Iron-induced relaxation mechanisms in the human substantia nigra: Towards quantifying iron load in dopaminergic neurons

Pathological iron accumulation in the human brain is a biomarker for neurodegeneration. Several diagnostically promising MR- based methods for in vivo iron quantification were proposed, based on the empirical relationship between R 2 * and iron concentration. However, these do not account for different chemical forms and cellular distribution of iron. We combined post mortem MRI, advanced quantitative histology and biophysical modeling to develop a generative theory linking obtained iron concentrations to quantitative MR parameters. The impact of nanoscale molecular interaction of water with iron and of iron-rich dopaminergic neurons was quantified in substantia nigra

Cell specific quantitative iron mapping on brain slices by immuno-μPIXE in healthy elderly and Parkinson’s disease

Iron is essential for neurons and glial cells, playing key roles in neurotransmitter synthesis, energy production and myelination. In contrast, high concentrations of free iron can be detrimental and contribute to neurodegeneration, through promotion of oxidative stress. Particularly in Parkinson’s disease (PD) changes in iron concentrations in the substantia nigra (SN) was suggested to play a key role in degeneration of dopaminergic neurons in nigrosome 1. However, the cellular iron pathways and the mechanisms of the pathogenic role of iron in PD are not well understood, mainly due to the lack of quantitative analytical techniques for iron quantification with subcellular resolution. Here, we quantified cellular iron concentrations and subcellular iron distribution in dopaminergic neurons and different types of glial cells in the SN both in brains of PD patients and in non-neurodegenerative control brains (Co). To this end, we combined spatially resolved quantitative element mapping using micro particle induced X-ray emission (μPIXE) with nickel-enhanced immunocytochemical detection of cell type-specific antigens allowing to allocate element-related signals to specific cell types. Distinct patterns of iron accumulation were observed across different cell populations. In the control (Co) SNc, oligodendroglial and astroglial cells hold the highest cellular iron concentration whereas in PD, the iron concentration was increased in most cell types in the substantia nigra except for astroglial cells and ferritin-positive oligodendroglial cells. While iron levels in astroglial cells remain unchanged, ferritin in oligodendroglial cells seems to be depleted by almost half in PD. The highest cellular iron levels in neurons were located in the cytoplasm, which might increase the source of non-chelated Fe3+, implicating a critical increase in the labile iron pool. Indeed, neuromelanin is characterised by a significantly higher loading of iron including most probable the occupancy of low-affinity iron binding sites. Quantitative trace element analysis is essential to characterise iron in oxidative processes in PD. The quantification of iron provides deeper insights into changes of cellular iron levels in PD and may contribute to the research in iron-chelating disease-modifying drugs

Cell specific quantitative iron mapping on brain slices by immuno-µPIXE in healthy elderly and Parkinson’s disease

Iron is essential for neurons and glial cells, playing key roles in neurotransmitter synthesis, energy production and myelination. In contrast, high concentrations of free iron can be detrimental and contribute to neurodegeneration, through promotion of oxidative stress. Particularly in Parkinson's disease (PD) changes in iron concentrations in the substantia nigra (SN) was suggested to play a key role in degeneration of dopaminergic neurons in nigrosome 1. However, the cellular iron pathways and the mechanisms of the pathogenic role of iron in PD are not well understood, mainly due to the lack of quantitative analytical techniques for iron quantification with subcellular resolution. Here, we quantified cellular iron concentrations and subcellular iron distributions in dopaminergic neurons and different types of glial cells in the SN both in brains of PD patients and in non-neurodegenerative control brains (Co). To this end, we combined spatially resolved quantitative element mapping using micro particle induced X-ray emission (mu PIXE) with nickel-enhanced immunocytochemical detection of cell type-specific antigens allowing to allocate element-related signals to specific cell types. Distinct patterns of iron accumulation were observed across different cell populations. In the control (Co) SNc, oligodendroglial and astroglial cells hold the highest cellular iron concentration whereas in PD, the iron concentration was increased in most cell types in the substantia nigra except for astroglial cells and ferritin-positive oligodendroglial cells. While iron levels in astroglial cells remain unchanged, ferritin in oligodendroglial cells seems to be depleted by almost half in PD. The highest cellular iron levels in neurons were located in the cytoplasm, which might increase the source of non-chelated Fe3+, implicating a critical increase in the labile iron pool. Indeed, neuromelanin is characterised by a significantly higher loading of iron including most probable the occupancy of low-affinity iron binding sites. Quantitative trace element analysis is essential to characterise iron in oxidative processes in PD. The quantification of iron provides deeper insights into changes of cellular iron levels in PD and may contribute to the research in iron-chelating disease-modifying drugs

Поведение морфолина и его триметилсилилпроизводного в реакциях с триметилсилилизоцианатом

Objectives. To study the patterns of behavior of morpholine and its trimethylsilyl derivative in reactions with trimethylsilyl isocyanate.Methods. The study employed infrared and nuclear magnetic resonance spectroscopy, as well as elemental analysis.Results. The formation of mixtures of tautomeric forms of silicon-containing urea—N-(trimethylsilyl) morpholine-4-carboxamide and trimethylsilylmorpholine-4-carboximidoate—was established.Conclusions. It is shown that the composition and structure of the resulting products are determined both by the presence of a morpholine substituent at the nitrogen atom and by the type of isocyanate used. Unlike the trimethylsilyl derivative of morpholine, morpholine itself reacts with trimethylsilyl isocyanate to form a mixture of tautomeric forms.Цели. Изучить закономерности поведения морфолина и его триметилсилилпроизводного в реакциях с триметилсилилизоцианатом.Методы. В исследовании использовались методы инфракрасной спектроскопии, спектроскопии ядерного магнитного резонанса и элементного анализа.Результаты. Установлено образование смеси таутомерных форм кремнийсодержащей мочевины: N-(триметилсилил)морфолин-4-карбоксамида и триметилсилилморфолин -4-карбоксимидоата.Выводы. Установлено, что состав и строение образующихся продуктов определяется как наличием заместителя при атоме азота морфолина, так и типом используемого изоцианата. Показано, что, в отличие от триметилсилильного производного морфолина, сам морфолин взаимодействует с триметилсилилизоцианатом с образованием смеси таутомерных форм

ОСОБЕННОСТИ ВЗАИМОДЕЙСТВИЯ ИЗОЦИАНАТОВ С ПРОИЗВОДНЫМИ ГИДРАЗИНА

The results of studies on chemical transformations of organic and organosilicon isocyanates in their interaction with hydrazine derivatives have been summarized in this review. It is shown that hydrazine and its derivatives including organosilicon compounds reacting with organic isocyanates form corresponding semicarbazides readily enough. The reaction conditions that effect the composition, structure and yield of the resulting target products are presented. A significant difference in the interaction of trimethylsilyl isocyanate with organic and organosilicon derivatives of hydrazine is demonstrated. It is demonstrated that the reason for the impossibility to isolate trimethylsilyl derivatives of semicarbazide is their low hydrolytic stability, as well as high silylating ability. Peculiarities of the reaction of trimethylsilyl isocyanate and dimethylchloromethyl isocyanate silane with 1,1-dimethylhydrazine, its trimethylsilyl analog and isoniazid are given. Possible schemes for the formation of a previously unknown O-trimethylsilyl-1,1-dimethylhydrazinecarboximidoate are presented. The results of using carbofunctional organosilicon isocyanates in these processes are discussed. Basic trends in practical use of the prepared compounds as physiologically active preparations in polymer chemistry and agriculture are shown.В обзоре обобщены результаты исследований по изучению химических превращений органических и кремнийорганических изоцианатов при их взаимодействии с производными гидразина. Показано, что с органическими изоцианатами гидразин и его производные, в том числе и кремнийорганические, достаточно легко образуют соответствующие семикарбазиды. Приведены условия проведения реакций, оказывающие влияние на состав, строение и выход образующихся целевых продуктов. Показано существенное отличие взаимодействия триметилсилилизоцианата с органическими и кремнийорганическими производными гидразина. Показано, что причиной невозможности выделения триметилсилильных производных семикарбазида является их низкая гидролитическая стабильность, а также высокая силилирующая способность. Обсуждены особенности реакций взаимодействия триметилсилилизоцианата и диметилхлорметилизоцианатосилана с 1,1-диметилгидразином, его триметилсилилным аналогом и изониазидом. Приведены возможные варианты схем образования ранее неизвестного О-триметилсилил-1,1-диметилгидразинкарбоксимидоата. Показаны результаты использования в данных процессах карбофункциональных кремнийорганических изоцианатов. Представлены основные направления практического использования получаемых соединений - в качестве физиологически активных препаратов, в полимерной химии и в сельском хозяйстве

PECULIARITIES OF ISOCYANATES INTERACTION WITH HYDRAZINE DERIVATIVES

The results of studies on chemical transformations of organic and organosilicon isocyanates in their interaction with hydrazine derivatives have been summarized in this review. It is shown that hydrazine and its derivatives including organosilicon compounds reacting with organic isocyanates form corresponding semicarbazides readily enough. The reaction conditions that effect the composition, structure and yield of the resulting target products are presented. A significant difference in the interaction of trimethylsilyl isocyanate with organic and organosilicon derivatives of hydrazine is demonstrated. It is demonstrated that the reason for the impossibility to isolate trimethylsilyl derivatives of semicarbazide is their low hydrolytic stability, as well as high silylating ability. Peculiarities of the reaction of trimethylsilyl isocyanate and dimethylchloromethyl isocyanate silane with 1,1-dimethylhydrazine, its trimethylsilyl analog and isoniazid are given. Possible schemes for the formation of a previously unknown O-trimethylsilyl-1,1-dimethylhydrazinecarboximidoate are presented. The results of using carbofunctional organosilicon isocyanates in these processes are discussed. Basic trends in practical use of the prepared compounds as physiologically active preparations in polymer chemistry and agriculture are shown

Correction of magnetization transfer saturation maps optimized for 7T postmortem MRI of the brain

PurposeMagnetization transfer saturation (MTsat) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased B1+ inhomogeneity at 7T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous B1+correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains.TheoryThe B1+ dependence of was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C is proposed to correct bias in MTsat by mapping it to the reference value of the saturation pulse flip angle.MethodsMTsat was estimated voxel-wise in five postmortem chimpanzee brains. “Individual-based global parameters” were obtained by calculating the meanC within individual specimen brains and “group-based global parameters” by calculating the means of the individual-based global parameters across the five brains.ResultsThe linear calibration model described the data well, though C was not entirely independent of the underlying tissue and B1+. Individual-based correction parameters and a group-based global correction parameter (C=1.2) led to visible, quantifiable reductions of B1+-biases in high-resolution MTsat maps.ConclusionThe presented model and calibration approach effectively corrects for B1+inhomogeneities in postmortem 7T data