IN-VITRO STUDIES OF FERRITIN IRON RELEASE AND NEUROTOXICITY

The increase in brain iron associated with several neurodegenerative d iseases may lead to an increased production of free radicals via the F enton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6 -hydroxydopamine (6-OHDA) releases iron from the ferritin core by redu cing it to the ferrous form. Iron release induced by 6-OHDA and struct urally related compounds and two other dopaminergic neurotoxins, 1-met hyl-4-phenylpyridinium iodide (MPP+) and -trichloromethyl-1,2,3,4-tetr ahydro-beta-carboline (TaClo), were compared, to identify the structur al characteristics important for such release. 1,2,4-Trihydroxybenzene (MB) was most effective in releasing ferritin-bound iron, followed by 6-OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP+, and T aClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potent ial and an ortho-dihydroxyphenyl structure are important in the mechan ism by which ferritin iron is mobilized. In the presence of ferritin, both 6-OHDA and THE strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These res ults suggest that ferritin iron release contributes to free radical-in duced cell damage in vivo.