NR ALEH
AU Stewart,L.R.; White,A.R.; Jobling,M.F.; Needham,B.E.; Maher,F.; Thyer,J.; Beyreuther,K.; Masters,C.L.; Collins,S.J.; Cappai,R.
TI Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126
QU Journal of Neuroscience Research 2001 Sep 15; 65(6): 565-72
PT journal article
AB Transmissible spongiform encephalopathies are characterised by the transformation of the normal cellular prion protein (PrPc) into an abnormal isoform (PrPtse). Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor antagonists can inhibit glutathione depletion and neurotoxicity induced by PrPtse and a toxic prion protein peptide, PrP106-126, in vitro. NMDA receptor activation is known to increase intracellular accumulation of Ca(2+), resulting in up-regulation of arachidonic acid (AA) metabolism. This can stimulate the lipoxygenase pathways that may generate a number of potentially neurotoxic metabolites. Because of the putative relationship between AA breakdown and PrP106-126 neurotoxicity, we investigated AA metabolism in primary cerebellar granule neuron cultures treated with PrP106-126. Our studies revealed that PrP106-126 exposure for 30 min significantly up-regulated AA release from cerebellar granule neurons. PrP106-126 neurotoxicity was mediated through the 5-lipoxygenase (5-LOX) pathway, as shown by abrogation of neuronal death with the 5-LOX inhibitors quinacrine, nordihydroguaiaretic acid, and caffeic acid. These inhibitors also prevented PrP106-126-induced caspase 3 activation and annexin V binding, indicating a central role for the 5-LOX pathway in PrP106-126-mediated proapoptosis. Interestingly, inhibitors of the 12-lipoxygenase pathway had no effect on PrP106-126 neurotoxicity or proapoptosis. These studies clearly demonstrate that AA metabolism through the 5-LOX pathway is an important early event in PrP106-126 neurotoxicity and consequently may have a critical role in PrPtse-mediated cell loss in vivo. If this is so, therapeutic intervention with 5-LOX inhibitors may prove beneficial in the treatment of prion disorders.
MH Animal; Annexin V/drug effects/metabolism; Anti-Inflammatory Agents, Non-Steroidal/pharmacology; Arachidonate 5-Lipoxygenase/*metabolism; Arachidonic Acid/*metabolism/secretion; Binding Sites/drug effects/physiology; Caspases/drug effects/metabolism; Cells, Cultured/drug effects/enzymology; Cerebellar Cortex/drug effects/enzymology; Enzyme Inhibitors/pharmacology; Excitatory Amino Acid Antagonists/pharmacology; Memantine/pharmacology; Mice; Mice, Inbred C57BL; Neurons/*drug effects/enzymology; Neurotoxins/*toxicity; Peptide Fragments/*toxicity; Prion Diseases/*enzymology/physiopathology; Prions/*metabolism/*toxicity; Quinacrine/pharmacology; Support, Non-U.S. Gov't
AD Department of Pathology, The University of Melbourne, Victoria, Australia.
SP englisch
PO USA