Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate
| Autor: | Laura Emily Clemensson, Helgi B. Schiöth, Huu Phuc Nguyen, Jonasz J. Weber |
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| Rok vydání: | 2019 |
| Předmět: |
Voltage-dependent anion channel
medicine.disease_cause Biochemistry Neuroprotection Mitochondrial Transmembrane Permeability-Driven Necrosis Mice chemistry.chemical_compound medicine Animals Homeostasis Humans Amyotrophic lateral sclerosis Cholestenones Pharmacology biology Calpain business.industry Neurodegeneration Neurodegenerative Diseases Spinal muscular atrophy medicine.disease Mitochondria Rats Oxidative Stress Cholesterol Neuroprotective Agents chemistry Mitochondrial permeability transition pore biology.protein Olesoxime Calcium business Neuroscience Oxidative stress |
| Zdroj: | Biochemical Pharmacology. 168:305-318 |
| ISSN: | 0006-2952 |
| Popis: | Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime’s neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime’s potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime’s action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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