title: Apolipoprotein-E controls adenosine triphosphate-binding cassette transporters ABCB1 and ABCC1 on cerebral microvessels after methamphetamine intoxication.
abstract: OBJECTIVE
  Methamphetamine is a powerful addictive, which has been associated with ischemic stroke and brain hemorrhage in humans. Whether and how methamphetamine influences the expression of tight junctions and adenosine triphosphate-binding cassette transporters, which have previously been shown to be regulated by apolipoprotein-E (ApoE) under conditions of brain ischemia, was unknown.
  
  
  METHODS
  C57BL/6J mice received intraperitoneal injections of methamphetamine (3 times 4 mg/kg separated by 3 hours) either alone or in combination with the ApoE receptor-2 inhibitor receptor-associated protein (40 μg/kg) or the inducible nitric oxide synthase inhibitor 1400W (5 mg/kg). Animals were euthanized 3 or 24 hours after methamphetamine exposure. Tissue responses were evaluated with Western blots, immunoprecipitation, and immunohistochemistry using total brain and cerebral microvessel extracts.
  
  
  RESULTS
  Methamphetamine induced a transient activation of stress kinases c-Jun N-terminal kinase 1/2 and p38 in the brain parenchyma and increased intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on cerebral microvessels without inducing loss of tight junction proteins and without inducing IgG extravasation. Methamphetamine transiently increased the expression of the luminal adenosine triphosphate-binding cassette transporter ABCB1 on cerebral microvessels and reduced the expression of the abluminal transporter ABCC1. Elevated expression of ApoE was noted in the brain parenchyma by methamphetamine, activating ApoE receptor-2 on brain capillaries, deactivating c-Jun N-terminal kinase 1/2 and c-Jun, and regulating ABCB1 and ABCC1 expression. Indeed, ApoE receptor-2 and inducible nitric oxide synthase inhibition prevented the ABCB1 and ABCC1 expression changes.
  
  
  CONCLUSIONS
  Acute exposure to methamphetamine at doses comparable to those consumed in drug addiction does not induce tight junction breakdown but differentially regulates adenosine triphosphate-binding cassette transporters through the ApoE/ApoE receptor-2/c-Jun N-terminal kinase 1/2 pathway.
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstr 55, D-45122 Essen, Germany.
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.forename: Andrés
authors.initials: A
authors.lastname: Urrutia
authors.forename: Ana
authors.initials: A
authors.lastname: Rubio-Araiz
authors.forename: Macarena
authors.initials: M
authors.lastname: Hernandez-Jimenez
authors.forename: Maria I
authors.initials: MI
authors.lastname: Colado
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000494:pharmacology; D002531:Cerebellum / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006801:Humans; D007097:Imines / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001057:Apolipoproteins E; D000697:Central Nervous System Stimulants; D007097:Imines; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008694:Methamphetamine; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; C421109:multidrug resistance-associated protein 1