Apolipoprotein-E Controls Adenosine Triphosphate-Binding Cassette Transporters ABCB1 and ABCC1 on Cerebral Microvessels After Methamphetamine Intoxication

Background and Purpose—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 g/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