3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus.
The recreational drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X7receptor-mediated event which induces MMP-9 activity. Increased BBB permeability often causes plasma proteins and water to access cerebral tissue leading to vasogenic edema formation. The current study was performed to examine the effect of a single neurotoxic dose of MDMA (12.5 mg/kg, i.p.) on in vivo edema development associated with changes in the expression of the perivascular astrocytic water channel, AQP4, as well as in the expression of the tight-junction (TJ) protein, claudin-5 and Evans Blue dye extravasation in the hippocampus of adult male Dark Agouti rats. We also evaluated the ability of the MMP-9 inhibitor, SB-3CT (25 mg/kg, i.p.), to prevent these changes in order to validate the involvement of MMP-9 activation in MDMA-induced BBB disruption. The results show that MDMA produces edema of short duration temporally associated with changes in AQP4 expression and a reduction in claudin-5 expression, changes which are prevented by SB-3CT. In addition, MDMA induces a short-term increase in both tPA activity and expression, a serine-protease which is involved in BBB disruption and upregulation of MMP-9 expression. In conclusion, this study provides evidence enough to conclude that MDMA induces edema of short duration due to BBB disruption mediated by MMP-9 activation.
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain.
Mercedes
M
Pérez-Hernández
CAI Resonancia Magnética Nuclear, Universidad Complutense, Paseo Juan XXIII, 28040 Madrid, Spain.
María Encarnación
ME
Fernández-Valle
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain.
Ana
A
Rubio-Araiz
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain.
Rebeca
R
Vidal
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain.
María Dolores
MD
Gutiérrez-López
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain. Electronic address: estheros@ucm.es.
Esther
E
O'Shea
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain; Red de Trastornos Adictivos del Instituto de Salud Carlos III, 28029 Madrid, Spain. Electronic address: colado@ucm.es.
María Isabel
MI
Colado
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D001929:Brain Edema / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006213:Hallucinogens / Q000633:toxicity*; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D010539:Permeability / Q000187:drug effects; D010958:Plasminogen / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D062507:Claudin-5; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D006213:Hallucinogens; D006573:Heterocyclic Compounds, 1-Ring; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C429533:SB 3CT compound; D013450:Sulfones; D010958:Plasminogen; D020780:Matrix Metalloproteinase 9; D018817:N-Methyl-3,4-methylenedioxyamphetamine
AQP4; Blood-brain barrier; Edema; Evans Blue dye (PubChem CID: 24832074); MDMA; MDMA hydrochloride (PubChem CID: 71285); MMP-9; SB-3CT; SB-3CT (PubChem CID: 9883002)