Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat.
Abnormal brain iron homeostasis has been proposed as a pathological event leading to oxidative stress and neuronal injury under pathological conditions. We examined the possibility that neuronal iron overload would mediate free radical production and delayed neuronal death (DND) in hippocampal CA1 area after transient forebrain ischemia (TFI). Mitochondrial free radicals (MFR) were biphasically generated in CA1 neurons 0.5-8 and 48-60 h after TFI. Treatment with Neu2000, a potent spin trapping molecule, as well as trolox, a vitamin E analogue, blocked the biphasic MFR production and attenuated DND in the CA1, regardless of whether it was administered immediately or even 24 h after reperfusion. The late increase in MFR was accompanied by iron accumulation and blocked by the administration of deferoxamine-an iron chelator. Iron accumulation was attributable to prolonged upregulation of the transferrin receptor and to increased uptake of peripheral iron through a leaky blood-brain barrier. Infiltration of iron-containing cells and iron accumulation were attenuated by depletion of circulating blood cells through X-ray irradiation of the whole body except the head. The present findings suggest that excessive iron transported from blood mediates slowly evolving oxidative stress and neuronal death in CA1 after TFI, and that targeting iron-mediated oxidative stress holds extended therapeutic time window against an ischemic event.
Neuroscience Graduate Program, Ajou University School of Medicine, San 5, Wonchun-Dong, Yeoungtong-Gu, Suwon 443-749, South Korea.
Ui Jin
UJ
Park
Young Ae
YA
Lee
Sun Mi
SM
Won
Jin Hwan
JH
Lee
Seung-Hee
SH
Kang
Joe E
JE
Springer
Yong Beom
YB
Lee
Byoung Joo
BJ
Gwag
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D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001324:Autoantigens; D000098902:CD163 Antigen; D006021:Glycophorins; D011956:Receptors, Cell Surface; D014168:Transferrin; C044589:epidermolysis bullosa acquisita antigen; D005070:Evans Blue; D000080242:8-Hydroxy-2'-Deoxyguanosine; D007501:Iron; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D010751:Phosphopyruvate Hydratase; D003849:Deoxyguanosine; D015032:Zinc