title: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors.
abstract: The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1β levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA-induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix.
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rubio-Araiz
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Perez-Hernandez
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Urrutia
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Porcu
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Erika
authors.initials: E
authors.lastname: Borcel
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Gutierrez-Lopez
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: O'Shea
authors.affiliation: Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Colado
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001831:Body Temperature / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D017628:Microglia / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D058911:Purinergic P2X Receptor Agonists / Q000633:toxicity*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012394:Rosaniline Dyes / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D024141:Collagen Type IV; D007074:Immunoglobulin G; D007797:Laminin; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; D013777:Tetrazoles; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C004692:coomassie Brilliant Blue