Pan Yijun, Kagawa Yoshiteru, Sun Jiaqi, Turner Bradley J, Huang Cheng, Shah Anup D, Schittenhelm Ralf B, Nicolazzo Joseph A
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia.
Department of Organ Anatomy, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai 980-0872, Miyagi, Japan.
Pharmaceutics. 2022 Dec 14;14(12):2803. doi: 10.3390/pharmaceutics14122803.
For peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood-brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS (e.g., SOD1 mice), we characterized BBB transporter expression and function in transgenic C9orf72 BAC (C9-BAC) mice expressing a hexanucleotide repeat expansion, the most common genetic cause of ALS. Using an in situ transcardiac brain perfusion technique, we identified a 1.4-fold increase in H-2-deoxy-D-glucose transport across the BBB in C9-BAC transgenic (C9) mice, relative to wild-type (WT) mice, which was associated with a 1.3-fold increase in brain microvascular glucose transporter 1 expression, while other general BBB permeability processes (passive diffusion, efflux transporter function) remained unaffected. We also performed proteomic analysis on isolated brain microvascular endothelial cells, in which we noted a mild (14.3%) reduction in zonula occludens-1 abundance in C9 relative to WT mice. Functional enrichment analysis highlighted trends in changes to various BBB transporters and cellular metabolism. To our knowledge, this is the first study to demonstrate altered BBB function in a C9orf72 repeat expansion model of ALS, which has implications on how therapeutics may access the brain in this mouse model.
对于经外周给药的药物而言，要到达中枢神经系统（CNS）并治疗肌萎缩侧索硬化症（ALS），它们必须穿过血脑屏障（BBB）。越来越多的证据表明，在ALS患者和ALS动物模型（如SOD1小鼠）中，血脑屏障的超微结构发生了改变，我们对表达六核苷酸重复扩增的转基因C9orf72 BAC（C9-BAC）小鼠的血脑屏障转运体表达及功能进行了表征，六核苷酸重复扩增是ALS最常见的遗传病因。利用原位经心脑灌注技术，我们发现与野生型（WT）小鼠相比，C9-BAC转基因（C9）小鼠的血脑屏障对H-2-脱氧-D-葡萄糖的转运增加了1.4倍，这与脑微血管葡萄糖转运蛋白1的表达增加1.3倍有关，而其他一般的血脑屏障通透性过程（被动扩散、外流转运体功能）未受影响。我们还对分离出的脑微血管内皮细胞进行了蛋白质组学分析，结果发现与WT小鼠相比，C9小鼠的紧密连接蛋白-1丰度轻度降低（14.3%）。功能富集分析突出了各种血脑屏障转运体和细胞代谢变化的趋势。据我们所知，这是第一项证明在C9orf72重复扩增ALS模型中血脑屏障功能发生改变的研究，这对在该小鼠模型中治疗药物如何进入大脑具有启示意义。
