3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus. (15th May 2017)

• Record Type: Journal Article
• Authors: Pérez-Hernández, Mercedes; Fernández-Valle, María Encarnación; Rubio-Araiz, Ana; Vidal, Rebeca; Gutiérrez-López, María Dolores; O'Shea, Esther; Colado, María Isabel
• Is Part Of: Neuropharmacology. Volume 118(2017)
• Page Start: 157
• Page End: 166
• Publication Date: 2017-05-15
• Subjects: MDMA -- Blood-brain barrier -- Edema -- AQP4 -- MMP-9 -- SB-3CT; AQP4 aquaporin 4 -- GFAP glial fibrillary acidic protein -- LRP-1 lipoprotein receptor-related protein 1 -- MDMA 3, 4-methylenedioxymethamphetamine -- MMP metalloproteinase -- TJ tight junction -- tPA tissue plasminogen activator; MDMA hydrochloride (PubChem CID: 71285) -- SB-3CT (PubChem CID: 9883002) -- Evans Blue dye (PubChem CID: 24832074); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.03.019
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The recreational drug of abuse, 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X7 receptor-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. Highlights: Claudin-5 decrease and Evans Blue extravasation indicate BBB disruption after MDMA. MDMA-induced edema was visualized in vivo by magnetic resonance. MMP-9 inhibition by SB-3CT prevents edema formation and BBB disruption. Biphasic changes in AQP4 could be related to edema formation and resolution.