Abstract
BackgroundA hallmark of the prion diseases is the conversion of the host-encoded cellular prion protein (PrPC) into a disease related, alternatively folded isoform (PrPSc). The accumulation of PrPSc 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 FindingsTreatment with glimepiride, a sulphonylurea approved for the treatment of diabetes mellitus, induced the release of PrPC from the surface of prion-infected neuronal cells. The cell surface is a site where PrPC molecules may be converted to PrPSc and glimepiride treatment reduced PrPSc 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 A2 (cPLA2) and the production of prostaglandin E2 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 PrPC 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.ConclusionsCollectively, these results indicate that glimepiride may be a novel treatment to reduce PrPSc formation and neuronal damage in prion diseases.
Highlights
The transmissible spongiform encephalopathies, otherwise known as prion diseases include Creutzfeldt-Jakob disease and kuru in humans, as well as important livestock diseases such as scrapie in sheep and goats and bovine spongiform encephalopathy in cattle
Collectively, these results indicate that glimepiride may be a novel treatment to reduce PrPSc formation and neuronal damage in prion diseases
This effect of glimepiride was not shared by glibenclamide or glipizide, two other sulphonylureas used to treat diabetes mellitus, which did not alter the PrPC content of neurones
Summary
The transmissible spongiform encephalopathies, otherwise known as prion diseases include Creutzfeldt-Jakob disease and kuru in humans, as well as important livestock diseases such as scrapie in sheep and goats and bovine spongiform encephalopathy in cattle. The central event in these diseases is the conversion of a host encoded cellular prion protein (PrPC) into abnormally folded, disease-associated isoforms (PrPSc) in the brains of infected animals [1]. The primary amino acid sequence remains the same, during the conversion process a portion of the a-helix and random coil structure in PrPC is refolded into a b-pleated sheet in PrPSc [2]. This change in secondary structure is accompanied by changes in the biological and biochemical properties of the PrPSc protein, including reduced solubility and an increased resistance to proteases [3]. Novel therapeutics are desperately required to treat neurodegenerative diseases including the prion diseases
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