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

Elmorsy, Ekramy and Elzalabany, Laila M. and Elsheikha, Hany M. and Smith, Paul A. (2014) Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier. Brain Research, 1583 . pp. 255-268. ISSN 1872-6240

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Abstract

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 µM 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 ultrastructure 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.

Item Type: Article
Keywords: Antipsychotic; Blood–brain barrier; Apoptosis; Evans blue; Endothelium; ROS
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1016/j.brainres.2014.08.011
Depositing User: Eprints, Support
Date Deposited: 01 Jun 2017 07:55
Last Modified: 02 Jun 2017 16:31
URI: http://eprints.nottingham.ac.uk/id/eprint/43321

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