Cyclo-oxygenase inhibitors protect against prion-induced neurotoxicity in vitro.

Abstract

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.