Pérez-Hernández Mercedes, Fernández-Valle María Encarnación, Rubio-Araiz Ana, Vidal Rebeca, Gutiérrez-López María Dolores, O'Shea Esther, Colado María Isabel
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.
CAI Resonancia Magnética Nuclear, Universidad Complutense, Paseo Juan XXIII, 28040 Madrid, Spain.
Neuropharmacology. 2017 May 15;118:157-166. doi: 10.1016/j.neuropharm.2017.03.019. Epub 2017 Mar 16.
The recreational drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X 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.
滥用的消遣性毒品3,4-亚甲基二氧基甲基苯丙胺（MDMA，摇头丸）通过早期P2X受体介导的事件破坏大鼠血脑屏障（BBB）的完整性，该事件诱导MMP-9活性。血脑屏障通透性增加通常会导致血浆蛋白和水进入脑组织，从而导致血管源性水肿的形成。本研究旨在检测单次给予神经毒性剂量的MDMA（12.5mg/kg，腹腔注射）对成年雄性黑褐大鼠海马体内与血管周围星形胶质细胞水通道蛋白AQP4表达变化、紧密连接（TJ）蛋白claudin-5表达变化以及伊文思蓝染料外渗相关的水肿发展的影响。我们还评估了MMP-9抑制剂SB-3CT（25mg/kg，腹腔注射）预防这些变化的能力，以验证MMP-9激活在MDMA诱导的血脑屏障破坏中的作用。结果表明，MDMA会产生短期水肿，这在时间上与AQP4表达变化和claudin-5表达降低相关，而SB-3CT可预防这些变化。此外，MDMA会导致组织型纤溶酶原激活物（tPA）活性和表达短期增加，tPA是一种丝氨酸蛋白酶，参与血脑屏障破坏和MMP-9表达上调。总之，本研究提供了充分的证据表明，MDMA由于MMP-9激活介导的血脑屏障破坏而诱导短期水肿。
