Transmissible spongiform encephalopathies: in-vitro evaluation of the therapeutic potentiality of new molecules

摘要

Transmissible spongiform encephalopathies' (TSE) is a group of degenerative, progressive, fatal disorders, belonging to the conformational diseases, which are characterized by the conformational change of a cellular protein into a pathological protease resistant form (Carrell and Gooptu, 1998). In TSE, the abnormal protease resistant isoform of the normal prion protein (PrP~(sen)) is named PrP~(res). PrP~(res) deposits are commonly found in the SNC. Recent research suggests some hypothesis regarding the mechanism of the conformational changes responsible for conversion of PrP~(sen) into PrP~(res). In one model it is supposed that, when PrP~(res) interacts with PrP~(sen), or with a partially destabilized intermediate, a misfolding of the normal protein occurs, which then acquires the same conformation as the pathological protein (Horwich and Weissman, 1997). This change can be considered a chain reaction process, leading to an exponential increase in PrP~(res) molecules (Prusiner, 1998). Since no immunological response in infected subjects is observed for TSE the diagnostic and prophylaxis tools usually applied to viral and bacterial infections are not helpful. It is necessary to develop a therapeutic approach based on the use of antiamyloidogenic and/or amy-loidolytic agents, since amyloid deposition is the major factor responsible for neuro-degeneration (Forloni et al., 1996). In this work we investigated the potential ability of four Congo Red (CR) derivatives to induce the reversion of PrP~(res) into PrP~(sen) in vitro, using the 263K scrapie strain, partially purified from infected hamster brain.