Ischemia-induced brain iron delocalization: Effect of iron chelators

Oubidar, Mohamed; Boquillon, Micheline; Marie, Christine; Schreiber, Lisbeth; Bralet, J

doi:10.1016/0891-5849(94)90205-4

Cited by 56 publications

(33 citation statements)

References 51 publications

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“…As in the case of the PD nigra, cerebral cortices and hippocampi affected by Alzheimer's disease and CNS tissues subjected to ischemidreperfusion exhibit enhanced glial HO-1 immunoreactivity, abnormal iron deposits, and mitochondrial insufficiency (Oubidar et al, 1994;Reichmann and Riederer, 1994;Schipper et al, 1995;Geddes et al, 1996;Janetzky et al, 1997). In addition, cytokines implicated in the pathogenesis of multiple sclerosis, such as tumor necrosis factor-a and interleukin-1 p, stimulate HO-1 expression in cultured astroglia followed by sequestration of non-transferrinderived iron by the mitochondrial compartment (K. Mehindate, S. Dion, and H. M. Schipper, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Schipper

Bernier

Mehindate

et al. 1999

Journal of Neurochemistry

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Abstract:Little is currently known concerning the mechanisms responsible for the excessive deposition of redox-active iron in the substantia nigra of subjects with Parkinson's disease (PD). In the present study, we demonstrate that dopamine promotes the selective sequestration of non-transferrin-derived iron by the mitochondrial compartment of cultured rat astroglia and that the mechanism underlying this novel dopamine effect is oxidative in nature. We also provide evidence that up-regulation of the stress protein heme oxygenase-1 (HO-1) is both necessary and sufficient for mitochondrial iron trapping in dopamine-challenged astroglia. Finally, we show that opening of the mitochondrial transition pore (MTP) mediates the influx of non-transferrin-derived iron into mitochondria of dopamine-stimulated and HO-1 -transfected astroglia. Our findings provide an explanation for the pathological iron sequestration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transition metal trapping by "stressed" astroglial mitochondria (e.g., using HO-1 inhibitors or modulators of the MTP) may afford effective neuroprotection in patients with PD and other neurological afflictions.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Schipper

Bernier

Mehindate

et al. 1999

Journal of Neurochemistry

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“…Indeed, as a result of its high hydrosolubility, deferoxamine cannot rapidly reach the intracellular space of brain after acute systemic treatment (Lloyd et al, 1991). To our knowledge, whether liposoluble iron chelator can decrease histological damage induced by brain ischemia has never been reported; however, it was previously shown that the liposoluble iron chelator 2,2Ј-dipyridyl (DP) decreased edema induced by focal brain ischemia (Oubidar et al, 1994).…”

mentioning

confidence: 92%

“…Arguments exist for the existence of disruption of the cerebral iron homeostasis after ischemia. Thus, ischemic brain tissue was reported to accumulate ultrafiltrable iron (Oubidar et al, 1994;Lipscomb et al, 1998) and to express a high level of ferritin (Chi et al, 2000), an indirect marker of free iron excess. Indeed, the main mechanism elaborated by cells to keep the intracellular free iron level within normal range is the regulation by free iron level itself of the synthesis of ferritin (Eisenstein, 2000), the main intracellular iron storage protein.…”

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confidence: 99%

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2′-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

Demougeot¹,

Hoecke²,

Bertrand³

et al. 2004

J Pharmacol Exp Ther

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We examined the efficacy of the liposoluble iron chelator 2,2Ј-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1␣ (HIF-1␣) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (ϩ100%) and HIF-1␣ (Ϫ50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.

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“…In hypoxia and reoxygenation-mediated neuronal injury, an important role is ascribed to the ionized iron, which may participate in Fenton-type reactions and thus catalyze the generation of reactive oxygen species (Oubidar et al, 1994). Deferoxamine mesylate chelates ionized iron in Fe 3+ state (Halliwell & Gutteridge, 1999), thus making it unavailable for catalytic action in a Fenton type reaction.…”

Section: Discussionmentioning

confidence: 99%

Effect of lipid peroxidation conditions on calcium-dependent activity of phosphodiesterase 3′,5′-cAMP in the rat brain

et al. 2006

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3',5'-cAMP plays an important role as a second messenger molecule controlling multiple cellular processes in the brain. Its levels are decreased by phosphodiesterases (PDEs), responsible for hydrolysis of intracellular cAMP. A part of the PDE activity is dependent on the effect of calcium, mediated by its binding to calmodulin. During oxidative stress, precisely these changes in calcium concentration are responsible for cell damage. We have examined the effects of oxidative stress conditions on the activity of PDE in rat brain homogenates. We found a different influence of activated lipid peroxidation conditions (Fe 2+ with ascorbate and increased temperature) on the calcium-dependent and calciumindependent PDE activity. The inhibition of Ca 2+ -dependent PDE was observed, while Ca 2+ -independent PDE was not influenced. We assume that it might be the impact of lipid peroxidation products or any mechanism activated by the higher temperature on the interaction of the Ca 2+ -dependent isoform of PDE with the complex calcium-calmodulin. Another explanation might be that the formation of the functioning calcium-calmodulin complex is impossible in these conditions.

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Ischemia-induced brain iron delocalization: Effect of iron chelators

Cited by 56 publications

References 51 publications

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2′-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

Effect of lipid peroxidation conditions on calcium-dependent activity of phosphodiesterase 3′,5′-cAMP in the rat brain

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