Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons

Antioxidants and iron chelating molecules are known as neuroprotective agents in animal models of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we designed and synthesized a novel bifunctional molecule (M10) with radical scavenging and iron chelating ability on an amino acid carrier likely to be a substrate for system L, thus targeting the compound to the central nervous system (CNS). M10 had a moderate iron affinity in HEPES buffer (pH 7.4) with logK(3)=12.25+/-0.55 but exhibited highly inhibitory action against iron-induced lipid peroxidation, with an IC(50) value (12microM) comparable to that of desferal (DFO). EPR studies indicated that M10 was a highly potent *OH scavenger with an IC(50) of about 0.3 molar ratio of M10 to H(2)O(2). In PC12 cell culture, M10 was at least as potent as the anti-Parkinson drug rasagiline in protecting against cell death induced by serum-deprivation and by 6-hydroxydopamine (6-OHDA). These results suggest that M10 deserves further investigation as a potential agent for the treatment of neurodegenerative disorders such as AD and PD.     

Brain iron deposition and the free radical-mitochondrial theory of ageing

The central hypothesis of this paper states that oxidative stress, augmented iron deposition, and mitochondrial insufficiency in the ageing and degenerating CNS constitute a single neuropathological 'lesion', and that the advent of one component of this triad obligates the appearance of the others. Evidence in support of this unifying perspective is adduced from human neuropathological studies, experimental paradigms of ageing-associated neurological disorders, and a comprehensive model of astroglial senescence. A pivotal role for the enzyme, heme oxygenase-1 (HO-1) in consolidating this tripartite lesion in the ageing and diseased CNS is emphasized. The data are discussed in the context of a revised 'free radical-mitochondrial-metal' theory of brain ageing, and some scientific and clinical implications of the latter are considered.     

Iron status in a group of Norwegian children aged 6-24 months

An adequate iron status is of vital importance for health and development in infancy and early childhood. Iron status was evaluated in a group of full-term Norwegian children followed longitudinally, at the ages of 6 mo (n = 278), 12 mo (n = 249) and 24 mo (n = 231) by measuring haemoglobin (Hb), mean cell volume (MCV) and serum ferritin. At 6, 12 and 24 mo of age, 3, 10 and 12%, respectively, had iron deficiency anaemia (IDA) defined as Hb <110 g/l in combination with ferritin <15 microg/l. With more restrictive criteria for defining IDA (Hb <110 g/l or <105 g/l in combination with ferritin <12 microg/l), the prevalence decreased to 1-2% at 6 mo and 2-5% at 12 and 24 mo of age. If children with a history of fever in the previous month were excluded, the proportion of children with depleted iron stores (ferritin <10 microg/l) increased from 2 to 3% at 6 mo, from 5 to 7% at 12 mo and from 9 to 13% at 24 mo. Conclusion: Mild iron deficiency anaemia exists among otherwise healthy Norwegian infants and toddlers. The prevention and early treatment of iron deficiency should be a priority for the child health services.     

Serum ceruloplasmin and ferroxidase activity are not decreased in hepatic failure related to alcoholic cirrhosis: clinical and pathophysiological implications

BACKGROUND: A decrease in serum ceruloplasmin (Cp), a protein involved in iron metabolism through its ferroxidase activity, is classically claimed to be observed in severe hepatic failure of non-wilsonian chronic liver disease and therefore to be a confounding factor for the diagnosis of Wilson's disease. Moreover, a simultaneous decrease in ferroxidase activity could be hypothesized as playing a role in the development of the hepatic siderosis frequently observed in advanced chronic liver diseases. The aim of this study was to test the validity of these two statements. METHODS: This study investigated Cp, determined by immunonephelometry, and its ferroxidase 1 activity determined by Erel's method in 33 male patients with severe alcoholic cirrhosis compared with 66 healthy male volunteers, selected on strict criteria. Each patient was age-matched with two controls. Nonparametric tests were used for statistical analysis. RESULTS: The mean values of Cp were significantly higher in cirrhotic patients as compared with control subjects. A significant elevation of Cp was also observed in the subgroup of 11 cirrhotic patients who had normal serum C-reactive protein levels. The mean values of ferroxidase 1 activity were similar to those obtained in control subjects. CONCLUSIONS: Low serum Cp should not be expected in severe hepatic cirrhosis of non-wilsonian origin. Hepatic siderosis in advanced chronic liver disease is likely to be unrelated to decreased ferroxidase activity.     

Comparison of a Combination Ferrous Fumarate Product and a Polysaccharide Iron complex as Oral Treatments of Iron Deficiency Anemia: A Taiwanese Study

Despite efforts to improve iron supplements for iron deficiency anemia, there is no consensus on products that balance efficacy, safety and tolerability, and cost. Ferrous products are effective, but they are associated with more gastrointestinal side effects than ferric products. Ferric products tend to have lower absorption. We present results from a 12-week study that randomized 72 people with uncomplicated iron deficiency anemia to receive a ferrous iron supplement (Ferall, a combination of ferrous fumarate with ascorbic acid, folic acid, and cyanocobalamin) or a ferric iron polysaccharide complex (Niferex, ferro-glycine sulfate) plus ascorbic acid. The ferrous product was significantly more effective, the primary and secondary endpoints including changes in levels of hemoglobin and serum ferritin. There was a slightly higher frequency of gastrointestinal side effects in patients taking the ferrous product, but both supplements were well tolerated. No participant withdrew from the study because of side effects. We concluded that the ferrous product is safe and effective for use in uncomplicated iron deficiency anemia. The lack of direct comparison between single-agent ferrous fumarate and the combination ferrous product limited interpretation of results in terms of possible effects due to other components, such as ascorbic acid.     

A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease

Aluminum (Al(III)) and iron (Fe(III)) are reported to accumulate in neurofibrillary tangles of the Alzheimer's disease (AD) brain. In these lesions Al (III) and Fe (III) bind with hyperphosphorylated tau (PHFtau), the major constituent of the lesions, and induce its aggregation. It is thought that inhibition and dissociation of such Al (III)/Fe (III) binding associated with PHFtau could slow or halt the tau-related neurofibrillary degeneration in patients with AD. A study, using a previously developed in vitro system in which Al (III) and Fe (III) interact with PHFtau on AD brain sections and on immunoblot membranes showed that the potent Al (III)/Fe (III) chelator desferrioxamine elicited Al (III) chelation when subjected to autoclave heating. Here, the ability of a recently developed chemical chelator Feralex-G to remove PHFtau-bound Al (III)/Fe (III), using reaction conditions at 37 degrees C, was examined and compared with that of desferrioxamine. Chelation of Fe(III) was achieved by both compounds with no discernible difference in their chelating ability. In contrast, in the present system, the two chelators gave a different Al (III) chelation response. When incubated at 37 degrees C, desferrioxamine failed to attain notable Al (III) chelation, while Feralex-G displayed efficient Al (III) chelation. Thus, when considering competitive Al (III) removal from brain PHFtau, Feralex-G is a stronger chelator for Al(III) than desferrioxamine. The efficient Al (III) chelation attainable by Feralex-G adds weight to its potential clinical usefulness as a medicine in the aluminum/iron chelation therapy for patients with AD.     

Role of environmental factors in the pathogenesis of classic and African-endemic Kaposi sarcoma

Kaposi sarcoma (KS) is a mesenchymal tumour associated with human herpesvirus-8 (HHV-8) infection. However, the incidence of HHV-8 infection is far higher than the prevalence of KS, suggesting that viral infection per se is not sufficient for the development of aggressive phenotype and that one or more additional cofactors are required. The great geographical variation in African-endemic and classic KS incidence points to a role for environmental factors in the etiology of Kaposi sarcoma. However, there are few unequivocably established environmental factors involved in KS pathogenesis. This review focuses on the environmental factors thought to be associated with KS, more particularly iron exposure and facilitation of transmission of HHV-8 infection by contact with blood-sucking arthropods.     

妊娠母体及绒毛铁、锌含量的检测

目的:测定早期妊娠母体及绒毛中微量元素铁、锌的含量,并探讨二者的关系。方法:采集12孕周内人工流产患者的绒毛组织及枕后新近长出头发,5∶2HNO3+H2O2体系消解,电感耦合等离子体发射光谱仪(ICP)检测微量元素铁、锌的含量,统计软件SPSS10.0进行数据分析。结果:①绒毛中铁量为(18.26±6.81)μg/g,锌含量为(17.44±10.12)μg/g;母发中铁、锌含量分别为(49.61±34.01)μg/g、(216.39±90.26)μg/g,明显高于绒毛中铁、锌含量(P<0.05)。②绒毛与母体头发中铁含量的相关系数为0.31(P<0.05)、锌含量的相关系数为0.04(P>0.05)。结论:绒毛中铁含量与母发存在正相关性,可以通过检测母亲头发中铁的含量了解胚胎营养状况;而绒毛中的锌与母发中的锌不存在相关性。     

城市儿童缺铁与铅中毒关系的探讨

目的:了解城市儿童缺铁(ID)与铅中毒的关系。方法:先后间隔(9.3±4.6)个月,分两次测定1275名儿保门诊儿童的血铅浓度、血红蛋白、平均红细胞体积(MCV)和红细胞分布宽度(RDW)。进行缺铁与发生铅中毒的Logisitic回归分析。结果:两次检测均无缺铁组(NID)作为对照组,两次检测均为缺铁组(第1组)预测铅中毒的优势比(OR值)为5.54(95%CL:2.25~13.62);第1次缺铁,第2次无缺铁组(第2组)OR值为2.73(95%CL:0.90~8.27);第1次无缺铁而第2次为缺铁组(第3组)OR值为0.81(95%CL:0.10~6.30)。结论:城市儿童缺铁更易导致铅中毒,营养不足的儿童加强铁的供应有利于预防铅中毒。