From the Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience.
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam.
J Neuropathol Exp Neurol. 2020 Mar 1;79(3):266-276. doi: 10.1093/jnen/nlz142.
For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC) transporters which efflux drugs that affect drug exposure and response in the brain. We investigated the expression and cellular distribution of the ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) using immunohistochemistry in spinal cord (SC), motor cortex, and cerebellum from a large cohort of genetically well characterized ALS patients (n = 25) and controls (n = 14). The ALS group included 17 sporadic (sALS) and 8 familial (fALS) patients. Strong P-gp expression was observed in endothelial cells in both control and ALS specimens. Immunohistochemical analysis showed higher P-gp expression in reactive astroglial cells in both gray (ventral horn) and white matter of the SC, as well as in the motor cortex of all ALS patients, as compared with controls. BCRP expression was higher in glia in the SC and in blood vessels and glia in the motor cortex of ALS patients, as compared with controls. P-gp and BCRP immunoreactivity did not differ between sALS and fALS cases. The upregulation of both ABC transporters in the brain may explain multidrug resistance in ALS patients and has implications for the use of both approved and experimental therapeutics.
对于肌萎缩侧索硬化症（ALS），由于 ATP 结合盒（ABC）转运蛋白的活性，将药物有效水平维持在大脑中具有挑战性，这些转运蛋白会将影响大脑中药物暴露和反应的药物排出。我们使用免疫组织化学方法研究了 ABC 转运蛋白 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）在一大组遗传特征良好的 ALS 患者（n=25）和对照组（n=14）的脊髓（SC）、运动皮层和小脑中的表达和细胞分布。ALS 组包括 17 名散发性（sALS）和 8 名家族性（fALS）患者。在对照和 ALS 标本中，内皮细胞中均观察到强烈的 P-gp 表达。免疫组织化学分析显示，与对照组相比，在 SC 的灰质（腹角）和白质以及所有 ALS 患者的运动皮层中，反应性星形胶质细胞中 P-gp 表达更高。与对照组相比，ALS 患者的 SC 中的神经胶质和运动皮层中的血管和神经胶质中 BCRP 表达更高。sALS 和 fALS 病例之间 P-gp 和 BCRP 免疫反应性没有差异。大脑中这两种 ABC 转运蛋白的上调可能解释了 ALS 患者的多药耐药性，并对批准和实验性治疗的使用具有影响。
