Pentosan polysulfate strenghens blood-brain barrier functions : A possible role of anti-dementia drug

结合血脑屏障(BBB)损害导致神经退行性疾病(如Creutzfeld-Jacob病和阿尔茨海默病)的进展的临床研究结果，多硫酸戊聚糖(PPS)可预防PrP106-126(PrP106-126)(PrP106-126)诱导的脑毛细血管内皮细胞(BBB细胞)损伤，推测PPS是一种抗痴呆药物。在本研究项目中，我们研究了PPS对BBB功能的影响，方法是：1)我们新开发的BBB试剂盒，包括三种细胞：大鼠血脑屏障细胞、周细胞和星形胶质细胞，2)GP8永生化大鼠脑内皮细胞，3)SHRSP延迟性神经元死亡的体外模型。PPS(2 0~2 0 0μg/ml)与血脑屏障试剂盒中的细胞共同孵育60min，可增加内皮细胞的跨内皮电阻，降低荧光素钠和伊文思蓝白蛋白的通透性。在GP8细胞中，淀粉样蛋白Aβ多肽片段25-35、I-40和PrP106-126处理导致内皮细胞毒性。10 0μMPrP10 6-12 6与GP8细胞孵育2 4h后，mdr1a基因表达下降。PPS可减轻由淀粉样蛋白和PrP106-123多肽处理引起的形态和功能损伤。在短暂性脑缺血10min后给予PPS，可延缓SHRSP大鼠海马CA1区锥体细胞缺血相关迟发性神经元死亡的发生。因此，必须考虑PPS作为一种抗痴呆药物在治疗血脑屏障损害方面具有治疗潜力的可能性。

Taken together with clinical findings that blood-brain barrier (BBB) damages contribute to the progress of neurodegenerative disease such as Creutzfeld-Jacob's disease and Alzheimer's disease, as pentosan polysulfate (PPS) prevents a PrP106-126 (neurotoxic peptide of prion protein)-induced damage of brain capillary endothelial cells (BBB cells), it is postulated that PPS is an anti-dementia drug. In this research project, we investigated the effect of PPS on BBB functions, by using 1) our newly developed in vitro model of the BBB kit constructed with three types of cell ; rat BBB cells, pericytes, and astrocytes, 2) GP8 immortalized rat brain endothelial cells, and 3) in vitro model of delayed neuronal death of SHRSP. PPS (20-200 μg/ml) coincubated with cells in BBB kit for 60 min increased transendothelial electrical resistance, and decreased permeabilities of sodium fluorescein and Evans' blue-albumin. In GP8 cells, treatment with amyloid Aβ peptide fragment 25-35, I-40, and PrP106-126 resulted in an endothelial toxicity. Incubation of GP8 cells with 100 μM PrP106-126 for 24 h decreased mRNA expression of mdrla gene. PPS attenuated both morphological and functional damages caused by amyloid-, and PrP106-123 peptides treatment. PPS, when given intraperitoneally 10 min after the transient forbrain ischemia, delayed the onset of ischemia-related delayed neuronal death of the hippocampus CA1 pyramidal cells of SHRSP. Thus, the possibility that PPS has a therapeutic potential in the treatment of BBB damages as an anti-dementia drug would have to be considered.