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The molecular mechanism of neurodegeneration in transmissible spongiform encephalopathies remains uncertain. In this study, it was demonstrated that prion-infected hypothalamic neuronal GT1 cells displayed a higher sensitivity to induced oxidative stress over noninfected cells. In addition, the infected cells presented an increased lipid peroxidation and signs of apoptosis associated with a dramatic reduction in the activities of the glutathione-dependent and superoxide dismutase antioxidant systems. This study indicates for the first time that prion infection results in an alteration of the molecular mechanisms promoting cellular resistance to reactive oxygen species. This finding is vital for future therapeutic approaches in transmissible spongiform encephalopathies and the understanding of the function of the prion protein.

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Prion diseases are fatal neurodegenerative disorders that are caused by the conversion of a normal hostencoded protein, PrP C , to an abnormal, disease-causing form, PrP Sc . This paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein PrP Sc to undetectable levels in scrapieinfected neuroblastoma cells. Beta-cyclodextrin removed PrP Sc from the cells at a concentration of 500 M following 2 weeks of treatment. Structure activity studies revealed that antiprion activity was dependent on the size of the cyclodextrin. The half-maximal inhibitory concentration (IC 50 ) for beta-cyclodextrin was 75 M, whereas ␣-cyclodextrin, which possessed less antiprion activity, had an IC 50 of 750 M. This report presents cyclodextrins as a new class of antiprion compound. For decades, the pharmaceutical industry has successfully used cyclodextrins for their complex-forming ability; this ability is due to the structural orientation of the glucopyranose units, which generate a hydrophobic cavity that can facilitate the encapsulation of hydrophobic moieties. Consequently, cyclodextrins could be ideal candidates for the treatment of prion diseases.

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Abstract:Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders that have the unique property of being infectious, sporadic, or genetic in origin. Although some doubts remain on the nature of the responsible agent of these diseases, it is clear that a protein called PrP Sc Sc generation has not been observed in infected cultures. Using transfected cells expressing wild-type or mutated mouse PrPs, we show here that amphotericin B is able to interfere with the generation of abnormal PrP isoforms in culture. Its action seems related to a modification of PrP trafficking through the association of this glycosylphosphatidylinositol-anchored protein with detergent-resistant microdomains. These results represent a first step toward the comprehension of the mechanism of action of amphotericin B in transmissible spongiform encephalopathies. Key Words: Transmissible spongiform encephalopathies-Prion protein-Amphotericin B. J. Neurochem. 74, 754 -762 (2000).Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders that include bovine spongiform encephalopathy in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease, GerstmannSträussler-Scheinker syndrome, and fatal familial insomnia in human (for reviews, see Pocchiari, 1994;Parchi and Gambetti, 1995). TSEs can have infectious, sporadic, or genetic origins. In all three cases, brains from affected individuals contain the abnormal scrapie isoform of the prion protein (PrP), PrP Sc , and can be used to transmit disease to laboratory animals. PrP Sc (also called PrP-res) is distinct from the host protein, the cellular isoform of PrP (PrP C ; also called PrP-sen), because of its biochemical properties, including proteinase K (PK) resistance and insolubility (Meyer et al., 1986). It is thought that the generation of PrPSc from PrP C involves a conformational transition, which is accompanied by changes in the secondary structure of the protein (Caughey et al., 1991b;Gasset et al., 1992;Pan et al., 1993). How this conversion is related to the infectious process in TSEs is subject to controversy (Chesebro, 1998). However, the central role of PrP in the disease is exemplified, first, by the fact that PrP-null mice are resistant to the disease (Bueler et al., 1993), second, by the strong genetic linkages existing between mutations in the PrP gene and genetic forms of TSEs (Parchi and Gambetti, 1995), and third, by the fact that the efficiency of experimental transmission of the disease from one species to another is dependent on the similarity of the PrP sequences between species (for review, see Prusiner et al., 1998).In experimental transmission of TSEs in laboratory animals, different classes of drugs, administered at the moment of inoculation or during incubation, have been able to delay the appearance of disease. This was shown to be the case with the polyene antibiotic amphotericin B (AmB) and its derivative MS-8209 (Pocchiari et al., 1987;Xi et al., 1992;Demaimay et al., 1994). These drugs are among th...

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