title: The TNF-α/NF-κB signaling pathway has a key role in methamphetamine-induced blood-brain barrier dysfunction.
abstract: Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.
authors.affiliation: 1] Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Coelho-Santos
authors.affiliation: 1] Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Leitão
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Filipa L
authors.initials: FL
authors.lastname: Cardoso
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Palmela
authors.affiliation: Neurosurgery Service, Coimbra Hospital and University Centre, Coimbra, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rito
authors.affiliation: 1] Neurosurgery Service, Coimbra Hospital and University Centre, Coimbra, Portugal [2] Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Marcos
authors.initials: M
authors.lastname: Barbosa
authors.affiliation: 1] Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal [2] Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Brito
authors.affiliation: 1] Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Fontes-Ribeiro
authors.affiliation: 1] Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D008694:Methamphetamine / Q000009:adverse effects* / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008694:Methamphetamine