A ROLE FOR 12-LIPOXYGENASE IN NERVE-CELL DEATH CAUSED BY GLUTATHIONE DEPLETION

An early and highly specific decrease in glutathione (GSH) in the subs tantia nigra is associated with Parkinson's disease, and low levels of GSH lead to the degeneration of cultured dopaminergic neurons. Using immature cortical neurons and a clonal nerve cell line, it is shown th at a decrease in GSH triggers the activation of neuronal 12-lipoxygena se (12-LOX), which leads to the production of peroxides, the influx of Ca2+, and ultimately to cell death. The supporting evidence includes: 1) inhibitors of arachidonate metabolism and 12-LOX block cell death induced by GSH depletion; 2) there is an increase in 12-LOX activity a nd a membrane translocation in HT22 cells, and an induction of the enz yme in primary cortical neurons following the reduction of GSH; 3) 12- LOX is directly inhibited by GSH; and 4) exogenous arachidonic acid po tentiates cell death. These data show that the LOX pathway is a critic al intermediate in at least some forms of neuronal degeneration.