Glimepiride Potential for Treatment of Prion Diseases


Top - PrPc; Bottom - PrPSc Source: European Commission
Top - PrPc; Bottom - PrPSc

Source: European Commission

Prion diseases comprise the transmissible spongiform encephalopathies, including scrapie in sheep, bovine spongiform encephalopathy (BSE, “Mad Cow” disease) in cattle and Creutzfeldt-Jakob disease in humans. Central to these diseases is the conversion of normal cellular prion protein (PrPc) into the abnormally folded, pathogenic species (PrPSc) in the brain. The misfolding results in prion protein with distinct biochemical properties compared to the normal protein, such as reduced solubility and decreased susceptibility to proteases. Aggregates of PrPSc accumulate in association with neurons in affected brain areas, which is thought to lead to the synapse degeneration and neuronal death observed in infected hosts.

Researchers in the UK and Italy have now shown that glimepiride, a sulfonyl urea approved for the treatment of non insulin dependent diabetes mellitus (NIDDM), is able to reduce PrPSc formation in cell culture. The rationale for the study was based on the knowledge that generation of PrPSc is dependent on the presence of PrPc and that this appeared to require PrPc expressed at the cell surface. PrPc is linked to the membrane by a glycosylphosphatidylinositol (GPI) anchor and can be released from the surface of cells by treatment with phosphatidylinositol-phospholipase C (PI-PLC). Consistent with the hypothesis that cell-surface PrPc is required, treatment of prion-infected neuronal cells with PI-PLC reduced PrPSc formation.

Since glimepiride has been shown to stimulate the release of some GPI-anchored proteins in adipocytes (via stimulation of an endogenous GPI-PLC), the team explored the effects of the drug on PrPc/PrPSc in neuronal cell culture. Similarly to PI-PLC, glimepiride reduced the amount of cell-surface PrPc in primary cortical neurons and neuronal cell lines. In addition, glimepiride reduced formation of PrPSc in three prion-infected neuronal cell lines.

The study, published in PLoSone, also demonstrated that glimepiride treated neurons were resistant to the toxicity of a PrP-derived peptide, PrP82-146.

The team note that modulation of cell-surface PrPc may also have application in Alzheimer’s disease since it is a receptor for β-amyloid oligomers. Whether glimepiride is sufficiently CNS-penetrant to be effective remains to be seen.

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