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

我们从实验和临床两个方面研究了多硫酸戊聚糖(PPS)作为抗病毒药物和抗痴呆药物的治疗效果。在我们的体外研究中，我们通过Western blotting发现原代培养的小鼠脑内皮细胞(BBB细胞)表达PrP^c蛋白。PrP^c的纤溶肽片段与PrP106-126共同孵育后，对BBB细胞的毒性呈剂量依赖性。PPS可减轻血管内皮细胞损伤。淀粉样蛋白B肽片段1-40和25-35对BBB细胞和GP8.3永生化大鼠脑具有毒性作用，包括空泡化、其他形态损伤和细胞凋亡。这些淀粉样多肽片段也增加了BBB细胞清道夫受体的结合和摄取Dil-AcLDL。PPS对淀粉样蛋白B多肽片段引起的BBB功能改变有明显的预防作用。在体脑缺血相关四血管闭塞海马神经元死亡模型的研究中，在缺血后即刻静脉注射PPS(3 mg/kg)，可保护海马CA1区锥体细胞免受缺血相关迟发性神经元死亡的影响。我们给8例克雅病(CJD)患者口服PPS。口服PPS有7例无效，仅有部分患者出现“对人的反应”和“肌阵挛频率”。一项专利被评估为在30米步行时间和一些更高的大脑功能方面有效。由于聚苯硫醚被认为不能通过血脑屏障，我们设计了低分子量聚苯硫醚(LMW-PPS)。PPS膜透析法提取的LMW-PPS组分可有效抑制PrP^&lt；SC&gt；感染的神经母细胞瘤细胞产生PrP^&lt；SC&gt；此外，根据血脑屏障试剂盒的体外数据，该组分被假定通过血脑屏障。PPS在治疗血脑屏障损伤方面具有一定的治疗潜力。LMW-PPS在CJD动物模型上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.