Diethyldithiocarbamate, copper and neurological disorders.

Diethyldithiocarbamate (DEDTC) given orally to rats without any addition of copper considerably increased the concentration of Cu in the brain without any change in the other tested tissues. Cysteine, comparatively studied, did not induce any change in the brain Cu level. Based on these findings and the literature data concerning DEDTC effects in animal and human, we put forward the hypothesis that the main effect of DEDTC is to provoke in the brain not a deficiency but an excess of Cu liberated from the lipophilic complex Cu-DEDTC. Cu is then engaged in an oscillatory oxido reduction giving a Cu++ cation radical able to induce deleterious effects on tissues in a similar way as paraquat. The practical consequences of this hypothesis are considered.     

Mitochondrial dysfunction in neurological disorders with epileptic phenotypes

A broad variety of mutations of the mitochondrial DNA or nuclear genes that lead to the impairment of mitochondrial respiratory chain or mitochondrial ATP synthesis have been associated with epileptic phenotypes. Additionally, evidence for an impaired mitochondrial function in seizure focus of patients with temporal lobe epilepsy and Ammon’s horn sclerosis, as well as, animal models of temporal lobe epilepsy has been accumulated. This implies a direct pathogenic role of mitochondrial dysfunction in the process of epileptogenesis and seizure generation in certain forms of epilepsy.     

Nitric oxide and neurological disorders

This article aims to give a broad overview of some of the potential targets for nitric oxide (NO) in the brain. The relevance of NO in both physiological and pathological scenarios is considerable. There is substantial evidence that neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, involve NO in their pathogenesis. Here we describe a number of cellular components which may be affected by NO, with particular relevance to neurological diseases. As the mitochondrion (in particular the electron transport chain) would appear to be of importance when considering the deleterious effects of NO, this review has a particular emphasis on that organelle. Cellular and mitochondrial antioxidants such as glutathione and ubiquinone are also discussed. In addition, the pivotal role of the astrocyte in both neuroprotection or neurodegeneration are examined.     

Paraoxonase 1 in neurological disorders

Abstract

Paroxonase 1 displays multiple physiological activities that position it as a putative player in the pathogenesis of neurological disorders. Here we reviewed the literature focusing on the role of paraoxonase 1 (PON1) as a factor in the risk of stroke and the major neurodegenerative diseases. PON1 activity is reduced in stroke patients, which significantly correlates inversely with carotid and cerebral atherosclerosis. The presence of the R allele of the Q192R PON1 polymorphism seems to potentiate this risk for stroke. PON1 exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress. PON1 is also a key detoxifier of organophosphates and organophosphate exposure has been linked to the development of neurological disorders in which acetylcholine plays a significant role. In Parkinson's disease most of the studies suggest no participation of either L55M or the Q192R polymorphisms in its pathogenesis. However, many studies suggest that the MM55 PON1 genotype is associated with a higher risk for Parkinson's disease in individuals exposed to organophosphates. In Alzheimer's disease most studies have failed to find any association between PON1 polymorphisms and the development of the disease. Some studies show that PON1 activity is decreased in patients with Alzheimer's disease or other dementias, suggesting a possible protective role of PON1. No links between PON1 polymorphisms or activity have been found in other neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. PON1 is a potential player in the pathogenesis of several neurological disorders. More research is warranted to ascertain the precise pathogenic links and the prognostic value of its measurement in neurological patients.     

肠道菌群与神经系统疾病

人类肠道菌群是数以万亿的细菌组成的高度多样化的生态系统,菌群失调与多个系统疾病有关联。肠道菌群通过菌群-肠-脑轴与神经系统多途径双向互作,能引起神经免疫炎症反应、肠黏膜和血脑屏障功能改变、直接刺激迷走神经和肠道神经系统脊神经、神经内分泌-下丘脑-垂体-肾上腺轴,造成神经系统疾病。肠道菌群的代谢产物也有一定的作用。文中综述自闭症谱系障碍、多发性硬化、帕金森病、癫痫、吉兰巴雷综合征、阿尔茨海默病、视神经脊髓炎、肝性脑病、肌萎缩侧索硬化、精神分裂症、抑郁症、慢性疲劳综合征、亨廷顿病、脑卒中等肠道菌群改变特征及其干预措施的研究进展。目前肠道菌群的研究还处在初级阶段,因果关系和机制方面的研究比较少,这对精准实施菌群临床干预措施具有重要意义,期待将来有所突破成为一些神经系统疾病治疗的新路径。     

Modeling human neurological disorders with induced pluripotent stem cells

Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient‐specific genetic information. For example, disease‐specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi‐omics analysis of neural cells originating from patient‐derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large‐scale screening of chemical libraries with disease‐specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient‐derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs.

     

Cerebrospinal fluid samples from patients with various neurological disorders have a transmissible cytotoxic activity with similar properties

When inoculated into cell cultures to search for cytopathic viruses, six out of 384 cerebrospinal fluid (CSF) samples from patients with different neurological disorders proved to have a transmissible cytotoxic activity (TCA) not correlated to a conventional infectious agents. Properties shown by a TCA previously detected in the CSF sample of a patient with brain ischemia (Portolani et al., 2005) were shared by each of the newly isolated TCAs. We conclude that independently of the neurological clinical picture shown by the patient, the TCA detected in the CSF samples under study could have the same origin.     

Coping style in primary care adult patients with abridged somatoform disorders

Background and objective Empirical data are scarce regarding the adaptive response to stress for patients with somatoform disorders. Our objective was to identify the preferred coping strategies of patients with abridged somatisation, a common condition in primary care. Because of the functional impairment associated with somatisation, we predicted a preference for less effective, emotion-focused coping strategies over more effective, problem-focused adaptations.Design We conducted a cross-sectional, observational study of physician referred primary care patients who presented with persistent, medically unexplained, physical symptoms. Patients were classified into two abridged somatisation groups by symptom frequency and duration, as determined by the Diagnostic Interview Schedule. The groups were compared with each other and with a non-clinical reference group; outcome variables were eight emotion- and problem-focused strategies, as measured by the Ways of Coping Questionnaire.Results Of the 72 eligible individuals, 48 participated in the study. Median age was 48 years and 75% of patients were women; 26 had somatic syndrome and 22 had a subthreshold somatising level. Patients with abridged somatisation disorders preferred emotion-focused coping strategies - typically detachment and impact minimisation, wishful thinking and problem avoidance.Conclusions Patients with abridged somatising disorder responded to stress with predominantly emotion-focused strategies, which may be associated with a lower level of positive adaptive outcome. Our findings suggest that patients with abridged somatising disorders might benefit from emphasis on problem-focused coping strategies, delivered through primary care, to improve quality of life and decrease healthcare utilisation costs.     

Autoimmune channelopathies and related neurological disorders

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.