Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 - Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
CNC.IBILI, University of Coimbra, Coimbra, Portugal.
Mol Neurobiol. 2018 Mar;55(3):2056-2069. doi: 10.1007/s12035-017-0439-0. Epub 2017 Mar 10.
Methamphetamine (METH) abuse/misuse is a worldwide problem, and despite extensive characterization of its neurotoxicity over the last years, many questions remain unanswered. Recently, it was shown that METH compromises the blood-brain barrier (BBB) and causes a disturbance in the water homeostasis leading to brain edema. Importantly, water transport at BBB is regulated by water channels, aquaporins (AQPs), with AQP4 being expressed in astrocytic end-feet surrounding brain endothelium. Thus, the main goal of this work was to unravel the role of AQP4 under conditions of METH consumption. Our results show that METH (4× 10 mg/kg, 2 h apart, i.p.) interferes with AQP4 protein levels causing brain edema and BBB breakdown in both mice striatum and hippocampus, which culminated in locomotor and motivational impairment. Furthermore, these effects were prevented by pharmacological blockade of AQP4 with a specific inhibitor (TGN-020). Moreover, siRNA knockdown of this water channel protected astrocytes from METH-induced swelling and morphologic alterations. Herein, we unraveled AQP4 as a new therapeutic target to prevent the negative impact of METH.
甲基苯丙胺（METH）滥用/误用是一个全球性问题，尽管近年来对其神经毒性进行了广泛的描述，但仍有许多问题尚未得到解答。最近，研究表明 METH 会损害血脑屏障（BBB）并导致水动态平衡紊乱，从而导致脑水肿。重要的是，BBB 处的水转运由水通道，水通道蛋白（AQP）调节，AQP4 表达在围绕脑内皮细胞的星形胶质细胞终足中。因此，这项工作的主要目标是揭示在 METH 消耗条件下 AQP4 的作用。我们的研究结果表明，METH（4×10mg/kg，间隔 2 小时，腹腔注射）会干扰 AQP4 蛋白水平，导致小鼠纹状体和海马中的脑水肿和 BBB 破裂，从而导致运动和动机障碍。此外，用特异性抑制剂（TGN-020）抑制 AQP4 可预防这些作用。此外，siRNA 敲低这种水通道可防止星形胶质细胞因 METH 诱导的肿胀和形态改变。在这里，我们揭示了 AQP4 是一个新的治疗靶点，可以预防 METH 的负面影响。
