Does nitric oxide contribute to iron-dependent brain injury after experimental cerebral ischaemia?

Abstract

Experimental and clinical data suggest that iron has a key role in cerebral ischaemia. We measure infarct volume and analyse the nitric oxide responses to brain injury in rat stroke model after increased oral iron intake. Permanent middle cerebral artery occlusion (MCAO) was performed in a group of 20 male Wistar rats, 10 of which were fed with a control diet and 10 of which were fed with iron-enriched diet containing 2.5% carbonyl iron for 9 weeks. L-arginine and nitric oxide metabolites were determined in blood samples before and at 2, 6, 8 and 48 h after MCAO. Infarct volume, thiobarbituric acid reaction substances (TBARS) and tissue iron were measured at 48 h. Infarct volume was 66% greater in the iron-fed rats than in the control group. Iron-fed animals showed significantly higher levels of TBARS. Liver iron stores (3500 +/- 199 vs 352 +/- 28 microg Fe/g, p<0.0001) but not brain iron stores (131 +/- 11 vs 139 +/- 8 microg Fe/g, p=0.617), were significantly higher in the iron-fed group. L-arginine levels were slightly lower in iron-fed rats and decreased significantly in both groups at 6 and 8 hours after MCAO. The levels of the stable end products of NOS (NOx = nitrite + nitrate) were significantly higher in iron-fed rats before MCAO (16.2 +/- 2.2 vs. 9.6 +/- 0.8 micromol x L(-1), p<0.05), with a further increase during the six first hours after MCAO in both groups. These results suggest that the iron overload that increases both superoxide and nitric oxide production leads to peroxynitrite formation, thus enhancing brain damage.

NOx and ADMA changes with focal ischemia, amelioration with the chaperonin GroEL

“…We find that NO x levels are increased in the brain after ischemic injury, consistent with results from other laboratories in animal studies [7,14] and in patients following stroke [4]. The increase in cerebral NO x is reflected by increases in CSF and plasma NO x .…”

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

“…Iron involvement in oxidative stress caused by ischemic stroke has been confirmed from experimental [191,193,194,207,236], clinical [17,18,192,209,210] and epidemiological [237][238][239] data. Nevertheless, the mechanisms by which iron participates in neuronal death have not been well defined until now.…”

“…Experimental iron overload induced using an iron-rich diet causes larger infarct volumes after permanent MCAO in rats, which is associated with higher oxidative stress, excitotoxicty and inflammatory responses [193,207]. When permanent MCAO was maintained for 48 h, infarct volume was 66% greater in the iron fed-rats than in control.…”

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

“…Through PKC activation, iron enhances the toxicity of Aβ [136]. In stroke, iron overload contributes to peroxynitrate formation and the release of reactive oxygen species [137]. The similarities in injury response between the two diseases are the result of early immune suppression.…”