Experimental-therapeutic potency of pentosan pofysulfate as an anti-prion and anti-dementia drug

我们对聚硫酸戊聚糖（PPS）作为抗朊病毒和痴呆药物的治疗效果进行了实验和临床研究。在我们的体外研究中，我们发现小鼠脑内皮细胞（BBB细胞）原代培养表达朊蛋白（PrP^c）。与PrP106-126 （PrP^c的一种致纤维肽片段）孵育后，对血脑屏障细胞产生剂量依赖性毒性。PPS减轻了内皮损伤。淀粉样蛋白- b肽片段1-40和25-35对血脑屏障细胞和GP8.3永生化大鼠脑产生毒性，包括空泡化、其他形态损伤和凋亡。这些淀粉样蛋白肽片段也增加了血脑屏障细胞中清道夫受体的结合和对迪尔- acldl的摄取。PPS在防止淀粉样蛋白- b肽片段引起的血脑屏障功能改变方面具有显著的效力。在缺血相关海马神经元死亡的体内研究中，在缺血后立即静脉给予3mg /kg剂量的PPS，可以保护海马CA1锥体细胞免于缺血相关的延迟性神经元死亡。我们给8例克雅氏病（CJD）患者口服PPS。口服PPS除“对人的反应”和“肌阵挛发生频率”外，其余7例无效。一项专利被评估为对“30米步行时间”和一些高级大脑功能有效。由于PPS被认为不会通过血脑屏障，我们设计了低分子量PPS（LMW-PPS）。通过PPS膜透析获得的lw -PPS馏分可有效筛选抑制PrP^<Sc>感染的神经母细胞瘤细胞的PrP^<Sc>产生。此外，根据血脑屏障试剂盒的体外数据，假设该部分通过血脑屏障。PPS对血脑屏障损伤具有治疗潜力。LMW-PPS对CJD动物模型的治疗试验正在进行中。

We investigated therapeutic potency of pentosan polysulfate(PPS) as an anti-prion and-dementia drug, exprimentally and clinically. In our in vitro studies, we found by Western blottings that primary cultures of mouse cerebral endothelial cells(BBB cells) express prion protein(PrP^c). Incubation with PrP106-126,a fibrillogenic peptide fragment of PrP^c resulted in a dose-dependent toxicity to BBB cells. PPS attenuated the endothelial injury. Amyloid-B peptide fragment 1-40 and 25-35 induced toxicity to BBB cells and GP8.3 immortalized rat brain, including vacuolization, other morphological damages, and apoptosis. These amyloid-ss peptides fragment also increased the scavenger receptor binding and uptake Dil-AcLDL in BBB cells. PPS had a significant potency in preventing the amyloid-B peptides fragment-induced changes in BBB functions. In vivo studies with an ischemia-related neuronal hippocampus neuronal death of 4-vessel-occlusion model, when given intravenously immediately after ischemia at a dose of 3 mg/kg, PPS protected hippocampus CA1 pyramidal cells from ischemia-related delayed neuronal death. We administered PPS orally to eight patients with Creutzfeldt-Jacob disease(CJD). Oral PPS was not effective in seven case except ‘response to person' and ‘frequency of myoclonus' in some patients. One patent was evaluated to be effective in ‘30m walking time' and in some higher brain function. As PPS are thought not to pass through the BBB, we designed Low-molecular weight PPS(LMW-PPS). Fractions of LMW-PPS obtained with a membrane dialysis of PPS were effective in screening for inhibition PrP^<Sc> production of PrP^<Sc>-infected neuroblastoma cells. Also, the fraction was assumed to pass through the BBB, based on the in vitro data with the BBB kit. PPS has a therapeutic potential in the treatment of BBB damages. Therapeutic trails of LMW-PPS on animal models of CJD is ongoing.