title: Arsenite induces oxidative injury in rat brain: synergistic effect of iron.
abstract: Sodium arsenite (arsenite)-induced neurotoxicity and its interaction with ferrous citrate (iron) was investigated in rat brain. In vitro data showed that arsenite (1-10 micromol/L) concentration dependently increased lipid peroxidation and the potency of arsenite was less than that of iron. The oxidative activity of arsenite, sodium arsenate (arsenate), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were evaluated by inducing lipid peroxidation in cortical homogenates, and the potency for this effect was as follows: arsenite > arsenate > MMA and DMA. Several well-known antioxidants, including glutathione, melatonin, and beta-estradiol inhibited arsenite-induced lipid peroxidation in a concentration-dependent manner. Our in vivo study employed intranigral infusion of arsenite (5 nmol) in the substantia nigra (SN) of anesthetized rats. Four hours to 7 days after infusion, lipid peroxidation was elevated while glutathione was depleted in the infused SN. The dopamine content in the striatum ipsilateral to arsenite-infused SN was first elevated 24 h and then decreased 7 days after intranigral infusion of arsenite. Using pretreatment of l-buthionine-[S,R]-sulfoximine (l-BSO, i.c.v.) to reduce glutathione content in rat brain, arsenite-induced oxidative injury was augmented. Low doses of arsenite (1.5 nmol) and iron (3 nmol) alone induced minimal oxidative injury; however, co-infusion of arsenite and iron augmented neurotoxicity, including elevated lipid peroxidation and reduced striatal dopamine content. Moreover, expression of heme oxygenase-1, alpha-synuclein aggregation, and DNA fragmentation were significantly enhanced in SN co-infused with low doses of arsenite and iron. Taken together, our study demonstrates that arsenite was less potent than iron in inducing oxidative stress. Furthermore, concomitant arsenite and iron potentiated oxidative injury in the nigrostriatal dopaminergic system, indicating that interaction of metals plays a more clinically-relevant role in pathophysiology of central nervous system neurodegeneration.
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Su-Feng
authors.initials: SF
authors.lastname: Fan
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chao
authors.forename: Anya Maan-Yuh
authors.initials: AM
authors.lastname: Lin
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D004563:Electrochemistry; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D013378:Substantia Nigra / Q000201:enzymology / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D018053:Arsenites; D051844:alpha-Synuclein; D019328:Buthionine Sulfoximine; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione; C015001:arsenite; D004298:Dopamine