Cyclo-oxygenase inhibitors protect against prion-induced neurotoxicity in vitro.
The mechanisms of neuronal loss during the course of the prion diseases are not fully understood. In this study, neurones treated with certain non-steroidal anti-inflammatory drugs (NSAIDs) were protected against the otherwise toxic effects of a peptide derived from the prion protein, or extracts containing infectious prions (PrP ). These NSAIDs inhibit the cyclo-oxygenase (cox) enzymes that metabolise arachidonic acid to prostaglandins (PG). Conversely, drugs that inhibited the metabolism of arachidonic acid to leucotrienes enhanced neurotoxicity. Studies with selective inhibitors highlighted the importance of the cox-1 isoform in prion-induced neurotoxicity. The cox-1 inhibitors also inhibited neuronal PGE production and protected both neuroblastoma cells and primary cortical neurones against prions. They also reduced microglia-mediated killing of prion-treated neurones.
Bate
Clive
C
Institute of Comparative Medicine, Glasglow University Veterinary School, Glasgow, UK. c.bate@vet.gla.ac.uk
Rutherford
Scott
S
Gravenor
Mike
M
Reid
Stuart
S
Williams
Alun
A
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D018698:Glutamic Acid / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D017096:Prion Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D011328:Prions / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018620:PrPSc Proteins; D011328:Prions; C419707:prion protein (105-132); D018698:Glutamic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone