Post resuscitation iron delocalization and malondialdehyde production in the brain following prolonged cardiac arrest

Nayini, Narsimha R; White, Blaine C.; Aust, Steven D.; Huang, Ran; Indrieri, R. J.; Evans, AT; Bialek, Howard; Jacobs, W. A.; Komara, James

doi:10.1016/0748-5514(85)90014-5

Cited by 80 publications

(17 citation statements)

References 50 publications

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“…As shown in Fig. 5, tissue levels oflow molecular weight iron chelates are increased in ischemic reperfused lung in a similar magnitude as reported in ischemic reperfused brain (17) and heart (49). Furthermore, the increase iron is prevented by 8-methoxypsoralen, piperonyl butoxide, or cimetidine.…”

Section: Discussionsupporting

confidence: 66%

“…In reperfusion injury iron appears to promote tissue damage by catalyzing hydroxyl radical ('OH) generation via the Fenton reaction and by propagating lipid peroxidation. Recently, the iron chelator deferoxamine has been shown to prevent reperfusion injury in the heart (14), intestine (15), skin (16), brain (17), and lung (18). While much activity has been directed toward defining the source of O°and H202 in reperfusion injury, little attention has been paid to locating the intracellular sources of iron, although ferritin has been implicated (19,20).…”

Section: Introductionmentioning

confidence: 99%

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Role of cytochrome P-450 in reperfusion injury of the rabbit lung.

Bysani¹,

Kennedy²,

Ky³

et al. 1990

J. Clin. Invest.

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Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P450 enzymes are an important pulmonary source of superoxide anion (02) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical COH) formation and propagation of lipid peroxidation, we postulated that cytochrome P450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P450 enzymes in a rabbit model of reperfusion lung injury. The P450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of '25I-albumin from the vascular space into lung water and alveolar fluid. P450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P450 inhibitors did not block enhanced 0°generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P450 enzymes are not likely a major source of enhanced 05 generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P450 in reperfusion injury to the lung and suggest potential new therapies for the disorder. (J.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Role of cytochrome P-450 in reperfusion injury of the rabbit lung.

Bysani¹,

Kennedy²,

Ky³

et al. 1990

J. Clin. Invest.

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“…Iron chelators such as deferoxamine are logical candidates to probe the role of these reactions in ischemic brain. Deferoxamine-treatment has been associated with reduced lipid peroxidation, improved post-ischemic vasoreactivity, cerebral perfusion and ATP recovery (Hurn et al, 1995;Liachenko et al, 2003;Nayini et al, 1985;Nelson et al, 1992). Unfortunately, histological/behavioral outcome studies have failed to find consistent benefit from this strategy (Fleischer et al, 1987;Kumar et al, 1988), possibly due to its short-half-life.…”

Section: Metal Chelatorsmentioning

confidence: 99%

Oxidants, antioxidants and the ischemic brain

Warner

Sheng

Batinić‐Haberle

2004

Journal of Experimental Biology

538

362

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SUMMARY Despite numerous defenses, the brain is vulnerable to oxidative stress resulting from ischemia/reperfusion. Excitotoxic stimulation of superoxide and nitric oxide production leads to formation of highly reactive products,including peroxynitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Use of transgenic mutants and selective pharmacological antioxidants has greatly increased understanding of the complex interplay between substrate deprivation and ischemic outcome. Recent evidence that reactive oxygen/nitrogen species play a critical role in initiation of apoptosis, mitochondrial permeability transition and poly(ADP-ribose) polymerase activation provides additional mechanisms for oxidative damage and new targets for post-ischemic therapeutic intervention. Because oxidative stress involves multiple post-ischemic cascades leading to cell death, effective prevention/treatment of ischemic brain injury is likely to require intervention at multiple effect sites.

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“…The extent of this iron delocalization correlates well with the increase in oxidative stress (measured as the peroxidation of tissue lipids) encountered upon reperfusion and with the subsequent physiological dysfunction of the organs upon transplantation [6]. Delocalization of iron as a result of ischaemia/reperfusion has also been shown to occur in brain tissue [7]. The central role of iron in the formation of highly toxic oxygen-derived free radicals and the evidence for delocalization of this metal ion to potentially more active forms during ischaemia/reperfusion provides a basis for the use of iron chelators for alleviating the damage caused by prolonged ischaemia.…”

Section: Introductionmentioning

confidence: 99%

The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia

et al. 1993

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The effect of CP130 (a synthetic hexadentate pyridinone iron chelator) on the formation of two markers of lipid peroxidation (TBA-reactive material and Schiff's bases) in rabbit kidneys following a 72 h period of cold (0-4 degrees C) ischaemia was investigated by either adding CP130 to the flush/storage solution (hypertonic citrate solution) or by administering the agent intravenously 15 min before removal of the organs. In both cases, CP130 blocked the adverse rises in lipid peroxidation caused by ischaemia and subsequent reoxygenation of the homogenates in vitro. Both CP130 and desferrioxamine (DFX) (administered intravenously 15 min before ischaemia and 5 min before reperfusion) were also found to significantly reduce post-ischaemic rates of in vitro lipid peroxidation in kidneys rendered warm ischaemic for 90 min followed by reperfusion for 5 or 60 min in situ. Kidneys exposed to warm ischaemia and reperfusion developed interstitial and intracellular oedema, congestion and haemorrhage. DFX administration had little effect on the histological outcome, whereas CP130 significantly reduced interstitial oedema (at 5 min reperfusion compared to the DFX-treated group), intracellular oedema (at 60 min reperfusion compared to the DFX-treated group) and congestion (at 5 min reperfusion compared with a control group not given any agent). It is concluded that while CP130 and DFX exhibited similar antioxidant properties, CP130 provided better protection from ischaemia/reperfusion injury at the histological level. Synthetic iron chelators may therefore be of benefit in clinical organ transplantation by protecting against tissue damage caused by prolonged ischaemia.

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Post resuscitation iron delocalization and malondialdehyde production in the brain following prolonged cardiac arrest

Cited by 80 publications

References 50 publications

Role of cytochrome P-450 in reperfusion injury of the rabbit lung.

Role of cytochrome P-450 in reperfusion injury of the rabbit lung.

Oxidants, antioxidants and the ischemic brain

The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia

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