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

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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.