Protective effect of nitric oxide against iron-induced neuronal damage.
We investigated the effect of nitric oxide (NO) on iron-induced neuronal damage. Incubation of PC12 cells after the addition of FeCl2 induced rapid increases (within 1 hr) in lipid peroxidation and a concentration (0.1-2 mM)-dependent decrease in cell viability at 48 hr, both of which were blocked by deferoxamine and 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazine-3-o ne hydrochloride (MCLA) (a superoxide scavenger) but not by mannitol (a hydroxyl radical scavenger). Iron-induced cytotoxicity was also antagonized by superoxide dismutase with catalase. On the other hand, the NO donors S-nitroso-N-acetylpenicillamine (SNAP), 3-¿(+/-)-(E)-ethyl-2'-[(E)-hydroxylamino]-5-nitro-3-hexenecarbo moyl¿-pyridine (NOR-4), and 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (NOC-18) decreased cell viability 48 hr after addition without increasing lipid peroxidation. However, when added with 1 mM FeCl2, NO donors including NOC-18, SNAP and NOR-4 (0.1-1 mM) inhibited lipid peroxidation in a concentration-dependent manner and suppressed cell death at lower concentrations. Addition of MCLA and NOC-18 also suppressed decreases in iron-induced [3H]thymidine incorporation. In rat brain homogenate, NOC-18 and SNAP both suppressed iron-induced lipid peroxidation. These findings suggest that NO has a dual effect on neuronal viability and can act as an antioxidant which protects neurons from iron-induced damage.
Nara
K
K
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
Konno
D
D
Uchida
J
J
Kiuchi
Y
Y
Oguchi
K
K
D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005296:Ferrous Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D005296:Ferrous Compounds; D016166:Free Radical Scavengers; D007093:Imidazoles; D020030:Nitric Oxide Donors; D011719:Pyrazines; D017392:Thiobarbituric Acid Reactive Substances; C063412:2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo(1,2-alpha)pyrazin-3-one; C029451:ferrous chloride