In:
Journal of Neuroscience Research, Wiley, Vol. 65, No. 6 ( 2001-09-15), p. 565-572
Abstract:
Transmissible spongiform encephalopathies are characterised by the transformation of the normal cellular prion protein (PrP C ) into an abnormal isoform (PrP TSE ). Previous studies have shown that N‐methyl‐D‐aspartate (NMDA) receptor antagonists can inhibit glutathione depletion and neurotoxicity induced by PrP TSE 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 PrP TSE ‐mediated cell loss in vivo. If this is so, therapeutic intervention with 5‐LOX inhibitors may prove beneficial in the treatment of prion disorders. J. Neurosci. Res. 65:565–572, 2001. © 2001 Wiley‐Liss, Inc.
Type of Medium:
Online Resource
ISSN:
0360-4012
,
1097-4547
Language:
English
Publisher:
Wiley
Publication Date:
2001
detail.hit.zdb_id:
1474904-X
SSG:
12
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