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PubMed1994

The role of tubular iron accumulation in the remnant kidney.

Iron has been implicated in the pathophysiology of several models of acute and chronic renal disease. In this study, energy-dispersive x-ray spectrometry was used to quantify and localize iron in rat remnant kidneys (RK) and normal kidneys (NK) and to determine its pathophysiologic significance. Substantial iron accumulation occurred in proximal tubular cell secondary lysosomes of RK (P < 0.001 versus NK) and reached a plateau at 8 wk after partial nephrectomy. In NK, minor increases of iron also occurred with aging (P < 0.02). Proximal tubular iron accumulation correlated independently with protein excretion (r = 0.90) and impairment of GFR (r = 0.70) and was associated with tubular damage and phosphate accumulation (both P < 0.001). Iron nitrilotriacetate (1 mg/kg ip) increased tubular lysosomal iron accumulation and tubular damage (P < 0.001 versus nitrilotriacetate) in NK, comparable to levels seen in untreated RK, and increased cortical cytosolic malondialdehyde, consistent with reactive oxygen species generation. The iron chelator deferoxamine (30 mg/kg per day ip) significantly reduced iron accumulation and tubular damage in RK at 4 wk, compared with deferoxamine chelated to iron and untreated RK. These results suggest that filtered iron enters the remnant tubular lysosomes across the brush border membrane by endocytosis and may produce tubular damage in chronic renal disease by the generation of reactive oxygen species.

Animals↗

PubMed1993

H2O2-mediated damage to lysosomal membranes of J-774 cells.

The effects of hydrogen peroxide on cell viability and, in particular, on lysosomal integrity were investigated in a model system of cultured, established, macrophage-like J-774 cells. The cells were found to rapidly degrade added hydrogen peroxide, withstanding concentrations < or = 250 microM without cell death; however, all tested concentrations (100-500 microM) substantially decreased cellular ATP to approximately the same degree. Concentrations of hydrogen peroxide > or = 500 microM resulted in a pronounced and rapid decrease in cell viability preceded by the loss of lysosomal integrity, as judged by the relocalization of acridine orange, a lysosomotropic weak base, in pre-labelled cells. Hydrogen peroxide-induced relocalization of acridine orange and cell death were either enhanced or much prevented, according to if the cells were initially allowed to endocytose ferric iron or the specific iron-chelator deferoxamine, respectively. Depletion of ATP, however, was not associated with the loss of lysosomal integrity and viability regardless of iron or deferoxamine pretreatment. Pre-exposure to E-64, an inhibitor of lysosomal thiol proteases, resulted in the reduction of both lysosomal membrane damage and cell death. The results are interpreted as indicating (i) generation of hydroxyl radicals within the secondary lysosomal compartment due to the occurrence of reactive ferrous iron, leading to (ii) peroxidative alterations of the lysosomal membrane resulting in (iii) loss of lysosomal membrane integrity with dissipation of the proton gradient and leakage of lysosomal contents, including hydrolytic enzymes, into the cell sap.

Acridine Orange↗

PubMed1998

Chain-breaking antioxidants and ferriheme-bound drugs are synergistic inhibitors of erythrocyte membrane peroxidation.

Induced erythrocyte membrane peroxidation (EMP) is considered as an accurate model of reperfusion injuries and as such was used to investigate protective effects of various drugs. EMP was induced by an azo initiator and monitored by oxygen uptake. Both hydrophilic (ascorbic acid) and lipophilic (alpha-tocopherol, probucol, nicanartine) chain-breaking antioxidants as well as ferriheme-bound drugs (deferoxamine, chloroquine) inhibited EMP. When antioxidants and ferriheme-bound drugs were combined, synergistic effects were observed. It is proposed that ferriheme compounds which catalyse peroxide induced lipid peroxidation were blocked by deferoxamine and/or chloroquine. So these drugs inhibited at least partly the membrane peroxidation process and added their effects to the ones of chain-breaking antioxidants.

Adult↗

PubMed1998

In vivo dual effects of vitamin C on paraquat-induced lung damage: dependence on released metals from the damaged tissue.

Vitamin C, a potent antioxidant, can act as a pro-oxidant in the presence of free transition metal ions by accelerating the Fenton reaction. An in vivo pro-oxidant role of vitamin C has been suggested, but direct evidence for it is scant. Here, we report the dual role of vitamin C on paraquat-induced lung injury, which appears to depend on the metal ions released from damaged cells. Vitamin C (10 mg/kg) given at the time when the extensive tissue damage was in progress aggravated the oxidative damage, while it protected against the damage when given before the initiation of the damage. The extent of oxidative tissue damage was monitored by measuring the expiratory ethane, one of the hydrocarbons produced during lipid peroxidation. Deferoxamine, given intraperitoneally as a bolus dose of 50 mg/kg, completely blocked the aggravation of oxidative damage by vitamin C. Moreover, deferoxamine unmasked the antioxidant effect of vitamin C. The results show that vitamin C can either aggravate or alleviate the oxidative tissue damage depending on the presence of metal ions released from damaged cells.

Animals↗

PubMed2002

Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products.

OBJECT: The mechanisms involved in brain edema formation following intracerebral hemorrhage (ICH) have not been fully elucidated. The authors have found that red blood cell lysis plays an important role in edema development after ICH. In the present study, they sought to determine whether degradation products of hemoglobin cause brain edema. METHODS: Hemoglobin, hemin, bilirubin, or FeCl2 were infused with stereotactic guidance into the right basal ganglia of Sprague-Dawley rats. The animals were killed 24 hours later to determine brain water and ion contents. Western blot analysis and immunohistochemistry were applied for heme oxygenase-1 (HO-1) measurement. The effects of an HO inhibitor, tin-protoporphyrin (SnPP), and the iron chelator deferoxamine, on hemoglobin-induced brain edema were also examined. Intracerebral infusion of hemoglobin, hemin, bilirubin, or FeCl2 caused an increase in brain water content at 24 hours. The HO-1 was upregulated after hemoglobin infusion and HO inhibition by SnPP-attenuated hemoglobin-induced edema. Brain edema induced by hemoglobin was also attenuated by the intraperitoneal injection of 500 mg/kg deferoxamine. CONCLUSIONS: Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.

Animals↗

PubMed2006

Long-term effects of experimental intracerebral hemorrhage: the role of iron.

OBJECT: Intracerebral hemorrhage (ICH) causes brain atrophy and neurological deficits. The mechanisms of brain atrophy after ICH are poorly understood, although recent evidence suggests that some ICH-induced brain injury results from the products of hemoglobin degradation, including iron. In this study the authors examine the role of iron in brain atrophy and neurological deficits following ICH. METHODS: Male Sprague-Dawley rats received an infusion of either 100 microl autologous whole blood or saline into the right caudate. Hematoxylin and eosin staining was used for histological examination, and iron levels and ferritin immunoreactivities were also examined. Deferoxamine was used as an iron chelator. Over the duration of the experiment, the rats underwent behavioral testing (forelimb placing, forelimb use asymmetry, and corner turn tests). Brain atrophy in the caudate with prolonged neurological deficits occurred after ICH. Although partial functional recovery occurred with time, residual neurological deficits were still detectable at 3 months postprocedure. Iron accumulation and ferritin upregulation were present in the ipsilateral caudate. Deferoxamine reduced brain atrophy and improved behavioral outcomes, and it also reduced brain ferritin immunoreactivity. CONCLUSIONS: An ICH results in an accumulation of iron in the brain that is not cleared within 3 months and that contributes to brain tissue loss and neurological deficits posthemorrhage. Iron chelation may be a useful therapy for patients with ICH.

Animals↗

PubMedDate not supplied

Peripheral neuropathy in thalassaemia.

BACKGROUND: Patients with thalassemia may complain of numbness and weakness of the lower extremities. The aim of the study was to document whether these patients suffer from a polyneuropathy and to determine any contributing factors for the development of neuropathy. PATIENTS AND METHODS: We examined 30 patients with thalassemia major and intermedia, clinically and electrophysiologically. We correlated these findings with demographics, blood status, and treatment and compared electrophysiologic data with 30 age- and sex-matched normal subjects or historical controls. RESULTS: We found that 78% of thalassemic patients suffered from a mild sensory polyneuropathy. The neuropathy seemed to be worse in the intermedia type. Thalassemic patients who received blood transfusions and deferoxamine had better nerve function than those who did not, irrespective of the dose of deferoxamine. The neuropathy was worse for older patients, irrespective of sex. The hemoglobin level, and the fact that some patients underwent splenectomy, did not affect the status of the patients' nerves. CONCLUSION: Patients with thalassemia may suffer from a sensory polyneuropathy especially as they grow older and if they are not optimally treated.

Adolescent↗

PubMed1999

In vivo and in vitro iron deficiency reduces protein kinase C activity and translocation in murine splenic and purified T cells.

We investigated the effects of iron deficiency anemia, iron repletion, and iron chelation by deferoxamine on protein kinase C (PKC) activity, an enzyme that plays a crucial role on T lymphocyte proliferation. The study involved 23 control (C), 18 pairfed (PF), and 24 iron deficient (ID) mice or ID mice that were repleted for 3 (n = 14), 7 (n = 17), or 14 (n = 14) days. The low iron (0.09 mmol iron/kg) and iron-supplemented (0.9 mmol iron/kg) diets were fed to mice for 53 days. Mean hemoglobin, hematocrit, and liver iron stores of ID mice were one third of those of C mice. Lymphocyte proliferation was reduced (P < 0.05) in spleen and purified T cells in ID but not PF mice. In concanavalin A, phytohemagglutinin, and anti-CD3 antibody-treated and untreated cells that were incubated in serum-free and serum-containing medium, PKC activity was significantly (P < 0.05) reduced in ID but not PF mice and returned to normal before correction of anemia. In mitogen-treated cells, while the ratios of membrane-bound to cytosol activity increased nearly seven-fold (from 0.4-0.63 in resting cells to 1.43-7.23) in spleen cells from C, PF, and repleted mice and 11-fold in T cells (P < 0.005), they remained below 1 in ID mice suggesting reduced translocation. In vitro iron chelation by deferoxamine for 120 min prior to cell activation reduced (P < 0.05) PKC activity by 46-60% in C and PF and 28-53% in ID mice. The data suggest that: 1) it is iron-deficiency but not anemia or differences in the proportion of immunocompetent T cells that reduced PKC activity in cells from ID mice; 2) reduced PKC translocation may play an important role on altered lymphocyte proliferation and associated functions in iron-deficient individuals.

Anemia, Iron-Deficiency↗

PubMed2000

Iron-mediated free radical injury in ethanol-exposed mouse neural crest cells.

Previous studies using cell and whole embryo cultures have shown that free radicals play an important role in the ethanol-induced death of mouse neural crest cells (NCCs; a significant cell type with respect to the genesis of alcohol-related birth defects). This investigation was spurred by reports of increased iron in ethanol-exposed fetuses and the knowledge that iron can initiate the production of reactive oxygen species. Initially, the ameliorative potential of two iron chelators, deferoxamine and phenanthroline, relative to ethanol-induced cell death was examined. Cotreatment of cultured NCCs with 100 mM ethanol and either 1 or 10 microM deferoxamine or 10, 50, or 250 microM phenanthroline significantly increased the percentage of viable cells as compared with exposure to 100 mM ethanol alone. These data indicate that iron is involved in the ethanol-induced cytotoxicity. To support this premise, the direct toxicity of iron to NCCs was also examined. As expected, loading the cells with Fe(II)/Fe(III) using 8-hydroxyquinoline as a carrier had an adverse effect on their viability as did treatment with a neurotoxin, 6-hydroxydopamine, that releases iron from ferritin storage. Cotreatment with an antioxidant, N-acetylcysteine, significantly diminished the toxicity of ethanol alone, that resulting from iron loading, as well as from the combination of ethanol exposure and iron loading. These results confirm the role of free radical-mediated damage in ethanol-induced cytotoxicity and highlight the potential role of iron relative to the genesis of alcohol-related birth defects.

Animals↗

PubMed2000

Role of molecular oxygen in the generation of hydroxyl and superoxide anion radicals during enzymatic Cr(VI) reduction and its implication to Cr(VI)-induced carcinogenesis.

Electron spin resonance (ESR) spin trapping measurements provide evidence for the generation of hydroxyl radicals (*OH) in the reduction of Cr(VI) by glutathione reductase (GSSG-R) in the presence of NADPH as a cofactor. Catalase inhibited the *OH generation, while the addition of H2O2 enhanced it, indicating that the *OH radical generation involves a Fenton-like reaction. The metal chelator, deferoxamine, inhibited the *OH generation with a concomitant generation of a deferoxamine nitroxide radical. EDTA and 1,10-phenanthroline also inhibited the *OH generation. Experiments performed under argon atmosphere decreased the yield of the *OH formation, showing that molecular oxygen plays a critical role. ESR spin trapping and measurements of fluorescence change of scopoletin in the presence of horseradish peroxidase show that reduction of Cr(VI) by GSSG-R/NADPH generates superoxide anion radicals (O2*-) as well as H2O2. It can be concluded that *OH radical is generated by the reaction of H2O2 with Cr(V), which is produced by enzymatic one-electron reduction of Cr(VI). H2O2 is produced by the reduction of molecular oxygen via O2*- as an intermediate. The *OH radicals generated by these reactions are capable of causing DNA strand breaks, which can be inhibited by catalase, formate, and experiments performed under argon.

Carcinogenicity Tests↗

PubMed2000

Financial analysis of chronic transfusion for stroke prevention in sickle cell disease.

Chronic red blood cell transfusion can prevent many of the manifestations of sickle cell disease. The medical costs of chronic transfusion and management of associated side effects, especially iron overload, are considerable. This study was undertaken to evaluate the financial impact of chronic transfusion for stroke prevention in patients with sickle cell anemia. Outpatient charges pertaining to hospital-based Medicare uniform bill (UB-92) codes, professional fees, and iron chelation were evaluated. Data were collected on 21 patients for a total of 296 patient months (mean, 14; median, 14 months/patient). Charges ranged from $9828 to $50 852 per patient per year. UB-92, chelation, and physician-related charges accounted for 53%, 42%, and 5% of total charges, respectively. Of UB-92 charges, 58% were associated with laboratory fees and 16% were related to the processing and administration of blood. Charges for patients who required chelation therapy ranged from $31 143 to $50 852 per patient per year (mean, $39 779; median, $38 607). Deferoxamine accounted for 71% of chelation-related charges, which ranged from $12 719 to $24 845 per patient per year (mean, $20 514; median, $21 381). The financial impact of chronic transfusion therapy for sickle cell disease is substantial with charges approaching $400 000 per patient decade for patients who require deferoxamine chelation. These data should be considered in reference to cost and efficacy analyses of alternative therapies for sickle cell disease, such as allogeneic bone marrow transplantation.

Adolescent↗

PubMed1998

[The protective effects of baicalin on pertussis bacilli-induced brain edema in rats].

OBJECTIVE: To evaluate the inhibitory effect of baicalin on iron-dependent lipid peroxidation (IDLPO) and the protective effect on pertussis bacilli-induced brain edema in rats. METHODS: In vitro, the inhibitory effect of baicalin and deferoxamine (DFX) was studied at different concentrations on IDLPO in brain homogenates of Sprague-Dawley rats. In vivo, the protective effect was studied of baicalin and DFX on brain edema induced by injecting purtussis bacilli into the left internal carotid artery in rats. Forty Sprague-Dawley rats were randomly divided into four groups. Group 1 (NS, n = 10), as control; Group 2 (PB, n = 10), pertussis bacilli control; Group 3 (DFX, n = 10), PB + deferoxamine; and Group 4 (BAI, n = 10), PB + baicalin. RESULTS: The baicalin was possessed of an inhibitory effect on IDLPO in rat brain homogenate, moreover, the inhibitory potency of baicalin was approximately 20 times higher than DFX treated alone. In vivo, the increase in the content of water(CW) and Evans blue (EB) was attenuated in groups DFX and BAI (CW: 79.8 +/- 0.7)% and (79.5 +/- 0.6)%; (EB: 11 +/- 7 micrograms/g and 12 +/- 5 micrograms/g) as compared with the group PB (CW: 80.4 +/- 0.9%, EB: 24 +/- 10 micrograms/g). The content of iron was significantly lower than in the left hemispheres (injected side) in the group DFX and the group BAI (79 +/- 9 micrograms/g and 77 +/- 10 micrograms/g) than in the left hemispheres in the group PB(132 +/- 28 micrograms.d-1.g), P < 0.05. The activation of CuZn-SOD (L155 +/- 36 U/mg pr, R177 +/- 75 U/mg pr) was decreased in the group BP compared with the group NS(L 201 +/- 49 U/mg pr, R 249 +/- 49 U/mg pr), P < 0.05. The activation of CuZn-SOD was significantly higher in the left brain tissues in the groups DFX and BAI (222 +/- 49 U/mg pr and 230 +/- 45 U/mg pr, respectively) than in the left brain tissues of the group of PB (P < 0.05). CONCLUSION: The baicalin and DFX have a protective effects on the pertussis bacilli-induced brain edema in rats, and the protective effects are related to the inhibitory effect on IDLPO, chelating Fe2+, and activated CuZn-SOD.

Animals↗

PubMed2000

[Renal osteodystrophy (3); its treatment in dialysis patients].

The prevalence and the clinical gravity of the various histopathological varieties of renal osteodystrophy in dialysis patients depends on the severity of both the aluminium intoxication and that of hyperparathyroidism. The prevalence of bone pains, fractures and hypercalcemias are the highest in adynamic bone diseases (ABD) with severe aluminium intoxication, then in osteitis fibrosa and mixed osteopathy, in the ABD with moderate aluminium intoxication and rare in the mild lesion in spite of similar moderate aluminium intoxication. In the absence of aluminium intoxication, hypercalcemia and hyperphosphatemia prevalence is higher only when intact PTH is more that 4 times the upper limit of normal. When PTH is between 1 and 2 folds the ULN this prevalence is null and bone mineral density is the highest. 2. The low turnover aluminic bone diseases (osteomalacic or adynamic) will be cured by long term deferoxamine treatment. The hazards of such treatment justify the performance of a bone biopsy to ensure the diagnosis. Their prevention relies on adequate treatment of tapwater and definitive exclusion of long term administration of aluminum phosphate binders. 3. Non aluminic osteomalacia will be treated according to the same guidelines given for the uremic patients before dialysis. 4. Non aluminic adynamic bone disease will be cured by means aiming at stimulating PTH secretion as discontinuing 1 alpha hydroxylated vitamin D derivatives, and, if there is no hyperphosphatemia by discontinuation of calcium supplement. In case of hyperphosphatemia in dialysis patients CaCO3 doses have to be nevertheless increased after the dialysate calcium concentration (DCa) has been decreased in order to induce a negative perdialytic calcium balance for PTH secretion stimulation. In the near future substitution of CaCO3 by non calcemic non aluminic phosphate binders will suffice. 5. Osteitis fibrosa due to hyperparathyroidism will be treated first by securing an optimal vitamin D repletion (bringing plasma 25OH vitamin D around 30 and 60 ng/ml or 75-150 nmol/l) and by correcting hypocalcemia and hyperphosphatemia by CaCO3 at high doses (3-12 g/day) taken with the meals. In case of hypercalcemia dialysate calcium concentration will be decreased to correct it or, in a near future, CaCO3 will be decreased to 3 g/day and hyperphosphatemia will be controlled by non calcemic, non aluminic phosphate binders. When hyperphosphatemia is controlled whereas plasma calcium is normal or low, 1 alpha hydroxylated vitamin D derivatives can be administered. 6. Instrumental parathyroidectomy should be considered when plasma levels of intact PTH remain above 7 folds the upper limit of normal whereas hyperphosphatemia persists and hypercalcemia occurs in order to prevent thining of the corticals and subsequent fracture risk. In case of previous exposition to aluminum, a deferoxamine test and/or a bone biopsy will be performed to decide a long term DFO treatment before the parathyroidectomy in order to prevent the transformation of a mixed osteopathy into an aluminic adynamic bone disease. 7. The difficulty of hyperparathyroidism control in dialysis patients is due to poor compliance to phosphate binders and to irreversible parathyroid hyperplasia with occured before the dialysis stage. This stress the primary importance if its early prevention without iatrogenia by first CaCO3 and vitamin D repletion, as soon as the creatinine clearance decreases below 60 ml/min/1.73 m2.

Aluminum↗

PubMedDate not supplied

Functional changes of alveolar macrophages in carragheenan-induced aspiration pneumonia model mice.

Alveolar macrophages (AMs) are cells with unique characteristics because of their localization in the aerobic environment and are receiving stimuli by inhalation. To estimate the functional changes of AMs induced by inflammation, a murine model of aspiration pneumonia was made by an intratracheal injection with carragheenan, whose mortality rate was approximately 25%. The cell component which increased predominantly in the inflammatory site was polymorphonuclear leukocytes, and the number of AMs did not show a remarkable increment. Control group showed a high level of intracellular oxidation of 2'7'-dichlorofluorescin (DCFH) by AMs, while that in carragheenan-treated mice decreased significantly (p < 0.05). There were two populations in AMs classified according to the oxidative activity of DCFH; the population showing high oxidative activity of DCFH was asialo GM1 positive, in contrast, that with lower oxidative activity was asialo GM1 negative. Decrease in DCFH-oxidative activity of AMs in control group was observed after a treatment with KCN or deferoxamine. But in the carragheenan-treated group, this decrease was not observed after treatment with KCN. These results show that both oxygen-derived radical produced in mitochondria, which is inhibited by KCN, and cytoplasmic OH radical, which is selectively inhibited by deferoxamine, are concerned with intracellular oxidation of DCFH by AMs, and that a decrease in DCFH-oxidative activity in the carragheenan-treated group was attributed to the depression of mitochondrial respiration. Nevertheless, increased expressions of Ia and F4/80 in AMs of the carragheenan-treated group were observed and phagocytic activity was well preserved at the control level. These results suggest that AMs may play a crucial role, as well as differentiated phagocytes possessing antigen-presenting ability and/or digestive activity against various types of foreign bodies despite showing an obvious decrement in oxidative activity. These results imply that AMs have a strong oxidative activity and deal with various types of antigens in normal states, but in case of acute inflammation they will change into mature type macrophages with high expression of class II molecules which correlates with an antigen-presenting capacity.

Amino Acid Oxidoreductases↗

PubMed2002

[Study on silica induced DNA damage and its influence factor].

OBJECTIVE: To detect DNA damage in Chinese Hamster Lung Fibroblast(CHLF) exposed to low doses of silica particles(7.5 - 120.0 micrograms/ml). METHODS: Comet assay was used to detect DNA damage. The cells were divided into various groups by doses and incubation time of silica particles to observe silica-induced DNA damage; and the influence of hydroxyl radicals and calcium ion in DNA damage by using deferoxamine and verapamil was also studied. The tail lengths of comet were used to measure DNA damage. RESULTS: The tail lengths were significantly longer in exposed cells, compared to matched controls(P < 0.01), and were increased in a dose-dependent manner from 7.5-120.0 micrograms/ml. The tail lengths of two-hour group were longer than one-hour group. When exposed to 90 micrograms/ml silica particles, 0.5-2.0 mmol/L deferoxamine and 2.5-20.0 micrograms/ml verapamil could attenuate silica-induced DNA damage effectively, their protective effects were increased in a concentration-dependent manner. CONCLUSION: Small dose of SiO2 could induce CHLF DNA damage. Calcium ion and hydroxyl radical may take part in this process, antioxidant and calcium antagonate may protect SiO2 induced DNA damage.

Animals↗

PubMed1992

Pharmacologic interventions for prevention of spinal cord injury caused by aortic crossclamping.

The efficacy of pharmacologic agents for prevention and control of oxygen-derived free radical damage in ischemia-reperfusion injury of the spinal cord was assessed in a swine model of thoracic and thoracoabdominal aortic crossclamping. Animals were exposed to 30 minutes of ischemia that induced lethal, irreversible injury and paraplegia. The experimental groups were as follows: group A (n = 7), control group, receiving no pharmacologic intervention; group B (n = 7), deferoxamine 50 mg/kg/day administered intravenously over 3 to 4 hours before ischemia; group C (n = 7), allopurinol pretreatment 50 mg/kg/day for 3 days; and group D (n = 7), superoxide dismutase 60,000 units administered with 50,000 units before removal of the aortic crossclamp and 10,000 units over 10 minutes of reperfusion. Proximal hypertension was controlled with sodium nitroprusside and volume depletion. The methods of assessment were neurologic by a modified Tarlov criteria and blood flow by radiolabeled microspheres. Results of blood flow assessment confirmed a true ischemic episode of 30 minutes for all animals in all groups. The blood flow fell significantly during ischemia (p less than 0.01) and a hyperemic response was evident in the early reperfusion period. All animals in control group A were paraplegic. The group B (deferoxamine) results were superior; 85% had grade III function on a modified Tarlov scale, with animals in the group standing and even walking with difficulty. Only one animal in this group had good movements of hind limbs but was unable to stand or walk. Neurologic recovery was limited in the allopurinol group (group C), with 85% showing slight neurologic recovery with limited movement of the hind limbs. The animals in the superoxide dismutase group (group D) all had good recovery, with strong motor response of hind limbs, but were not able to stand. In summary, the results of this experimental protocol confirmed the possible role of oxygen-derived free radicals in the pathophysiology of spinal cord injury, induced by aortic crossclamping. Moreover, it proved that ischemia-reperfusion injury could be altered by pharmacologic interventions.

Allopurinol↗

PubMed1991

Trace transition metal-catalyzed reactions in the microsomal metabolism of alkyl hydrazines to carbon-centered free radicals.

Radical production from alkyl hydrazines (i.e. phenelzine and benzylhydrazine) in rat liver microsomes has been proposed to occur via cytochrome P-450-catalyzed one-electron oxidation followed by beta-scission of an alkyl radical. In microsomes treated with phenelzine (2-phenylethylhydrazine), NADPH, and the spin trap alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN), the 4-POBN/2-phenylethyl radical adduct was detected by electron paramagnetic resonance spectroscopy. The addition of catalase and superoxide dismutase resulted in a 28.5 and 24% decrease in radical production, respectively. The concentration of the 4-POBN/2-phenylethyl radical adduct decreased significantly in the presence of metal chelators, i.e. EDTA, diethylenetriaminepentaacetic acid (DTPA), or deferoxamine mesylate. When phenelzine was incubated with deferoxamine mesylate-washed microsomes and NADPH in Chelex-treated incubation buffer, no significant radical adduct formation was detected. Addition of iron-chelator complexes (either Fe(3+)-DTPA or Fe(3+)-EDTA) greatly stimulated production of the 4-POBN/2-phenylethyl radical adduct in this system. These results show that the 2-phenylethyl radical produced from phenelzine in a microsomal system arises via a trace transition metal-catalyzed reaction. This reaction may occur through oxidation of phenelzine by the hydroxyl radical, which has also been spin-trapped with 4-POBN in this system.

Animals↗

PubMed1990

Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies.

We have examined the distribution of radiolabeled liposomes in tumor-bearing mice after i.v. injection. Two mouse tumors (B16 melanoma, J6456 lymphoma) and a human tumor (LS174T colon carcinoma) inoculated i.m., s.c., or in the hind footpad were used in these studies. When various liposome compositions with a mean vesicle diameter of approximately 100 nm were compared using a radiolabel of gallium-67-deferoxamine, optimal tumor localization was obtained with liposomes containing a phosphatidylcholine of high phase-transition temperature and a small molar fraction of monosialoganglioside or hydrogenated phosphatidylinositol (HPI). At 24 h after injection, average values of tumor uptake higher than 10% of the injected dose per g and liver-to-tumor ratios close to 1 were reproducibly obtained. Increasing the molar fraction of HPI from 9% to 41% of the total phospholipid resulted in enhancement of liver uptake and decrease of tumor uptake. Methodological aspects that influence vesicle size appear to affect significantly liposome localization in the tumor. However, varying the phospholipid dose within a 10-fold range caused only minor changes in the percent of injected dose recovered in the tumor. A high uptake by tumors was also observed using other radiolabels [[3H]inulin and indium-111-labeled bleomycin (111In-Bleo)] in monosialoganglioside- and HPI-containing liposomes. In the case of 111In-Bleo, encapsulation in liposomes resulted in approximately 20- to 40-fold increase in tumor accumulation of the radiolabel at 24 h after injection. The marked localization of liposomes in the mouse footpad inoculated with tumor as opposed to the contralateral mock-injected footpad was also documented by imaging experiments with gallium-67-deferoxamine and 111In-Bleo-labeled liposomes. These results support the contention that some glycolipid-containing liposomes previously shown to have long circulating half-lives accumulate significantly in a variety of tumors and are promising tools for the delivery of anti-tumor agents.

Animals↗