Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126

Transmissible spongiform encephalopathies are characterised by the transfor mation of the normal cellular prion protein (PrPc) into an abnormal isoform (PrPTSE). Previous studies have shown that N-methyl-D-aspartate (NMDA) rec eptor antagonists can inhibit glutathione depletion and neurotoxicity induc ed by Prp(TSE) and a toxic prion protein peptide, PrP106-126, in vitro. NMD A receptor activation is known to increase intracellular accumulation of Ca 2+, resulting in up-regulation of arachidonic acid (AA) metabolism. This ca n stimulate the lipoxygenase pathways that may generate a number of potenti ally neurotoxic metabolites. Because of the putative relationship between A A breakdown and PrP106-126 neurotoxicity, we investigated AA metabolism in primary cerebellar granule neuron cultures treated with PrP106-126. Our stu dies revealed that PrP106-126 exposure for 30 min significantly up-regulate d 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, nordihydroguaiareti c acid, and caffeic acid. These inhibitors also prevented PrP106-126-induce d caspase 3 activation and annexin V binding, indicating a central role for the 5-LOX pathway in PrP106-126-mediated proapoptosis. Interestingly, inhi bitors of the 12-lipoxygenase pathway had no effect on PrP106-126 neurotoxi city or proapoptosis. These studies clearly demonstrate that AA metabolism through the 5-LOX pathway is an important early event in PrP106-126 neuroto xicity 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. (C) 2001 Wiley-Liss, Inc.