title: Haloperidol inhibits the development of atherosclerotic lesions in LDL receptor knockout mice.
abstract: OBJECTIVE
  Antipsychotic drugs have been shown to modulate the expression of ATP-binding cassette transporter A1 (ABCA1), a key factor in the anti-atherogenic reverse cholesterol transport process, in vitro. Here we evaluated the potential of the typical antipsychotic drug haloperidol to modulate the cholesterol efflux function of macrophages in vitro and their susceptibility to atherosclerosis in vivo.
  
  
  METHODS
  Thioglycollate-elicited peritoneal macrophages were used for in vitro studies. Hyperlipidaemic low-density lipoprotein (LDL) receptor knockout mice were implanted with a haloperidol-containing pellet and subsequently fed a Western-type diet for 5 weeks to induce the development of atherosclerotic lesions in vivo.
  
  
  RESULTS
  Haloperidol induced a 54% decrease in the mRNA expression of ABCA1 in peritoneal macrophages. This coincided with a 30% decrease in the capacity of macrophages to efflux cholesterol to apolipoprotein A1. Haloperidol treatment stimulated the expression of ABCA1 (+51%) and other genes involved in reverse cholesterol transport, that is, CYP7A1 (+98%) in livers of LDL receptor knockout mice. No change in splenic ABCA1 expression was noted. However, the average size of the atherosclerotic size was significantly smaller (-31%) in the context of a mildly more atherogenic metabolic phenotype upon haloperidol treatment. More importantly, haloperidol markedly lowered MCP-1 expression (-70%) and secretion (-28%) by peritoneal macrophages.
  
  
  CONCLUSIONS
  Haloperidol treatment lowered the susceptibility of hyperlipidaemic LDL receptor knockout mice to develop atherosclerotic lesions. Our findings suggest that the beneficial effect of haloperidol on atherosclerosis susceptibility can be attributed to its ability to inhibit macrophage chemotaxis.
authors.affiliation: Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Joya E
authors.initials: JE
authors.lastname: Nahon
authors.forename: Anne Q
authors.initials: AQ
authors.lastname: Reuwer
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D066273:Diet, Western; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D014150:Antipsychotic Agents; D016632:Apolipoprotein A-I; D018932:Chemokine CCL2; D002784:Cholesterol; D006220:Haloperidol; D011973:Receptors, LDL; C577833:Abca1 protein, mouse; C491768:Ccl2 protein, mouse