Phospholipase A2 inhibitors or platelet-activating factor antagonists prevent prion replication.
A key feature of prion diseases is the conversion of the cellular prion protein (PrP(C)) into disease-related isoforms (PrP(Sc)), the deposition of which is thought to lead to neurodegeneration. In this study a pharmacological approach was used to determine the metabolic pathways involved in the formation of protease-resistant PrP (PrP(res)) in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells). Daily treatment of these cells with phospholipase A(2) (PLA(2)) inhibitors for 7 days prevented the accumulation of PrP(res). Glucocorticoids with anti-PLA(2) activity also prevented the formation of PrP(res) and reduced the infectivity of SMB cells. Treatment with platelet-activating factor (PAF) antagonists also reduced the PrP(res) content of cells, while the addition of PAF reversed the inhibitory effect of PLA(2) inhibitors on PrP(res) formation. ScGT1 cells treated with PLA(2) inhibitors or PAF antagonists for 7 days remained clear of detectable (PrPres) when grown in control medium for a further 12 weeks. Treatment of non-infected cells with PLA(2) inhibitors or PAF antagonists reduced PrP(C) levels suggesting that limiting cellular PrP(C) may restrict prion formation in infected cells. These data indicate a pivotal role for PLA(2) and PAF in controlling PrP(res) formation and identify them as potential therapeutic agents.
Bate
Clive
C
Department of Veterinary Pathology, Glasgow University Veterinary School, Bearsden Road, Glasgow G61 1QH, Scotland, United Kingdom. c.bate@vert.gla.ac.uk
Reid
Stuart
S
Williams
Alun
A
D002460:Cell Line; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000737:chemistry; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D018620:PrPSc Proteins / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D010743:Phospholipids; D010972:Platelet Activating Factor; D018620:PrPSc Proteins; D011328:Prions; D003907:Dexamethasone; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone