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    Glimepiride Reduces the Expression of PrPC, Prevents PrPSc Formation and Protects against Prion Mediated Neurotoxicity

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    21
    Author
    Bate, C; Tayebi, M; Diomede, L; Salmona, M; Williams, A
    Date
    2009-12-09
    Source Title
    PLoS One
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Tayebi, Mourad
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Bate, C., Tayebi, M., Diomede, L., Salmona, M. & Williams, A. (2009). Glimepiride Reduces the Expression of PrPC, Prevents PrPSc Formation and Protects against Prion Mediated Neurotoxicity. PLOS ONE, 4 (12), https://doi.org/10.1371/journal.pone.0008221.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258931
    DOI
    10.1371/journal.pone.0008221
    Abstract
    BACKGROUND: A hallmark of the prion diseases is the conversion of the host-encoded cellular prion protein (PrP(C)) into a disease related, alternatively folded isoform (PrP(Sc)). The accumulation of PrP(Sc) within the brain is associated with synapse loss and ultimately neuronal death. Novel therapeutics are desperately required to treat neurodegenerative diseases including the prion diseases. PRINCIPAL FINDINGS: Treatment with glimepiride, a sulphonylurea approved for the treatment of diabetes mellitus, induced the release of PrP(C) from the surface of prion-infected neuronal cells. The cell surface is a site where PrP(C) molecules may be converted to PrP(Sc) and glimepiride treatment reduced PrP(Sc) formation in three prion infected neuronal cell lines (ScN2a, SMB and ScGT1 cells). Glimepiride also protected cortical and hippocampal neurones against the toxic effects of the prion-derived peptide PrP82-146. Glimepiride treatment significantly reduce both the amount of PrP82-146 that bound to neurones and PrP82-146 induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) and the production of prostaglandin E(2) that is associated with neuronal injury in prion diseases. Our results are consistent with reports that glimepiride activates an endogenous glycosylphosphatidylinositol (GPI)-phospholipase C which reduced PrP(C) expression at the surface of neuronal cells. The effects of glimepiride were reproduced by treatment of cells with phosphatidylinositol-phospholipase C (PI-PLC) and were reversed by co-incubation with p-chloromercuriphenylsulphonate, an inhibitor of endogenous GPI-PLC. CONCLUSIONS: Collectively, these results indicate that glimepiride may be a novel treatment to reduce PrP(Sc) formation and neuronal damage in prion diseases.

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