Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats.

Palmer, Charles; Roberts, Rebecca; Bero, Christopher J.

doi:10.1161/01.str.25.5.1039

Cited by 197 publications

(108 citation statements)

References 46 publications

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“…Desferrioxamine also prevented the permeability response to arachidonic acid at modest concentrations (100 ìÒ rather than > 1 mÒ), which relates to its ability to prevent lipid peroxidation rather than direct free radical formation (Caraceni, Vanthiel & Borle, 1995). A similar concentration of desferrioxamine was found to be effective in reducing ischaemic brain injury in neonatal rats (Palmer, Roberts & Bero, 1994). Further evidence for the hypothesis that free radical generation is responsible for the permeability response was obtained using eicosapentaenoic acid (EPA), a major constituent of fish oils.…”

Section: Discussionmentioning

confidence: 94%

Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat

Easton

Fraser

1998

The Journal of Physiology

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We have investigated the permeability‐increasing effect of arachidonic acid on pial venular capillaries in vivo using the single microvessel occlusion technique. Permeability to Lucifer Yellow dye (476 Da) increased dose dependently when arachidonic acid was applied focally to the abluminal surface of the vessels. This was completely reversible at all but the highest dose. The permeability increase was 1.65 × 10−6± 0.247 × 10−6 cm s−1 (mean ± s.e.m.) at 0.25 mm, 3.53 × 10−6± 0.872 × 10−6 cm s−1 at 0.5 mm, 12.61 × 10−6± 3.44 × 10−6 cm s−1 at 1 mm and 18.46 × 10−6± 5.90 × 10−6 cm s−1 at 2 mm arachidonic acid. There was a similar reversible dose‐dependent permeability increase to eicosapentaenoic acid. These permeability increases could be prevented by co‐application of a mixture of the anti‐oxidants superoxide dismutase and catalase (30 and 100 U ml−1), or by the iron chelator desferrioxamine (100 μm). The permeability increases were also prevented by the cyclooxygenase and 5‐lipoxygenase blockers indomethacin (100 μm) and nordihydroguariaretic acid (100 μm), respectively, when applied together, but not singly. It was concluded that the permeability response to arachidonic acid depends on the formation of free radicals and subsequent lipid peroxidation.

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Section: Discussionmentioning

confidence: 94%

Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat

Easton

Fraser

1998

The Journal of Physiology

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“…DMA and DFC have siderophore (iron chelating) structural features and strong radical scavenging activity (Aniya et al 1999). It has been reported that the compounds which have the siderophore structural features such as deferoxamine could rapidly penetrate the blood-brain barrier (BBB) and accumulate in brain tissue at a significant concentration after systemic administration (Keberle 1964;Palmer et al 1994). In addition, lipophilic agents can penetrate the lipid membranes by diffusion and a set of specialised transport mechanisms (Abbott & Romero 1996).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of dimerumic acid and deferricoprogen fromMonascus purpureusNTU 568-fermented rice against 6-hydroxydopamine-induced oxidative stress and apoptosis in differentiated pheochromocytoma PC-12 cells

Tseng

Hsu

Pan

2016

Pharmaceutical Biology

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Pan (2016) Neuroprotective effects of dimerumic acid and deferricoprogen from Monascuspurpureus NTU 568-fermented rice against 6-hydroxydopamine-induced oxidative stress and apoptosis in differentiated pheochromocytoma PC-12 cells, Pharmaceutical Biology, 54:8, 1434-1444, DOI: 10.3109/13880209.2015 Objective The effects of DMA and DFC on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and potential protective mechanisms in differentiated PC-12 pheochromocytoma cells were investigated. Materials and methods DMA (0-60 mM) or DFC (0-10 mM) was co-treated with 6-OHDA (200 mM, 24 h exposure) in differentiated PC-12 cells. Cell viability and intercellular reactive oxygen species (ROS) were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2 0 ,7 0 -dichlorofluorescein-diacetate (DCFH-DA) assays, respectively. Cell apoptosis was determined by DNA fragmentation analysis and propidium iodide staining by flow cytometry. Western blot analysis was used to measure the levels of cell protein expression. Results DMA and DFC significantly increased cell viability to 72% and 81% in 6-OHDA-induced differentiated PC-12 cell cultures, respectively. Furthermore, DMA and DFC reduced 6-OHDAinduced formation of extracellular and intercellular ROS by 25% and 20%, respectively, and decreased NADPH oxidase-2 expression in differentiated PC-12 cells. DMA and DFC inhibited 6-OHDA-induced apoptosis and decreased activation of caspase-3 via regulation of Bcl-2-associated X protein (Bax) and Bcl-2 protein expression in differentiated PC-12 cells. Conclusion DMA and DFC may protect against 6-OHDA toxicity by inhibiting ROS formation and apoptosis. These results showed that the metabolites from M. purpureus NTU 568 fermentation were potential therapeutic agents for PD induced by oxidative damage and should be encouraged for further research. ARTICLE HISTORY

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“…However, there appears to be specific mechanism(s) facilitating the drug's uptake by neuronal cells. 7 …”

Section: Pharmacokineticsmentioning

confidence: 99%

Deferoxamine Mesylate

Selim

2009

Stroke

115

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Abstract-Iron resulting from hemoglobin degradation is linked to delayed neuronal injury after intracerebral hemorrhage. Extensive preclinical investigations indicate that the iron chelator, deferoxamine mesylate, is effective in limiting hemoglobin-and iron-mediated neurotoxicity. However, clinical studies evaluating the use of deferoxamine in intracerebral hemorrhage are shortcoming. This article reviews the potential role of deferoxamine as a promising neuroprotective agent to target the secondary effects of intracerebral hemorrhage to limit brain injury and improve outcome, and ongoing efforts to translate the preclinical findings into clinical investigations. Key Words: deferoxamine Ⅲ ICH Ⅲ edema Ⅲ neuroprotection A t present, there is no specific treatment for spontaneous intracerebral hemorrhage (ICH) beyond supportive medical care. Therapeutic attempts to target hematoma and its expansion might provide some benefit in carefully selected patients. However, this strategy alone is likely to be of limited usefulness because hematoma expansion often occurs within the first hours after onset. Furthermore, neuronal injury in ICH is not only related to hematoma expansion. Other secondary processes, including apoptosis, necrosis, autophagy, inflammation, and edema formation, have been implicated. 1,2 A potential adjunctive approach to the treatment of ICH might be to target hemoglobin-and iron-mediated neurotoxicity. Iron-Mediated NeurotoxicityHemoglobin degradation products resulting from hemolysis after ICH include the iron-containing heme. Iron plays a role in neuronal injury by catalyzing a sequence of reactions "Haber-Weiss reaction" that yield highly reactive toxic hydroxyl radicals leading to oxidative stress and cell death, activating lipid peroxidation, and exacerbating excitotoxicity. 3,4 The time course for hemoglobin hemolysis and toxicity after ICH is 2 to 3 days. 5,6 This delayed time window can have important therapeutic advantages. Deferoxamine MesylateDeferoxamine has been used in clinical practice for more than 30 years in iron-overloaded patients with acute iron intoxication or overload due to transfusion-dependent anemia. It is a hydrophilic chelator, which chelates Fe ϩϩϩ and hemosiderin forming a stable complex that prevents iron from entering into Haber-Weiss reaction. The drug is relatively well tolerated. Serious adverse effects are uncommon. Hypotension and shock occur in 2% of patients, mostly with rapid intravenous administration at high doses. The infusion rate should not exceed 15 mg/kg per hour, and the total amount administered should not exceed 6000 mg in 24 hours. PharmacokineticsDeferoxamine is rapidly absorbed. Plasma concentrations between 80 and 130 mol/L are recorded 3 minutes after intravenous injections. The drug's serum protein-binding rate is Ͻ10%. It is distributed throughout all body fluids and has a volume of distribution of 0.8 to 1.35 L/kg. The drug is mostly metabolized by oxidative deamination, yielding metabolite B. The drug, its iron chelate complex (ferrioxamin...

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Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats.

Cited by 197 publications

References 46 publications

Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat

Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat

Neuroprotective effects of dimerumic acid and deferricoprogen fromMonascus purpureusNTU 568-fermented rice against 6-hydroxydopamine-induced oxidative stress and apoptosis in differentiated pheochromocytoma PC-12 cells

Deferoxamine Mesylate

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