[Oxidative stress and the brain].
Although the cause of Parkinson's disease is unknown, oxidative stress has been implicated in its pathogenesis. This theory postulates that normal metabolic processes in the nigrostriatal dopaminergic system may lead to loss of neurons, and that iron-dependent membrane lipid peroxidation may play an important role in the neuronal death. Recent research concerning iron-dependent lipid peroxidation is presented. First, catechols (including dopa and dopamine) and iron form strong oxidizing complexes and induce lipid peroxidation (LPO) in phospholipid liposomes. Active oxygen species including superoxide, hydrogen peroxide, hydroxyl radical and singlet oxygen, do not participate in this LPO, which is inhibited by an excess of dopa (dopamine). Cultured neurons and the substantia nigra are vulnerable to LPO. Second, synthetic melanin prepared by the autooxidation of catechols promotes LPO in the presence of iron. The effects of scavenging agents indicate that this LPO is mediated by superoxide, but not by other oxygen free radicals. Neuronal cell cultures are destroyed by this LPO. Third, catechols and superoxide produced by microglia cause the release of iron from ferritin. Microglia stimulated by phorbol myristate acetate produce superoxide and cause the release of iron from ferritin. Catechols also induce mobilization of ferritin iron. The released iron (i.e. loosely-bound iron) is available to iron-dependent LPO. These data suggest that the biochemical and morphological characteristics of the substantia nigra, which are concomitant with its functional role, provoke iron-dependent lipid peroxidation. It is essential to elucidate how iron bound loosely to low molecules comes into contact with catechols, neuromelanin and superoxide. Drugs that chelate iron site-specifically or modulate the microglial function may bring about some favorable changes in the disease process.
Tanaka
M
M
Department of Neurology, Gunma University Faculty of Medicine.
D000818:Animals; D002396:Catechols / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D017628:Microglia / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D013481:Superoxides / Q000378:metabolism
D002396:Catechols; D013481:Superoxides; D005293:Ferritins; D007501:Iron; C034221:catechol; D004298:Dopamine