Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

Advances in the development of newly developed fluorinated drugs, approved or in clinical trials, as organized by biological targets/disease states, are reviewed. In a few cases, compounds in early stages of development will be discussed, particularly where new promising targets are involved. Important topics such as anticancer and antiviral drugs were covered in the two previous reviews in this series. Included herein will be fluorinated drugs for treatment of diseases of the central nervous system, various cardiovascular diseases and obesity, antibacterial agents, and antifungal therapy.     

The Myelin Membrane of the Central Nervous System—Essential Macromolecular Structure and Function

The neural sheaths that surround the nerve fibers (axons) are composed of myelin-specific complex lipids and are assembled during the myelination phase either by the oligodendrocytes in the central nervous system (CNS) or by the Schwann cells in the peripheral nervous system. These multilayered myelin membranes insulate the axons and permit a rapid, saltatory conduction of excitation and a reduced axon diameter in comparison with noninsulated axons. Myelination was hence the decisive evolutionary event in miniaturization of the central nervous system (brain and spinal cord). The morphology of the myelin membrane has been studied in detail mainly by electron microscopy. Most of its biochemistry has been elucidated in recent years by molecular-level analysis of both the lipid components (cholesterol, phospholipids and sphingolipids) and the constituent proteins. The multilamellar system is distinguished by a characteristic periodicity due to the 5-nm-thick bilayer formed by the myelin-specific lipids. The bilayer interacts with the myelin basic protein (MBP) on the cytosolic side of the plasma membrane process, while the integral membrane protein proteolipid protein (PLP) has hydrophilic domains exposed on both the cytosolic and extracytosolic faces of the bilayer. Numerous protein-chemical and -immunotopochemical findings have been summarized in a model of the myelin membrane. Through molecular biological studies, the genetic structure and chromosomal location of the myelin proteins have been determined. By employing techniques of molecular and cell biology together, it is now possible to analyze the process of myelinogenesis, the time- and location-specific expression of myelin-specific genes in the brain. Gene-technological methods have been used to define the mutations in the models jimpy mouse and myelin-deficient rat. These are animal models that correspond to genetically determined myelin defects (dysmyelinoses) in humans. Using them, it will be possible to study the cell death of oligodendrocytes on a molecular level; this process is the result of expression of mutant myelin proteins and is incompatible with life. Oligodendrocytes and the myelin structures they synthesize are the target structures of cytotoxic lymphocytes (T_c). In the course of the demyelination process in multiple sclerosis, these cause the breakdown of the myelin sheaths, in gradually appearing inflammations. T_c lymphocytes recognize myelin structures as epitopes and destroy them. The picture of the myelin membrane's molecular composition, which we are now perfecting, will also lead to a better understanding of demyelination on a molecular level, and hence to new therapeutic possibilities.     

Clinical perspectives of high-resolution mass spectrometry-based proteomics in neuroscience: exemplified in amyotrophic lateral sclerosis biomarker discovery research

Biomarker discovery is a central application in today's proteomic research. There is an urgent need for valid biomarkers to improve diagnostic tools and treatment in many disorders, such as the rapidly progressing neurodegenerative disorder amyotrophic lateral sclerosis (ALS) that has a fatal outcome in about 3 years and yet no curative treatment. Screening for clinically relevant biomarkers puts high demands on high-throughput, rapid and precise proteomic techniques. There is a large variety in the methods of choice involving mainly gel-based approaches as well as chromatographic techniques for multi-dimensional protein and peptide separations followed by mass spectrometry (MS) analysis. This special feature article will discuss some important aspects of MS-based clinical proteomics and biomarker discovery in the field of neurodegenerative diseases and ALS research respectively, with the aim to provide a prospective view on current and future research aspects in the field. Furthermore, examples for application of high-resolution MS-based proteomic strategies for ALS biomarker discovery will be demonstrated with two studies previously reported by our group. These studies include among others, utilization of capillary liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS) for advanced protein pattern classification in cerebrospinal fluid (CSF) samples of ALS patients as well as highly sensitive protein identification in minimal amounts of postmortem spinal cord tissue and laser micro-dissected motor neurons using FT-ICR-MS in conjunction with nanoflow LC coupled to matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (LC-MALDI-TOF-TOF-MS).     

低频电磁辐射与脑神经细胞微管的相互作用

研究了低频电磁辐射场与脑神经系统的相互作用规律及其机理。电磁辐射为非电离低频电磁场, 将脑神经细胞骨架微管（MT）中的两态物理系统进行量子化,用密度矩阵描述脑神经系统中信息位的状态, 建立并求解脑神经系统中信息位的动力学方程。 结果表明: 当非电离低频电磁辐射射向大脑时, 脑神经系统中信息位的密度矩阵非对角元在任意时刻都不为零, 能够保持较好的量子相干性, 脑神经系统的功能不会受到破坏。     

Programmed cell death in developing human fetal CNS

The spatial and temporal distributions of programmed cell death (PCD) in developing central nervous system (CNS) of human fetuses ranging from 12 to 39 weeks of gestation were investigated using techniques of flow cytometry and terminal transferase-mediated nick end labeling (TUNEL). The results showed that PCD did occur in every representative brain region of all fetuses examined in different stages. It was found that there were two peaks of PCD appearing at the 12th and 39th weeks respectively, which suggested that the first peak of apoptosis may be involved in the selective elimination of neurons overproduced during the early development and the second may play an important role in establishing the correct neuronal circuitry.     

Identification of an Orally Bioavailable,Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [³H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (K_i = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.     

Entropy Analysis of Neonatal Electrodermal Activity during the First Three Days after Birth

The entropy-based parameters determined from the electrodermal activity (EDA) biosignal evaluate the complexity within the activity of the sympathetic cholinergic system. We focused on the evaluation of the complex sympathetic cholinergic regulation by assessing EDA using conventional indices (skin conductance level (SCL), non-specific skin conductance responses, spectral EDA indices), and entropy-based parameters (approximate, sample, fuzzy, permutation, Shannon, and symbolic information entropies) in newborns during the first three days of postnatal life. The studied group consisted of 50 healthy newborns (21 boys, average gestational age: 39.0 ± 0.2 weeks). EDA was recorded continuously from the feet at rest for three periods (the first day—2 h after birth, the second day—24 h after birth, and the third day—72 h after birth). Our results revealed higher SCL, spectral EDA index in a very-low frequency band, approximate, sample, fuzzy, and permutation entropy during the first compared to second and third days, while Shannon and symbolic information entropies were lower during the first day compared to other periods. In conclusion, EDA parameters seem to be sensitive in the detection of the sympathetic regulation changes in early postnatal life and which can represent an important step towards a non-invasive early diagnosis of the pathological states linked to autonomic dysmaturation in newborns.     

Recording from an Identified Neuron Efficiently Reveals Hazard for Brain Function in Risk Assessment

Modern societies use a continuously growing number of chemicals. Because these are released into the environment and are taken up by humans, rigorous (but practicable) risk assessment must precede the approval of new substances for commerce. A number of tests is applicable, but it has been very difficult to efficiently assay the effect of chemicals on communication and information processing in vivo in the adult vertebrate brain. Here, we suggest a straightforward way to rapidly and accurately detect effects of chemical exposure on action potential generation, synaptic transmission, central information processing, and even processing in sensory systems in vivo by recording from a single neuron. The approach is possible in an identified neuron in the hindbrain of fish that integrates various sources of information and whose properties are ideal for rapid analysis of the various effects chemicals can have on the nervous system. The analysis uses fish but, as we discuss here, key neuronal functions are conserved and differences can only be due to differences in metabolism or passage into the brain, factors that can easily be determined. Speed and efficiency of the method, therefore, make it suitable to provide information in risk assessment, as we illustrate here with the effects of bisphenols on adult brain function.     

心血管病人的心率变异性

目的研究植物神经系统对心血管功能的影响和作用.方法采用频谱分析的方法进行临床观察.结果给缺血性心脏病病人使用东莨菪硷贴剂24 h后,所有心率变异性参数均显著增加,缺血发作的频率及持续时间均减少.在急性心肌梗死时,频谱中所有的心率变异性指数(LF,HF,VLF和ULF4个区域)均呈典型性降低,其中标准差s<20ms时,致命性室性心律失常发生率显著升高,频谱图上不同的特征改变对心衰的判断预后亦有意义.心率变异性参数分析反映了心血管病人植物神经系统功能状态,副交感神经占优势时,则疾病趋于改善,而交感神经活性增强时则疾病预后不良.结论可将心率变异性的频谱分析法用于临床诊断及疾病的风险评价.     

"神经系统疾病的基础与临床"讨论课教学实践

神经系统是人体解剖学课程中最复杂的系统,为帮助学生正确理解和运用神经系统的解剖学知识,特开设"神经系统疾病的基础与临床"讨论课.介绍课程的开设方法,存在的优点及不足,提出讨论课对学生学习能力、思维能力及临床诊治水平的提高有着不可替代的作用,值得在一定范围内积极推广.