scholarly journals Minocycline-Induced Attenuation of Iron Overload and Brain Injury After Experimental Intracerebral Hemorrhage

Stroke ◽  
2011 ◽  
Vol 42 (12) ◽  
pp. 3587-3593 ◽  
Author(s):  
Fan Zhao ◽  
Ya Hua ◽  
Yangdong He ◽  
Richard F. Keep ◽  
Guohua Xi
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Iron Overload ◽  
Brain Edema ◽  
Neuronal Death ◽  
Iron Chelator ◽  
Total Iron ◽  
Brain Iron

Background and Purpose— Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. Methods— This study was divided into 4 parts: (1) rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination; (2) rats had an ICH treated with minocycline or vehicle. Serum iron, brain iron, and brain iron handling proteins were measured; (3) rats had an intracaudate injection of saline, iron, iron+minocycline, or iron+macrophage/microglia inhibitory factor and were used for brain edema and neuronal death measurements; and (4) rats had an intracaudate injection of iron and were treated with minocycline. The brains were used for edema measurement. Results— After ICH, serum total iron and brain nonheme iron increased and these changes were reduced by minocycline treatment. Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood–brain barrier leakage, and brain cell death, all of which were significantly reduced by coinjection with minocycline. Conclusions— The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for patients with ICH because both iron accumulation and microglia activation contribute to brain damage after ICH.

Abstract 2156: Minocycline-induced Attenuation Of Iron Overload And Brain Injury Following Experimental Intracerebral Hemorrhage

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Fan Zhao ◽  
Ya Hua ◽  
Richard F Keep ◽  
Guohua Xi
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Iron Overload ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Neuronal Death ◽  
Total Iron ◽  
Brain Barrier ◽  
Brain Iron ◽  
Blood Brain

Background and Purpose: Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. Methods: This study was divided into three parts. (1) Male Sprague-Dawley rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination. (2) Rats had an ICH treated with minocycline or vehicle. Rats were euthanized 1, 3 and 7 days later for serum iron, brain iron, and brain iron handling protein measurements. (3) Rats had a 50µl intracaudate injection of either saline, FeCl2, FeCl2+minocycline or FeCl2+macrophage/microglia inhibitory factor and were euthanized at one day later for measurements of brain edema, blood-brain barrier disruption and neuronal death. Results: After ICH, serum total iron and brain non-heme iron increased and these changes were reduced by minocycline treatment (e.g. serum total iron at day 3: 158±36 vs. 245±22 µg/dL in the vehicle-treated group, p<0.01). Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood-brain barrier leakage and brain cell death, all of which were significantly reduced by co-injection with minocycline (p<0.05). Conclusions: The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for ICH patients because both iron accumulation and microglia activation contribute to brain damage following ICH.

The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 632-638 ◽  
Author(s):  
Louise Cragg ◽  
Robert P. Hebbel ◽  
Wesley Miller ◽  
Alex Solovey ◽  
Scott Selby ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Iron Overload ◽  
Oxidative Dna Damage ◽  
Iron Chelator ◽  
Liver Cells ◽  
Iron Chelators

Abstract Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

scholarly journals Iron Toxicity in Mice with Collagenase-Induced Intracerebral Hemorrhage

2010 ◽  
Vol 31 (5) ◽  
pp. 1243-1250 ◽  
Author(s):  
He Wu ◽  
Tao Wu ◽  
Xueying Xu ◽  
Jessica Wang ◽  
Jian Wang
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Neutrophil Infiltration ◽  
Iron Chelator ◽  
Iron Toxicity ◽  
Iron Accumulation ◽  
Neurologic Function ◽  
Old Mice ◽  
Intrastriatal Injection

Intracerebral hemorrhage (ICH) is a devastating form of stroke. In this study, we examined the efficacy of deferoxamine (DFX), an iron chelator, after collagenase-induced ICH in 12-month-old mice. Intracerebral hemorrhage was induced by intrastriatal injection of collagenase. Deferoxamine (200 mg/kg, intraperitoneal) or vehicle was administrated 6 hours after ICH and then every 12 hours for up to 3 days. Neurologic deficits were examined on days 1 and 3 after ICH. Mice were killed after 1 or 3 days of DFX treatment for examination of iron deposition, neuronal death, oxidative stress, microglia/astrocyte activation, neutrophil infiltration, brain injury volume, and brain edema and swelling. Collagenase-induced ICH resulted in iron overload in the perihematomal region on day 3. Systemic administration of DFX decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, and reduced microglial activation and neutrophil infiltration without affecting astrocytes. Although DFX did not reduce brain injury volume, edema, or swelling, it improved neurologic function. Results of our study indicate that iron toxicity contributes to collagenase-induced hemorrhagic brain injury and that reducing iron accumulation can reduce neuronal death and modestly improve functional outcome after ICH in mice.

scholarly journals Detrimental Role of miRNA-144-3p in Intracerebral Hemorrhage Induced Secondary Brain Injury is Mediated by Formyl Peptide Receptor 2 Downregulation BothIn VivoandIn Vitro

2018 ◽  
Vol 28 (6) ◽  
pp. 723-738 ◽  
Author(s):  
Weijian Fan ◽  
Xiang Li ◽  
Dongping Zhang ◽  
Haiying Li ◽  
Haitao Shen ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Formyl Peptide Receptor ◽  
Akt Pathway ◽  
Secondary Brain Injury ◽  
Peptide Receptor ◽  
Formyl Peptide

Although microRNA-144-3p (miRNA-144-3p) has been shown to suppress tumor proliferation and invasion, its function in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) remains unclear. Thus, this study was designed to investigate the role of miRNA-144-3p in ICH. To accomplish this, we used adult male Sprague-Dawley rats to establish an in vivo ICH model by injecting autologous blood, while cultured primary rat cortical neurons were exposed to oxyhemoglobin (OxyHb) to mimic ICH in vitro. To examine the role of miRNA-144-3p in ICH-induced SBI, we used an miRNA-144-3p mimic and inhibitor both in vivo and in vitro. Following ICH induction, we found miRNA-144-3p expression to increase. Additionally, we predicted the formyl peptide receptor 2 (FPR2) to be a potential miRNA-144-3p target, which we validated experimentally, with FPR2 expression downregulated when miRNA-144-3p was upregulated. Furthermore, elevated miRNA-144-3p levels aggravated brain edema and neurobehavioral disorders and induced neuronal apoptosis via the downregulation of FPR2 both in vivo and in vitro. We suspected that these beneficial effects provided by FPR2 were associated with the PI3K/AKT pathway. We validated this finding by overexpressing FPR2 while inhibiting PI3K/AKT in vitro and in vivo. In conclusion, miRNA-144-3p aggravated ICH-induced SBI by targeting and downregulating FPR2, thereby contributing to neurological dysfunction and neural apoptosis via PI3K/AKT pathway activation. These findings suggest that inhibiting miRNA-144-3p may offer an effective approach to attenuating brain damage incurred after ICH and a potential therapy to improve ICH-induced SBI.

scholarly journals Sodium/Hydrogen Exchanger 1 Participates in Early Brain Injury after Subarachnoid Hemorrhage both in vivo and in vitro via Promoting Neuronal Apoptosis

2019 ◽  
Vol 28 (8) ◽  
pp. 985-1001 ◽  
Author(s):  
Huangcheng Song ◽  
Shuai Yuan ◽  
Zhuwei Zhang ◽  
Juyi Zhang ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Brain Edema ◽  
Neuronal Apoptosis ◽  
Early Brain Injury ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger

Sodium/hydrogen exchanger 1 (NHE1) plays an essential role in maintaining intracellular pH (pHi) homeostasis in the central nervous system (CNS) under physiological conditions, and it is also associated with neuronal death and intracellular Na+ and Ca2+ overload induced by cerebral ischemia. However, its roles and underlying mechanisms in early brain injury (EBI) induced by subarachnoid hemorrhage (SAH) have not been fully explored. In this research, a SAH model in adult male rat was established through injecting autologous arterial blood into prechiasmatic cistern. Meanwhile, primary cultured cortical neurons of rat treated with 5 μM oxygen hemoglobin (OxyHb) for 24 h were applied to mimic SAH in vitro. We find that the protein levels of NHE1 are significantly increased in brain tissues of rats after SAH. Downregulation of NHE1 by HOE642 (a specific chemical inhibitor of NHE1) and genetic-knockdown can effectively alleviate behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, inflammatory reactions, oxidative stress, neurondegeneration, and neuronal apoptosis, all of which are involved in EBI following SAH. However, upregulation of NHE1 by genetic-overexpression can produce opposite effects. Additionally, inhibiting NHE1 significantly attenuates OxyHb-induced neuronal apoptosis in vitro and reduces interaction of NHE1 and CHP1 both in vivo and in vitro. Collectively, we can conclude that NHE1 participates in EBI induced by SAH through mediating inflammation, oxidative stress, behavioral and cognitive dysfunction, BBB injury, brain edema, and promoting neuronal degeneration and apoptosis.

Biliary Iron Excretion in Rats Following Treatment With Analogs of Pyridoxal Isonicotinoyl Hydrazone

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4368-4372 ◽  
Author(s):  
Karel Bláha ◽  
Miroslav Cikrt ◽  
Jana Nerudová ◽  
Helena Fornusková ◽  
Premysl Ponka
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Clinical Manifestations ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
Atomic Absorption Spectrophotometry ◽  
Major Life ◽  
Pyridoxal Isonicotinoyl Hydrazone

Abstract Iron overload is a major life-threatening complication of thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise for the treatment of iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to mobilize iron from cells in vitro, are also effective in vivo. All of these chelators significantly enhanced biliary excretion of iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or oral administration to rats. The most effective was PFBH, which increased iron concentration in the bile about 150-fold, as compared with basal biliary iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg body weight. In contrast, desferrioxamine increased the biliary iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted ≈ 0.8 μg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 μg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 μg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of iron overload is warranted.

scholarly journals Brain injury after intracerebral hemorrhage in spontaneously hypertensive rats

2011 ◽  
Vol 114 (6) ◽  
pp. 1805-1811 ◽  
Author(s):  
Gang Wu ◽  
Xuhui Bao ◽  
Guohua Xi ◽  
Richard F. Keep ◽  
B. Gregory Thompson ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Neuronal Death ◽  
Spontaneously Hypertensive Rats ◽  
Neurological Deficits ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Autologous Whole Blood

Object Hypertension is the main cause of spontaneous intracerebral hemorrhages (ICHs), but the effects of hypertension on ICH-induced brain injury have not been well studied. In this study, the authors examined ICH-induced brain injury in spontaneously hypertensive rats (SHRs). Methods This 2-part study was performed in 12-week-old male SHRs and Wistar Kyoto (WKY) rats. First, the rats received an intracaudate injection of 0.3 U collagenase, and hematoma sizes were determined at 24 hours. Second, rats were injected with 100 μl autologous whole blood into the right basal ganglia. Brain edema, neuronal death, ferritin expression, microglia activation, and neurological deficits were examined. Results Hematoma sizes were the same in SHR and WKY rats 24 hours after collagenase injection. The SHRs had greater neuronal death and neurological deficits after blood injection. Intracerebral hemorrhage also resulted in higher brain ferritin levels and stronger activation of microglia in SHRs. However, perihematomal brain edema was the same in the SHRs and WKY rats. Conclusions Moderate chronic hypertension resulted in more severe ICH-induced neuronal death and neurological deficits, but did not exaggerate hematoma enlargement and perihematomal brain edema in the rat ICH models.

Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage

2003 ◽  
Vol 15 (4) ◽  
pp. 1-7 ◽  
Author(s):  
Takehiro Nakamura ◽  
Richard F. Keep ◽  
Ya Hua ◽  
Timothy Schallert ◽  
Julian T. Hoff ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Iron Chelator ◽  
Iron Accumulation ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Autologous Whole Blood ◽  
The Right

Object In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. Methods Male Sprague–Dawley rats received an infusion of 100 μl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor–1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis. Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1. Conclusions Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

Deregulated Cellular Iron Metabolism Factors Mediate Iron Overload in Myeloma Cells and Osteoclasts, and Promote Myeloma Growth and Bone Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3941-3941
Author(s):  
Rakesh Bam ◽  
Wen Ling ◽  
Sharmin Khan ◽  
Sathisha Upparahalli Venkateshaiah ◽  
Xin Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Bone Disease ◽  
Iron Chelator ◽  
Myeloma Cell ◽  
High Energy ◽  
Myeloma Cells

Abstract Abstract 3941 Iron overload is a significant clinical feature in multiple myeloma (MM) and has been implicated in osteoporosis. MM patients also frequently suffer from anemia presumably due to elevated hepcidin secretion and dysfunctional erythropoiesis. The aims of the study were to shed light on molecular mechanisms associated with iron overload in MM cells and study the effect of the novel iron chelator, Dp44mT, on MM cell growth, osteoclastogenesis and MM bone disease in vitro and in vivo. In our clinical global gene expression profiling (GEP) data the main iron transporter gene TFRC (transferrin receptor) was >3 folds higher (p<0.0001) in newly diagnosed MM cells (n=556) than normal plasma cells (n=25) while the iron exporter ferroportin was downregulated in MM cells by >4 folds (p<0.0001). Deregulated TFRC and ferroportin expression were more profound in the molecularly classified proliferation (PR) subtype. Osteoclasts which are known to have abundant mitochondria due to high energy consumption express excessive TFRC (>5 folds higher than highly proliferating MM cells). In primary MM cell-osteoclast cocultures (n=8) TFRC expression was upregulated in cocultured MM cells than baseline MM cells (p<0.03) while ferroportin was lower in cocultured osteoclasts than control osteoclasts (p<0.04). Our GEP, qRT-PCR and immunohistochemistry analyses revealed expression of hepcidin by osteoclasts but not MM cells. Hepcidin was not detected in conditioned media from osteoclasts cultured alone or cocultured with MM cells using ELISA, suggesting an autocrine role of hepcidin in maintaining excess iron in osteoclasts. In vitro, Dp44mT dose dependently inhibited growth of MM cell lines (n=3) at low nanomolar levels (IC50 at 3±0.8 nM, p<0.03, 48 hrs). In contrast, known chelators such as Deferoxamine and Deferasirox inhibited myeloma cell growth at 10–50 micromoles range. At 1nM Dp44mT also suppressed formation of multinucleated osteoclasts by 87% (p<0.001) and bone resorbing activity of mature osteoclasts on dentine slices by 94% (p<0.03). Dp44mT induced upregulation of BMP2 expression in osteoblast precursors and promoted osteoblast differentiation. In vivo, SCID-rab mice engrafted with luciferase-expressing U266 MM line (6 mice/group) or the Hg MM line (maintained through in vivo passaging, 10 mice/group) were subcutaneously treated with vehicle or Dp44mT (1 mg/kg/day) for 2–3 weeks. Using live-animal imaging, Dp44mT reduced growth of U266 cells by 3 folds from pretreatment levels (p<0.01) while in control group tumor burden was increased by 52 folds from pretreatment levels (p<0.002). Dp44mT also inhibited growth of Hg MM cells determined by measurement of circulating human immunoglobulins in mice sera (p<0.01). Osteoclasts numbers were lower by 36% (p<0.003) while osteoblasts numbers were higher by 59% (p<0.017) in myelomatous bones from hosts treated with Dp44mT than control vehicle. Our data suggest that interaction of myeloma cells with osteoclasts alters expression of distinct iron metabolism associated factors which elicit iron overload in both cell types, resulting in increased myeloma cell proliferation and osteoclast activity. This study also suggests that Dp44mT is an effective iron chelator with marked anti-MM activity. Disclosures: Barlogie: Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties. Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.

Biliary Iron Excretion in Rats Following Treatment With Analogs of Pyridoxal Isonicotinoyl Hydrazone

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4368-4372
Author(s):  
Karel Bláha ◽  
Miroslav Cikrt ◽  
Jana Nerudová ◽  
Helena Fornusková ◽  
Premysl Ponka
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Clinical Manifestations ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
Atomic Absorption Spectrophotometry ◽  
Major Life ◽  
Pyridoxal Isonicotinoyl Hydrazone

Iron overload is a major life-threatening complication of thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise for the treatment of iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to mobilize iron from cells in vitro, are also effective in vivo. All of these chelators significantly enhanced biliary excretion of iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or oral administration to rats. The most effective was PFBH, which increased iron concentration in the bile about 150-fold, as compared with basal biliary iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg body weight. In contrast, desferrioxamine increased the biliary iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted ≈ 0.8 μg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 μg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 μg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of iron overload is warranted.

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