Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat

Abstract

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 ironcontaining 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 ironmediated oxidative stress holds extended therapeutic time window against an ischemic event.

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats

“…Our results support the hypothesis that ironmediated BBB disruption in the CA1-2 areas contributes to delayed neuronal cell death in the CA1 following TFI, for the time course of BBB opening is similar to the kinetics of free radical generation in CA1 neurons; free radical levels are highest 8 and 48 h after TFI Park et al, 2010). Iron overload was observed in the endothelium within 30 min after TFI, which resulted in delayed iron overload and free radical production in the CA1 neurons (Park et al, 2010).…”

“…We have previously shown that iron overload is evident early in CA1 pyramidal neurons after TFI, in turn mediating free radical production and delayed neuronal degeneration Park et al, 2010). In this context, iron overload likely contributes to degeneration of CECs, and opening of the BBB.…”

“…Iron overload was observed in the endothelium within 30 min after TFI, which resulted in delayed iron overload and free radical production in the CA1 neurons (Park et al, 2010). Furthermore, DFO prevents BBB opening and delayed degeneration of the CA1 neurons.…”

Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

“…Iron has been found to be required for long-term potentiation in hippocampal CA1 neurons and it is known to participate in the stimulation of calcium release through ROS produced via the Fenton reaction and triggering the activation of cellular signaling pathways [9,10]. These results support a coordinated action between iron and calcium in synaptic plasticity and raise the possibility that elevated iron levels may contribute to neuronal degeneration through excessive intracellular calcium increase caused by iron-induced oxidative stress [11].…”

Neu2000 Potentiates a Kainate Response in Mouse Cortical Neurons

“…Recently, the activation of the GluK1 receptor was reported to play a protective role in cerebral ischemia-reperfusion injury by inhibiting a JNK3 pathway mediated by the GluK2 receptor (11). Since NEU proficiently rescues animals from ischemia-reperfusion injury (4,12), it is highly possible that NEU activity is specific to GluK1 receptors. This subtype specificity of NEU action may explain why NEU has greater efficacy and potency (4) than other chemicals with NMDA-receptor antagonism and anti-oxidation action such as dexanabinol (13) and 1-aminocyclopropanecarboxylic acid (14).…”