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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

Authors

Ekramy Elmorsy

Ayat Al-Ghafari

Fahd M. Almutairi

Amal Misbah Aggour

Wayne Carter



Abstract

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.

Journal Article Type Article
Publication Date Oct 31, 2017
Journal Toxicology in Vitro
Print ISSN 0887-2333
Electronic ISSN 1879-3177
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 44
APA6 Citation Elmorsy, E., Al-Ghafari, A., Almutairi, F. M., Aggour, A. M., & Carter, W. (2017). Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations. Toxicology in Vitro, 44, doi:10.1016/j.tiv.2017.07.011
DOI https://doi.org/10.1016/j.tiv.2017.07.011
Keywords Antidepressants; Blood brain barrier; Cytotoxicity; Oxidative stress; Genotoxicity; Antioxidants
Publisher URL http://www.sciencedirect.com/science/article/pii/S0887233317301972
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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