Coelho-Santos Vanessa, Leitão Ricardo A, Cardoso Filipa L, Palmela Inês, Rito Manuel, Barbosa Marcos, Brito Maria A, Fontes-Ribeiro Carlos A, Silva Ana P
1] Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
J Cereb Blood Flow Metab. 2015 Aug;35(8):1260-71. doi: 10.1038/jcbfm.2015.59. Epub 2015 Apr 22.
Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.
甲基苯丙胺（METH）是一种会导致神经和精神异常的精神兴奋剂。最近的研究表明，其神经毒性也可能源于其破坏血脑屏障（BBB）的能力。在此，我们表明METH迅速增加了跨内皮细胞（ECs）的囊泡运输，随后增加了细胞旁运输。此外，METH触发了肿瘤坏死因子-α（TNF-α）的释放，而阻断这种细胞因子或抑制核因子-κB（NF-κB）途径可预防内皮功能障碍。由于星形胶质细胞在调节血脑屏障功能中起关键作用，我们进一步表明，先前暴露于METH的星形胶质细胞获得的条件培养基也通过TNF-α/NF-κB途径对屏障特性产生负面影响。动物研究证实了体外实验结果。总体而言，我们表明METH直接干扰内皮细胞特性，或通过星形胶质细胞间接干扰，通过释放TNF-α并随后激活NF-κB途径，最终导致屏障功能障碍。
