Sunitinib-induced oxidative imbalance and retinotoxic effects in rats
| Autor: | Claudia Reyes-Goya, Oscar Aramburu, Alfonso Mate, Álvaro Santana-Garrido, Carmen Vázquez, Helder André |
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| Přispěvatelé: | Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (España), European Commission |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male genetic structures Glutathione reductase Ocular side effects Pharmacology medicine.disease_cause 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Antioxidants Retina Superoxide dismutase 03 medical and health sciences 0302 clinical medicine medicine Sunitinib Animals General Pharmacology Toxicology and Pharmaceutics Rats Wistar Protein Kinase Inhibitors chemistry.chemical_classification Oxidase test Glutathione Peroxidase NADPH oxidase biology Chemistry Superoxide Dismutase Glutathione peroxidase NOX4 NADPH Oxidases General Medicine eye diseases Rats Oxidative Stress 030104 developmental biology Glutathione Reductase Oxidative stress NOX1 biology.protein sense organs |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | [Aims] Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals. [Main methods] Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR. [Key findings] NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase. [Significance] This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions. This study was supported by Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (2017/00000440; CTS-584). AS is recipient of an FPU predoctoral fellowship from Ministerio de Ciencia, Innovación y Universidades (FPU17/03465). CR-G was supported by Ministerio de Ciencia, Innovación y Universidades, Ayudas para la Promoción de Empleo Joven e Implantación de la Garantía Juvenil en I+D+i 2017-2020 (PEJ2018-004474-A). |
| Databáze: | OpenAIRE |
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