in formalin-or chronic constriction injury-mediated neuropathic pain models.…”

“…Identified for its survival-promoting properties for motor neurons in culture, 131 olesoxime has been shown to inhibit both intrinsic and extrinsic neuronal death pathways (unpublished data). Beyond neuroprotective properties, olesoxime also promoted nerve regeneration in a number of in vitro and in vivo models of neurodegeneration.…”

Spinal Muscular Atrophy: Journeying From Bench to Bedside

“…However, its effect on the SMA phenotype of model mice was modest at best, and it is unlikely that such compounds hold sufficient promise to advance to clinical trials for SMA. Pharmacologic agents whose therapeutic action is independent of SMN expression have also received attention [100,101]. Olesoxime, a neuroprotective agent reported to target the mitochondrial permeability pore is emerging in European clinical trials as one promising candidate in the treatment of SMA [100].…”