Apomorphine rescues reactive oxygen species-induced apoptosis of fibroblasts with mitochondrial disease
| Autor: | Hitoshi Osaka, Takeshi Kouga, Takaaki Abe, Eriko F. Jimbo, Takanori Yamagata, Akihiko Miyauchi, Tetsuro Matsuhashi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Programmed cell death Growth Differentiation Factor 15 Adolescent Apomorphine Mitochondrial disease Apoptosis Pharmacology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine MELAS Syndrome Humans Medicine Idebenone Molecular Biology chemistry.chemical_classification Reactive oxygen species business.industry TOR Serine-Threonine Kinases Infant Newborn Cell Biology Fibroblasts medicine.disease 030104 developmental biology chemistry Child Preschool Lactic acidosis Molecular Medicine Female Leigh Disease Reactive Oxygen Species business Biomarkers 030217 neurology & neurosurgery Oxidative stress medicine.drug |
| Zdroj: | Mitochondrion. 49:111-120 |
| ISSN: | 1567-7249 |
| DOI: | 10.1016/j.mito.2019.07.006 |
| Popis: | Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease. |
| Databáze: | OpenAIRE |
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