Neuroprotection and neurodegenerative diseases: from biology to clinical practice

Neurodegenerative diseases and, in particular, Alzheimer disease, are characterized by progressive neuronal loss correlated in time with the symptoms of the disease considered. Whereas the symptoms of those incapacitating diseases are beginning to be managed with a relative efficacy, the ultimate objective of therapy nonetheless remains preventing cell (neuronal and/or astrocytic) death in a neurocytoprotective approach. In biologic terms, in the light of progress at basic research level, three strategies may be envisaged: (1) antagonizing the cytotoxic causal events (excess intracellular calcium, accumulation of abnormal proteins, excitotoxic effects of amino acids, oxidative stress, processes related to inflammation, etc.); (2) stimulating the endogenous protective processes (anti-free radical or DNA repair systems, production of neurotrophic factors, potential cytoprotective action of steroids, etc.); (3) promoting damaged structure repair strategies (grafts) or deep brain or cortical neurostimulation with a view to triggering (beyond the symptomatic actions) potential 'protective' cell mechanisms. The clinical transition of the various strategies whose efficacy is being tested in animal and/or cell models, experimental analogs of the diseases, and thus the objective demonstration in humans of pharmacological and/or surgical neurocytoprotection, is currently the subject of considerable methodological debate (What are the right psychometric assessment criteria? What are the most pertinent laboratory or neuroradiological markers, etc.?). A number of clinical trials have been completed or are ongoing with drugs that are reputed to be neuroprotective. Thus, elements of the response are beginning to be generated with a view to determining whether it will soon be possible to effectively slow or even stop the neurodegenerative process whose etiology, in most cases, remains obscure.     

Neurodegenerative diseases: basic and clinical research Abstracts

Posrischemic changes in hippocampal non-principal cells Neuronal activity in rat hippocampus slices following in vivo brain ischemia Sulphur amino acids — endogenous ligands for glutamate receptors? Novel NMDA receptor agonists structurally related to ibotenic acid and aspartic acid HIV- 1 nef protein exhibits structural and functional similarity to Neurotoxins Glial reactions to ischemic lesions of the rat hippocampus Microglial and astroglial reactions to perforant path axonal degeneration Unbiased stereological estimation of the total number of neurons in the aging human hippocampus Macroscopic volume measurements on brains from senile demented patients and age-matched controls Cerebral atrophy in 18 males with aids. Stereologic estimate on formalin-fixed brains Absolute number of neurons in substantia nigra in Parkinson's disease The rat nigrostriatal, dopaminergic system studied in organotypic slice cultures of ventral mesencephalon and striatum Basal forebrain neurons in adult rats can reinnervate fetal frontal cortex grafted to frontal cortex lesions. A double-fluorescent tracing study Neuronal plasticity and astrocytic reaction in Alzheimer's disease Problems concerning the use of rating scales and psychometric tests in the study of dementia [^99mTc]-HMPA0 and SPECT of the brain in normal aging SPECT in Alzheimer's disease     

NA干扰及其在神经变性性疾病研究中的应用

RNA干扰 (RNAi)是指生物体内利用具有同源性的双链RNA(dsRNA)诱发序列特异的转录后基因沉默(PTGS)的现象 ,它可以通过抑制蛋白表达模拟基因敲除技术。RNAi主要通过dsRNA被核酸酶Dicer切割成 2 1～ 2 5nt的小干扰RNA(siRNA) ,由siRNA介导识别并靶向切割同源mRNA分子而实现。随着研究的不断深入 ,RNAi的作用机制将逐步被阐明 ,其技术也将日趋完善和成熟 ,并将得到广泛的应用。本文就RNAi技术的研究进展及其在阿尔茨海默病、帕金森病等神经变性性疾病研究中的应用作一综述     

Neuropharmacologic aspects of apoptosis: significance for neurodegenerative diseases.

The cause of neuronal death in Parkinson's, Alzheimer's, and other neurodegenerative diseases is not known, except in some hereditary forms of these disorders in which a mutated gene has been identified. Even in these cases, the molecular mechanisms that underlie the loss of specific populations of neurons have not been determined, although it is highly probable that apoptosis is involved. Some of the biochemical events that occur during apoptosis have been elucidated. We focus in this review on the role played by the proapoptotic caspases, the antiapoptotic proteins of the Bcl-2 family, and the apoptosis associated signal transducers such as ceramide, calcium, and reactive nitrogen or oxygen species. The role of the mitochondria and the possible implication of cell cycle regulators will also be addressed. Of particular interest are the endogenous inhibitory mechanisms and the pharmacologic agents that can be used to block apoptosis signaling cascades, because they offer models for the development of therapeutic strategies designed to prevent the evolution of pathologic neurodegeneration.     

由基础实验向临床应用过渡的骨组织工程

采用传统的自体骨或同种异体骨移植及生物材料填充修复大块骨缺损存在种种弊端，效果不理想，严重限制了其临床应用。组织工程技术的兴起为解决这一难题带来了希望，然而，大块组织工程骨血管化等关键性技术难题至今未找到理想的解决办法，采用常规的思路对大块骨缺损进行修复遇到了巨大的挑战。为使骨组织工程走向临床应用，作者提出并建立“体内灌注诱导成骨微循环系统”。可调控的体内灌注诱导成骨微循环系统具有以下特点:可以控制诱导培养条件，如调控各种生长因子微量稳定的缓控释放;能有效解决大块组织工程骨中心部位的早期营养和血运重建难题;避免了组织工程骨体内构建存在的二次损伤，需要较高的技术条件、操作较为复杂等缺陷;实现血管化与成骨的同步构建;操作简便，安全高效。体内灌注诱导成骨微循环系统使体外构建和体内构建得以完美结合。可以预计，这种新型的组织工程骨构建技术在不久的将来必将走向临床应用，实现临床大段骨缺损的再生修复。     

Compound facial expressions of emotion: from basic research to clinical applications

Emotions are sometimes revealed through facial expressions. When these natural facial articulations involve the contraction of the same muscle groups in people of distinct cultural upbringings, this is taken as evidence of a biological origin of these emotions. While past research had identified facial expressions associated with a single internally felt category (eg, the facial expression of happiness when we feel joyful), we have recently studied facial expressions observed when people experience compound emotions (eg, the facial expression of happy surprise when we feel joyful in a surprised way, as, for example, at a surprise birthday party). Our research has identified 17 compound expressions consistently produced across cultures, suggesting that the number of facial expressions of emotion of biological origin is much larger than previously believed. The present paper provides an overview of these findings and shows evidence supporting the view that spontaneous expressions are produced using the same facial articulations previously identified in laboratory experiments. We also discuss the implications of our results in the study of psychopathologies, and consider several open research questions.     

N-acetylcysteine and neurodegenerative diseases: Basic and clinical pharmacology

Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer’s disease, Parkinson’s disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down’s syndrome have been associated with several mitochondrial alterations Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.     

Neurophysiology of Parkinson's disease: from basic research to clinical correlates.

The aim of the present review is to discuss recent acquisitions on the neurophysiological effects of the DA denervation of the striatum, obtained in vitro from single neurone electrophysiological recordings. Nigrostriatal DA system degeneration does not significantly alter the intrinsic properties of striatal cells, but triggers adaptive responses in the striatum, involving glutamatergic neurotransmission. By pairing intracellular recordings from 6-OHDA-denervated striatal projection neurones and the synaptic stimulation of glutamatergic corticostriatal pathway, in vitro experiments contributed to elucidate the intimate alterations that follow striatal DA deafferentation. This experimental approach also allowed to better understand the possible cellular bases of both beneficial and side effects of the pharmacological compounds commonly employed in the treatment of PD.     

Neuronal migration disorders: from genetic diseases to developmental mechanisms

Neurons that constitute the cerebral cortex must migrate hundreds of cell-body distances from their place of birth, and through several anatomical boundaries, to reach their final position within the correct cortical layer. Human neurological conditions associated with abnormal neuronal migration, together with spontaneous and engineered mouse mutants, define at least four distinct steps in cortical neuronal migration. Many of the genes that control neuronal migration have strong genetic or biochemical links to the cytoskeleton, suggesting that the field of neuronal migration might be closing in on the underlying cytoskeletal events.     

Oxidative stress treatment for clinical trials in neurodegenerative diseases

Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine.     

Hydrogen peroxide induces apoptosis in cerebral vascular smooth muscle cells: possible relation to neurodegenerative diseases and strokes

Recently, reactive oxygen species (ROS) have been suggested as important mediators of brain damage in a number of disease states, including traumatic brain injury, neurodegenerative diseases and strokes. Apoptosis has been suggested to play an important role in neurodegenerative diseases, traumatic brain injury and strokes. The aim of this study was to determine whether or not cerebral vascular smooth muscle cells (CVSMCs) undergo apoptosis following treatment with hydrogen peroxide (H2O2). Herein, we demonstrate, for the first time, that H2O2 can induce apoptosis in a concentration-dependent manner in primary cultured CVSMCs, as measured by several morphological and biochemical criteria. H2O2-induced apoptosis may be initiated by stimulating Ca2+-dependent endonuclease activity. The present new data suggest that apoptosis in cerebral VSMCs, induced by ROS, such as H2O2, could play important roles in neruodegenerative processes, traumatic brain injury and strokes.