Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier

Elmorsy, Ekramy; Elzalabany, Laila M.; Elsheikha, Hany M.; Smith, Paul A.

Abstract

© 2014 Elsevier B.V. All rights reserved. Although the mechanisms of action of antipsychotics (APs) on neuronal function are well understood, very little is known about their effects on cells of the blood-brain barrier (BBB); one function of which is to limit the access of these amphiphilic compounds to the central nervous system. To address this question we have investigated the cytological and functional effects of four APs: chlorpromazine (CLP), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ), at concentrations typical of high therapeutic dosage on a human brain microvascular endothelial cell (HBMEC) model of the BBB. At ~ 10 mM all four APs impaired the ability of HBMECs to reduce MTT which was followed by decreased Trypan blue exclusion and increased Lactate dehydrogenase release. These effects were associated with oxidative stress which was partly reversed by incubation in 10 mM glutathione. At their EC50 concentrations for MTT reduction, all four APs disrupted cellular ultrastruc- Ture and morphology. HAL, CPZ and CLZ increased Caspase -3, -8 and -9 activity, chromatin condensation and fragmentation, data indicative of apoptosis. These events were associated with decreased transcytosis of Evans blue and increased transendothelial potential difference and electrical resistance of this BBB model. These findings suggest that at high therapeutic concentrations, CPZ and CLZ are likely to incur cytoxic effects and apoptosis of BBB endothelia with an impairment of barrier functionality. Such events may underlie the aetiology of neuroleptic associated cerebral oedema and neuroleptic malignant syndrome.

Citation

Elmorsy, E., Elzalabany, L. M., Elsheikha, H. M., & Smith, P. A. (2014). Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier. Brain Research, 1583(1), 255-268. https://doi.org/10.1016/j.brainres.2014.08.011

• Journal Article Type: Article
• Acceptance Date: Aug 7, 2014
• Online Publication Date: Aug 16, 2014
• Publication Date: Oct 2, 2014
• Deposit Date: Jun 1, 2017
• Publicly Available Date: Jun 1, 2017
• Journal: Brain Research
• Print ISSN: 0006-8993
• Electronic ISSN: 1872-6240
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 1583
• Issue: 1
• Pages: 255-268
• DOI: https://doi.org/10.1016/j.brainres.2014.08.011
• Keywords: Antipsychotic; Blood–brain barrier; Apoptosis; Evans blue; Endothelium; ROS
• Public URL: https://nottingham-repository.worktribe.com/output/738588
• Publisher URL: https://doi.org/10.1016/j.brainres.2014.08.011
• Additional Information: This article is maintained by: Elsevier; Article Title: Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier; Journal Title: Brain Research; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.brainres.2014.08.011; Content Type: article; Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.
• Contract Date: Jun 1, 2017