NR AIQJ
AU Müller,W.E.G.; Laplanche,J.L.; Ushijima,H.; Schröder,H.C.
TI Novel approaches in diagnosis and therapy of Creutzfeldt-Jakob disease
QU Mechanisms of Ageing and Development 2000 Jul 31; 116(2-3): 193-218
PT journal article; review; review, tutorial
AB The scrapie prion protein, PrPsc, as well as its peptide fragment, PrP106-126, are toxic on neuronal cells, resulting in cell death by an apoptotic, rather than necrotic mechanism. The apoptotic process of neuronal cells induced by prion protein supports diagnosis and offers potential targets for therapeutic intervention of the prion diseases. Among the cerebrospinal fluid (CSF) proteins, which may serve as markers of neuronal cell death associated with prion diseases, the 14-3-3 protein(s) turned out to be the most promising one. A new sensitive assay allows the detection of even small changes in the normally low levels of these proteins. In vitro, the toxic effects displayed by PrPsc and its peptide fragment can be blocked by antagonists of N-methyl-D-aspartate (NMDA) receptor channels, like Memantine. Also Flupirtine, a non-opiod analgesic drug, which is already in clinical use, was found to display in vitro a strong cytoprotective effect on neurons treated with PrPsc or PrP106-126. This drug acts like a NMDA receptor antagonists, but does not bind to the receptor. Clinical trials on prion diseases with Flupirtine are in progress. Flupirtine was found to enhance the intracellular levels of the antiapoptotic protein Bcl-2 and the antioxidative agent glutathione (GSH). Due to its favourable pharmacokinetic profile, Flupirtine is considered to be a promising drug to prevent neuronal death in Creutzfeldt-Jakob disease (CJD) and other neurodegenerative disorders occurring with age, e.g. Alzheimer's disease.
ZR 167
MH Animal; Cell Death; Creutzfeldt-Jakob Syndrome/*diagnosis/*therapy; Human; Neurons/cytology/metabolism; PrPsc Proteins/metabolism; Prion Diseases; Support, Non-U.S. Gov't
AD Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität Mainz, Duesbergweg 6, D-55099, Mainz, Germany. wmueller@mail.uni-mainz.de
SP englisch
PO Irland