缺氧诱导因子影响脑铁代谢调控神经系统铁超载的机制研究进展

铁超载作为许多神经系统疾病的病理性特征, 可引起氧化应激反应, 导致神经细胞铁代谢异常。缺氧诱导因子(HIF)可通过调控脑铁的摄取、储存、排出和胞内调节等过程参与脑铁代谢, 抑制脑铁超载有望成为神经系统疾病治疗的新靶点。本文现围绕HIF调控脑铁代谢的生理/病理机制综述如下, 以期为相关神经系统疾病的治疗提供新的思路和方法。     

脑铁代谢与脑出血后脑损伤

脑出血后血肿周围脑组织损伤的机制十分复杂。最近研究显示,脑出血后铁离子和铁代谢蛋白的代谢异常是导致脑出血后脑损伤的原因之一。本文对目前脑铁分布、功能和脑内铁转运机制的认识,脑出血后异常增高的铁离子和铁代谢蛋白导致脑损伤的作用机制,以及异常脑铁代谢的磁共振成像检查和铁螯合剂的实验研究作了简要综述。     

脑内铁代谢与神经退行性疾病

铁的正常代谢是大脑发挥正常功能的必要因素。近年研究发现,脑内铁的代谢紊乱在阿尔茨海默病、帕金森病等神经退行性疾病的发生发展中起重要作用。本文对脑内铁正常和异常代谢调节情况及其与神经退行性疾病的关系做一综述。     

脑铁代谢失衡与迟发性运动障碍

对脑铁代谢的基本过程及脑铁代谢失衡与迟发性运动障碍的关系进行综述。     

脑铁代谢及铁超载毒性机制的研究

铁对维持正常的细胞功能至关重要,在大脑内参与许多重要的生物代谢过程,包括三磷酸腺苷、DNA和多种单胺类神经递质的合成等。铁还参与氧化还原反应的代谢过程。铁代谢异常也会引起中枢神经系统异常,铁含量过高时,能通过自由基导致明显的氧化损伤。铁诱导的氧化损伤与阿尔茨海默病（Alzheimer＇s disease,AD）和帕金森疾病（Parkinson＇s disease,PD）有关,但铁积累和氧化应激是致病因素或者仅仅是这些疾病的影响条件尚无定论。脑铁代谢受到严格的调控,但是在铁超载的情况下,     

铁代谢在创伤性颅脑损伤中的研究进展

创伤性颅脑损伤(traumatic brain injury,TBI)是一类由多种因素导致的颅脑损伤性疾病,可引起一系列复杂的病理生理过程.缺乏早期干预靶点是TBI预后不良的重要因素.另外,TBI不良预后与损伤脑组织铁代谢紊乱密切相关,铁代谢调节干预,尤其是铁螯合剂,在TBI中显示出巨大治疗潜力.本文将对铁代谢与TBI...     

MRI检测帕金森病脑铁含量的研究进展

近来研究表明,帕金森病有脑铁代谢紊乱、脑铁含量增多。由于脑铁使MRI中TW12信号降低,可根据TW12信号强度定量评估脑内各部铁含量的变化。因此,运用MRI不同序列可能为PD发病机理及定量诊断提供了一种有参考价值的无创的新的评估方法。     

载脂蛋白E基因型与铜代谢异常相关的帕金森病研究进展

帕金森病(Parkinson's disease,PD)是一种以运动障碍为主要表现的中枢神经系统退行性疾病,病理损害机制不明,可能与环境因素和基因变异共同作用有关[1].由于基底节铁代谢异常和沉积与PD发病有关[2],而铜蓝蛋白具有将二价铁离子氧化成三价铁离子的铁氧化酶活性,与脑内铁代谢密切相关.     

铁调素对体外多巴胺能神经细胞内铁聚积的作用

目的：探讨铁调素在多巴胺能神经细胞内铁代谢调节的作用。方法：体外培养MES23.5细胞,经用枸橼酸铁胺处理4 h后应用RT-PCR检测铁调素mRNA的表达,Western blot检测膜铁转运蛋白1（FPN1）的表达。结果：高铁作用4 h后观察到MES23.5细胞内铁调素表达增高,FPN1表达降低（P〈0.05）。结论：铁调素通过减少FPN1影响多巴胺能神经元的铁转出,参与帕金森病的铁聚积。     

铁与帕金森病相关性研究的近况

铁代谢紊乱、铁诱导的氧化应激及自由基生成与帕金森病的发病机制有关 ;而铁螯合剂在离体实验及帕金森病动物模型中均被证实能抑制氧化应激、保护多巴胺能神经元。本文就近年来帕金森病时铁代谢的变化、铁在帕金森病中的可能作用机制及铁螯合剂在帕金森病治疗中的应用前景作一综述。     

Iron metabolism in Parkinsonian syndromes.

Growing evidence suggests an involvement of iron in the pathophysiology of neurodegenerative diseases. Several of the diseases are associated with parkinsonian syndromes, induced by degeneration of basal ganglia regions that contain the highest amount of iron within the brain. The group of neurodegenerative disorders associated with parkinsonian syndromes with increased brain iron content can be devided into two groups: (1) parkinsonian syndromes associated with brain iron accumulation, including Parkinson's disease, diffuse Lewy body disease, parkinsonian type of multiple system atrophy, progressive supranuclear palsy, corticobasal ganglionic degeneration, and Westphal variant of Huntington's disease; and (2) monogenetically caused disturbances of brain iron metabolism associated with parkinsonian syndromes, including aceruloplasminemia, hereditary ferritinopathies affecting the basal ganglia, and panthotenate kinase associated neurodegeneration type 2. Although it is still a matter of debate whether iron accumulation is a primary cause or secondary event in the first group, there is no doubt that iron-induced oxidative stress contributes to neurodegeneration. Parallels concerning pathophysiological as well as clinical aspects can be drawn between disorders of both groups. Results from animal models and reduction of iron overload combined with at least partial relief of symptoms by application of iron chelators in patients of the second group give hope that targeting the iron overload might be one possibility to slow down the neurodegenerative cascade also in the first group of inevitably progressive neurodegenerative disorders.     

Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders

New findings on the role of LfR (lactotransferrin receptor), MTf (melanotransferrin), CP (ceruloplasmin) and DCT1 (Divalent Cation Transporter) in brain iron transport, obtained during the past 3 years, are important advances in the fields of physiology and pathophysiology of brain iron metabolism. According to these findings, disruption in the expression of these proteins in the brain is probably one of the important causes of the altered brain iron metabolism in age-related neurodegenerative diseases, including Parkinson's Disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the involvement of LfR, MTf and DCT1 in iron uptake by and CP in iron egress from different types of brain cells as well as control mechanisms of expression of these proteins in the brain are critical for elucidating the causes of excessive accumulation of iron in the brain and neuronal death in neurodegenerative diseases.     

Iron misregulation in the brain: a primary cause of neurodegenerative disorders

High iron concentrations in the brains of patients and the discovery of mutations in the genes associated with iron metabolism in the brain suggest that iron misregulation in the brain plays a part in neuronal death in some neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases and Hallervorden-Spatz syndrome. Iron misregulation in the brain may have genetic and non-genetic causes. The disrupted expression or function of proteins involved in iron metabolism increases the concentration of iron in the brain. Disturbances can happen at any of several stages in iron metabolism (including uptake and release, storage, intracellular metabolism, and regulation). Increased brain iron triggers a cascade of deleterious events that lead to neurodegeneration. An understanding of the process of iron regulation in the brain, the proteins important in this process, and the effects of iron misregulation could help to treat or prevent neurodegenerative disorders.     

Moderate iron deficiency in infancy: biology and behavior in young rats

Iron deficiency anemia in early childhood is associated with developmental delays and perhaps, irreversible alterations in neurological functioning. The goals were to determine if dietary induced gestational and lactational iron deficiency alters brain monoamine metabolism and behaviors dependent on that neurotransmitter system. Young pregnant rats were provided iron deficient or control diets from early in gestation through to weaning of pups and brain iron concentration, regional monoamine variables and achievement of specific developmental milestones were determined throughout lactation. Despite anemia during lactation, most brain iron concentrations did not fall significantly until P25, and well after significant changes in monoamine levels, transporter levels, and D₂R density changed in terminal fields. The changes in D₂R density were far smaller than previously observed models that utilized severe dietary restriction during lactation or after weaning. Iron deficient pups had normal birth weight, but were delayed in the attainment of a number of milestones (bar holding, vibrissae-evoked forelimb placing). This approach of iron deficiency in utero and during lactation sufficient to cause moderate anemia but not stunt growth demonstrates that monaminergic metabolism changes occur prior to profound declines in brain iron concentration and is associated with developmental delays. Similar developmental delays in iron deficient human infants suggest to us that alterations in iron status during this developmental period likely affects developing brain monaminergic systems in these infants.     

A new MRI ratio method for in-vivo estimation of signal hypointensity in aging and Alzheimer''s disease

1. 1. Alzheimer's Disease (AD) is accompanied by a disruption in iron metabolism. There is no universally accepted method for detecting brain iron.

2. 2. The authors have developed a novel “ratio” method which uses the red nucleus as an internal reference. We postulated that this method would improve our sensitivity in detecting differences in MRI signal intensities and that it would allow us to measure brain iron deposition.

3. 3. The ratio method reasonably reproduced previous reports of the normal deposition of iron in brain that occurs with aging. It failed to distinguish any differences in three brain areas: putamen, left frontal lobe and whole slice in AD patients versus age and sex matched controls.

4. 4. It also failed to detect differences with AD progression or severity.

5. 5. The ratio method itself warrants further investigation.

     

Isoforms of ferritin have a specific cellular distribution in the brain

Ferritin is the major iron storage protein and accounts for the majority of the iron in the brain. Thus, ferritin is a key component in protecting the brain from iron induced oxidative damage. The high lipid content, high rate of oxidative metabolism, and high iron content combine to make the brain the organ most susceptible to oxidative stress. The role of oxidative damage and disruption of brain iron homeostasis is considered clinically important to normal aging and a potential pathogenic component of a number of neurologic disorders including Alzheimer's disease and Parkinson's disease. Little is known, however, of the mechanism by which the brain maintains iron homeostasis at either the whole organ or cellular level. In this study we report the cellular distribution of the two isoforms of ferritin in the brain of adult subhuman primates. A subset of neurons immunolabel specifically for the H-chain ferritin protein, whereas cells resembling microglia are immunolabeled only after exposure to the L-chain ferritin antibody. Only one cell type immunostains for both H-and L-chain ferritin; these cells are morphologically similar and have the same distribution pattern as oligodendrocytes. Neither ferritin isoform is usually detected in astrocytes. These data indicate considerable differences in iron sequestration and use between neurons and glia and among neuronal and glial subtypes. This information will be essential in determining the role of each of these cells in maintaining general brain iron homeostasis and the relative abilities of these cells to withstand oxidative stress. © 1994 Wiley-Liss, Inc.     

In vivo detection of iron and neuromelanin by transcranial sonography – a new approach for early detection of substantia nigra damage

Summary. In more than 90% of patients with idiopathic Parkinson’s disease (PD) hyperechogenicity of the substantia nigra (SN) can be found by transcranial sonography (TCS) as a typical, stable sign. Animal experiments provided first evidence that SN hyperechogenicity may be associated with increased tissue iron levels. Two consecutive studies revealed the same association in human brain. Postmortem brains of 60 subjects without clinical signs for Parkinson’s disease during life time at different ages were scanned by ultrasound with planimetric measurement of the echogenic area of the SN. Afterwards the SN was dissected and used for histological examination and determination of iron content in all brains as well as ferritin and neuromelanin content in 40 brains. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. A multivariate analysis performed considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. Iron staining confirmed the biochemical findings. In PD a typical loss of neuromelanin and increase of iron is observed in this brain area. However, it is not clear yet, whether iron accumulation is a primary cause or a secondary phenomenon in the disease process. Screening of genes involved in brain iron metabolism showed a significant association of some sequence variations of the ceruloplasmin gene with PD. Others were associated with the ultrasound marker for increased iron levels in both PD patients and control subjects. As SN hyperechogenicity is typical for PD or subjects with a preclinical impairment of the nigrostriatal system, these findings indicate that TCS enables the detection of increased iron and decreased neuromelanin levels at the SN, even before the clinical manifestation of PD.     

Iron concentration reduced in ventral pallidum, globus pallidus, and substantia nigra by GABA-transaminase inhibitor, gamma-vinyl GABA

Recent histochemical studies indicate that there is considerable overlap of brain areas accumulating iron in oligodendrocytes with those in which GABA neurons terminate. The ventral pallidum, globus pallidus, substantia nigra and cerebellar nuclei are iron-rich areas, receive GABA-containing efferents, and have high concentrations of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD). The present study examines the effect of disruption of the metabolism of GABA on the accumulation of iron in GABAergic projection sites. Gamma-vinyl GABA, an enzyme activated inhibitor of GABA-transaminase, was injected unilaterally into the globus pallidus and adjacent striatum or into the substantia nigra of the rat brain. Additional animals received unilateral injections of saline into the same areas or an electrocoagulation lesion of the globus pallidus and surrounding striatum. Two days after injection or lesion all animals were perfused and 40 micron sections of the brain were processed with the Perls' + diaminobenzidine (DAB) histochemical method for iron. The intensity of iron stain was measured with densitometry. Gamma-vinyl GABA injection into the striatum/pallidum resulted in a significant reduction in iron concentration in the ipsilateral ventral pallidum, globus pallidus and substantia nigra. Gamma-vinyl GABA injected into the substantia nigra reduced iron in the injection site. This study provides evidence that the presence of iron in the brain is related to the utilization of GABA.     

Rethinking the role of ceruloplasmin in brain iron metabolism

For more than three decades, it has been widely accepted that ceruloplasmin plays an important role in iron efflux from mammalian cells, including brain cells, via the activity of ferroxidase. However, in light of recent findings, this view might not be completely accurate and the role of ceruloplasmin in brain iron metabolism may need to be re-evaluated. Based on recent studies, we propose in this article that the role of ceruloplasmin in iron uptake by brain neuronal cells might be more important than its role in iron release from the cells. A possible explanation of why the absence of ceruloplasmin induces excessive iron accumulation in neurons in aceruloplasminemia (ceruloplasmin gene mutations) was also discussed.     

Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity

Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34-97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 +/- 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain.