Glimepiride Reduces the Expression of PrPC, Prevents PrPSc Formation and Protects against Prion Mediated NeurotoxicityReportar como inadecuado




Glimepiride Reduces the Expression of PrPC, Prevents PrPSc Formation and Protects against Prion Mediated Neurotoxicity - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

A 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 Findings

Treatment 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.

Conclusions

Collectively, these results indicate that glimepiride may be a novel treatment to reduce PrPSc formation and neuronal damage in prion diseases.



Autor: Clive Bate , Mourad Tayebi, Luisa Diomede, Mario Salmona, Alun Williams

Fuente: http://plos.srce.hr/



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