Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood-Brain Barrier Damage.
Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood-Brain Barrier Damage.
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内质网应激介导甲基苯丙胺诱导的血脑屏障损伤
DOI：
10.3389/fphar.2017.00639
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发表时间：
2017
影响因子：
5.6
通讯作者：
Ma C
中科院分区：
文献类型：
--
作者：
Qie X;Wen D;Guo H;Xu G;Liu S;Shen Q;Liu Y;Zhang W;Cong B;Ma C
甲基苯丙胺（METH）滥用在世界范围内造成严重的健康问题，长期使用METH会破坏血脑屏障（BBB）。在此，我们探讨了内质网（ER）应激在体外MET诱导的血脑屏障内皮细胞损伤中的潜在机制，以及内质网应激抑制剂对C57 BL/6 J小鼠MET诱导的血脑屏障破坏的治疗潜力。永生化BMVEC（bEnd.3）细胞暴露于METH显著降低细胞活力，诱导凋亡，并减少细胞单层的紧密性。METH激活ER应激传感器蛋白，包括PERK、ATF 6和IRE 1，并上调促凋亡蛋白CHOP。ER应激抑制剂显著阻断CHOP的上调。敲低CHOP可保护bEnd.3细胞免受MET诱导的细胞毒性。此外，METH增加了活性氧（ROS）的产生，并诱导线粒体功能障碍，其特征在于Bcl 2/Bax比值降低，线粒体膜电位崩溃，细胞色素c。ER应激释放被ROS抑制部分逆转，细胞色素c释放被CHOP敲低部分阻断。最后，PBA显着衰减甲基诱导的荧光素钠（NaFluo）和伊文思蓝泄漏，以及紧密连接蛋白的损失，在C57 BL/6 J小鼠。这些数据表明，血脑屏障内皮细胞损伤是由甲基苯丙胺诱导的内质网应激，这进一步诱导线粒体功能障碍，PBA是一种有效的治疗甲基苯丙胺诱导血脑屏障破坏。
Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption.
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DOI：
10.1124/jpet.109.159244
发表时间：
2010-03-01
影响因子：
3.5
作者：
Hayashi, Teruo;Justinova, Zuzana;Su, Tsung-Ping
通讯作者：
Su, Tsung-Ping
Wnt/β-catenin信号传导控制血脑屏障的发展。
影响因子：
7.8
作者：
Liebner, Stefan;Corada, Monica;Bangsow, Thorsten;Babbage, Jane;Taddei, Andrea;Czupalla, Cathrin J.;Reis, Marco;Felici, Angelina;Wolburg, Hartwig;Fruttiger, Marcus;Taketo, Makoto M.;von Melchner, Harald;Plate, Karl Heinz;Gerhardt, Holger;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
3
作者：
Baeten, Kim M.;Akassoglou, Katerina
通讯作者：
Akassoglou, Katerina
影响因子：
--
作者：
Kim S;Cheon HS;Kim SY;Juhnn YS;Kim YY
通讯作者：
Kim YY
影响因子：
3.7
作者：
Beauvais G;Atwell K;Jayanthi S;Ladenheim B;Cadet JL
通讯作者：
Cadet JL