Prion peptide-mediated cellular prion protein overexpression and neuronal cell death can be blocked by aspirin treatment.

Prion diseases are infectious neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrPc) to the misfolded isoform (PrPsc). Prion peptide PrP 106-126 [PrP (106-126)] shares many physiological properties with PrPsc; it is neurotoxic in vitro and in vivo. PrP (106-126) induces neurotoxicity by the overexpression of PrPc and activation of the mitogen-activated protein (ERK1/2). Aspirin, an anti-inflammatory drug, is a known ERK inhibitor and prevents neurodegenerative disorders including prion diseases. The influence of aspirin treatment on prion protein-mediated neurotoxicity and expression of PrPc were the focus of this study. Cell viability and apoptosis were assessed by crystal violet staining and the TUNEL and DNA fragmentation assays. Apoptosis-associated protein expression of PrPc, p-53, p-ERK1/2, p-p38, Bcl-2 and cleaved-caspase-3 was examined by Western blotting and immunocytochemistry. Aspirin treatment inhibited PrP (106-126)-induced neuronal cell death in SH-SY5Y neuroblastoma cells. In addition, the PrP (106-126)-mediated increase of p-p38, p53, cleaved-caspase-3 and decrease of Bcl-2 expressions were blocked by aspirin and the ERK inhibitor, PR98059. Furthermore, we showed that the PrP (106-126)-mediated increase of PrPc and p-ERK1/2 were inhibited by PD98059 and aspirin. Taken together, these results demonstrate that ERK1/2 is a key modulator of the protective effect of aspirin on PrP-106-126-mediated cellular prion protein overexpression and neurotoxicity and also suggest that aspirin may prevent neuron cell damages caused by the prion peptide.