The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson’s disease
| Autor: | Kiyoshi Fukuhara, Yuki Yada, Yusuke Hiraku, Mariko Murata, Hatasu Kobayashi, Saeko Tada-Oikawa, Shinji Oikawa |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Time Factors Tyrosine 3-Monooxygenase DNA damage Tetrazolium Salts Apoptosis Caspase 3 Biology Biochemistry Neuroblastoma Cellular and Molecular Neuroscience chemistry.chemical_compound Salsoline Alkaloids Cell Line Tumor Tetrahydroisoquinolines Norsalsolinol Internal medicine Benzoquinones medicine Humans Neurotoxin chemistry.chemical_classification Reactive oxygen species Dose-Response Relationship Drug Tetrahydroisoquinoline Cytochrome c Cytochromes c Deoxyguanosine Phosphorus Isotopes Free Radical Scavengers NAD Cell biology Thiazoles Endocrinology chemistry 8-Hydroxy-2'-Deoxyguanosine biology.protein Autoradiography Copper DNA Damage Phenanthrolines |
| Zdroj: | Journal of Neurochemistry. 108:397-407 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2008.05774.x |
| Popis: | Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells. |
| Databáze: | OpenAIRE |
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