title: Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor.
abstract: Methamphetamine (METH) is a psychostimulant with high abuse potential and severe neurotoxicity. Recent studies in animal models have indicated that METH can impair the blood-brain barrier (BBB), suggesting that some of the neurotoxic effects resulting from METH abuse could be due to barrier disruption. We report here that while chronic exposure to METH disrupts barrier function of primary human brain microvascular endothelial cells (HBMECs) and human umbilical vein endothelial cells (HUVECs), an early pro-survival response is observed following acute exposure by induction of autophagic mechanisms. Acute METH exposure induces an early increase in Beclin1 and LC3 recruitment. This is mediated through inactivation of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K pathway, and upregulation of the ERK1/2. Blockade of Kappa opioid receptor (KOR), and treatment with autophagic inhibitors accelerated METH-induced apoptosis, suggesting that the early autophagic response is a survival mechanism for endothelial cells and is mediated through the kappa opioid receptor. Our studies indicate that kappa opioid receptor can be therapeutically exploited for attenuating METH-induced BBB dysfunction.
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meng
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: 1] Departments of Surgery, University of Minnesota, Minneapolis, MN, USA [2] Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Roy
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D000697:Central Nervous System Stimulants; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D008694:Methamphetamine; D008869:Microtubule-Associated Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009292:Narcotic Antagonists; D051057:Proto-Oncogene Proteins c-akt; D017473:Receptors, Opioid, kappa; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C491997:BECN1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C477012:MAP1LC3A protein, human; C515653:OPRK1 protein, human; C546842:MTOR protein, human; C535150:MAPK1 protein, human