title: Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier.
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 10mM 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.
authors.affiliation: School of Life Science, University of Nottingham Medical School, Queens Medical Centre, Nottinghamshire NG7 2UH, UK; Departments of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Ekramy
authors.initials: E
authors.lastname: Elmorsy
authors.affiliation: Departments of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Laila M
authors.initials: LM
authors.lastname: Elzalabany
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE12 5RD, UK.
authors.forename: Hany M
authors.initials: HM
authors.lastname: Elsheikha
authors.affiliation: School of Life Science, University of Nottingham Medical School, Queens Medical Centre, Nottinghamshire NG7 2UH, UK. Electronic address: paul.a.smith@nottingham.ac.uk.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000009:adverse effects; D003024:Clozapine / Q000009:adverse effects; D053960:DNA Breaks / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D006220:Haloperidol / Q000009:adverse effects; D006801:Humans; D055806:Microvessels / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018967:Risperidone / Q000009:adverse effects
chemical_list: D014150:Antipsychotic Agents; D017382:Reactive Oxygen Species; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D002746:Chlorpromazine
keywords: Antipsychotic; Apoptosis; Blood–brain barrier; Endothelium; Evans blue; ROS