Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations
Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier end...
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Elsevier
2017
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| Online Access: | https://eprints.nottingham.ac.uk/44278/ |
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| author | Elmorsy, Ekramy Al-Ghafari, Ayat Almutairi, Fahd M. Aggour, Amal Misbah Carter, Wayne |
| author_facet | Elmorsy, Ekramy Al-Ghafari, Ayat Almutairi, Fahd M. Aggour, Amal Misbah Carter, Wayne |
| author_sort | Elmorsy, Ekramy |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1–100 μM. At therapeutic concentrations (0.1 μM) no significant cytotoxicity was observed after 4, 24, or 48 h. At high therapeutic to overdose concentrations (1–100 μM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1 μM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~ 50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5 μM) and clomipramine (5.5 μM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants. |
| first_indexed | 2025-11-14T19:54:59Z |
| format | Article |
| id | nottingham-44278 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:54:59Z |
| publishDate | 2017 |
| publisher | Elsevier |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-442782020-05-04T19:14:36Z https://eprints.nottingham.ac.uk/44278/ Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations Elmorsy, Ekramy Al-Ghafari, Ayat Almutairi, Fahd M. Aggour, Amal Misbah Carter, Wayne Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1–100 μM. At therapeutic concentrations (0.1 μM) no significant cytotoxicity was observed after 4, 24, or 48 h. At high therapeutic to overdose concentrations (1–100 μM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1 μM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~ 50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5 μM) and clomipramine (5.5 μM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants. Elsevier 2017-10-31 Article PeerReviewed Elmorsy, Ekramy, Al-Ghafari, Ayat, Almutairi, Fahd M., Aggour, Amal Misbah and Carter, Wayne (2017) Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations. Toxicology in Vitro, 44 . pp. 154-163. ISSN 1879-3177 Antidepressants; Blood brain barrier; Cytotoxicity; Oxidative stress; Genotoxicity; Antioxidants http://www.sciencedirect.com/science/article/pii/S0887233317301972 doi:10.1016/j.tiv.2017.07.011 doi:10.1016/j.tiv.2017.07.011 |
| spellingShingle | Antidepressants; Blood brain barrier; Cytotoxicity; Oxidative stress; Genotoxicity; Antioxidants Elmorsy, Ekramy Al-Ghafari, Ayat Almutairi, Fahd M. Aggour, Amal Misbah Carter, Wayne Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title | Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title_full | Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title_fullStr | Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title_full_unstemmed | Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title_short | Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| title_sort | antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations |
| topic | Antidepressants; Blood brain barrier; Cytotoxicity; Oxidative stress; Genotoxicity; Antioxidants |
| url | https://eprints.nottingham.ac.uk/44278/ https://eprints.nottingham.ac.uk/44278/ https://eprints.nottingham.ac.uk/44278/ |