Christine Farquhar and colleagues (Jan 9, p 117)1
proved the prophylactic potential of intraperitoneal pentosan polysulphate in transmissible spongiform encephalopathies in mice. Oral administration of the drug in the same doses was ineffective, which can be easily explained by its poor absorption rate (3%) from the gastrointestinal tract.2
The efficacy of pentosan given weeks before or hours after the scrapie inoculation raises the question of where the action responsible for the long-term effect takes place.
Pentosan polysulphate is a highly polyanionic sulphated semisynthetic polysaccharide that is structurally related to the glycosaminoglycans synthesised by cells. Preclinical studies with parenterally administered radiolabelled pentosan polysulphate sodium showed distribution to the uroepithelium with a smaller amount found in the liver, spleen, lung, skin, periosteum, and bone marrow (www.alza.com/elmiron/elmironpi.htm
About two-thirds of the dose undergoes partial desulphation in the liver and spleen within 1 h, partial depolymerisation also occurs in the kidney, and it is then eliminated in the urine over 24 h. One explanation is that during distribution the active pentosan polysulphate molecules attach to their target cell(s), and result in delayed structural or functional changes which thereby prevents the propagation of prion disease.
In scrapie-infected neuroblastoma cells, pentosan polysulphate in vitro stimulates the endocytosis of prion protein (PrPc
), rapidly and dramatically decreases the amount of PrPc
present on the cell surface, and prevents the accumulation of protease-resistant prionisoform.3
That this mechanism has a pivotal role in the central nervous system of infected mice is unlikely, because the blood-brain barrier is practically non-permeable to pentosan polysulphate.4
The potential cellular targets of the long-term effect of pentosan polysulphate can thus be splenocytes, lymphocytes, bone-marrow macrophages, and endothelial cells of blood-nerve and blood-brain barriers.