Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases

Excess production of reactive oxygen species in the brain has been implicated as a common underlying risk factor for the pathogenesis of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In recent years, there is considerable interest concerning investigation of antioxidative and anti-inflammatory effects of phenolic compounds from different botanical sources. In this review, we first describe oxidative mechanisms associated with stroke, AD, and PD, and subsequently, we place emphasis on recent studies implicating neuroprotective effects of resveratrol, a polyphenolic compound derived from grapes and red wine. These studies show that the beneficial effects of resveratrol are not only limited to its antioxidant and anti-inflammatory action but also include activation of sirtuin 1 (SIRT1) and vitagenes, which can prevent the deleterious effects triggered by oxidative stress. In fact, SIRT1 activation by resveratrol is gaining importance in the development of innovative treatment strategies for stroke and other neurodegenerative disorders. The goal here is to provide a better understanding of the mode of action of resveratrol and its possible use as a potential therapeutic agent to ameliorate stroke damage as well as other age-related neurodegenerative disorders.     

Inhibitors of Renin as Potential Therapeutic Agents

Abstract

The reaction of usual (U) and atypical (A) cholinesterase phenotypes was studied with six organophosphorus compounds, two pyridinium oximes (HI-6 and PAM-2) and with 4–4-bipyridine (4,4-BP). No difference in the inhibition rate constants for the two phenotypes was found with the progressive inhibitors tabun, sarin, paraoxon and soman. The other two progressive inhibitors, VX and the positively charged phosphostigmine, inhibited the U phenotype more strongly than the A phenotype.

The positively charged reversible inhibitor HI-6 showed a higher affinity for the U than for the A phenotype, while PAM-2 and the non-charged 4,4′-BP did not show a significant difference in their affinity towards the two enzymes.

Both phenotypes phosphylated by VX or sarin were reactivatable by HI-6 and PAM-2, and the A phenotype was always reactivated more slowly than the U phenotype. The paraoxon-inhibited phenotypes were reactivated at equal rates with PAM-2 but were not reactivated with HI-6. The phosphylated phenotypes did not reactivate spontaneously during one hour.

The effect of reversible inhibitors upon the rate of phosphylation (protection) was tested with HI-6 (for inhibition by soman, tabun and paraoxon) and with 4,4′-BP (for inhibition by soman). By applying the concentrations of the protectors equal to their enzyme/inhibitor dissociation constants, a better protection of the U than of the A phenotype was achieved by HI-6, but equal protection was given by 4,4′-BP.     

The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases

Cellular and Molecular Neurobiology - In the last few decades, cytoplasmic organellar dysfunction, such as that of the endoplasmic reticulum (ER), has created a new area of research interest...     

Imaging the Perivascular Space as a Potential Biomarker of Neurovascular and Neurodegenerative Diseases

Although the brain lacks conventional lymphatic vessels found in peripheral tissue, evidence suggests that the space surrounding the vasculature serves a similar role in the clearance of fluid and metabolic waste from the brain. With aging, neurodegeneration, and cerebrovascular disease, these microscopic perivascular spaces can become enlarged, allowing for visualization and quantification on structural MRI. The purpose of this review is to: (i) describe some of the recent pre-clinical findings from basic science that shed light on the potential neurophysiological mechanisms driving glymphatic and perivascular waste clearance, (ii) review some of the pathobiological etiologies that may lead to MRI-visible enlarged perivascular spaces (ePVS), (iii) describe the possible clinical implications of ePVS, (iv) evaluate existing qualitative and quantitative techniques used for measuring ePVS burden, and (v) propose future avenues of research that may improve our understanding of this potential clinical neuroimaging biomarker for fluid and metabolic waste clearance dysfunction in neurodegenerative and neurovascular diseases.     

Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach

Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis. Since the function of autophagy is particularly important in various stress conditions, perturbation of autophagy can lead to cellular dysfunction and diseases. Accumulation of abnormal protein aggregates, a common cause of neurodegenerative diseases, can be reduced through autophagic degradation. Recent studies have revealed defects in autophagy in most cases of neurodegenerative disorders. Moreover, deregulated excessive autophagy can also cause neurodegeneration. Thus, healthy activation of autophagy is essential for therapeutic approaches in neurodegenerative diseases and many autophagy-regulating compounds are under development for therapeutic purposes. This review describes the overall role of autophagy in neurodegeneration, focusing on various therapeutic strategies for modulating specific stages of autophagy and on the current status of drug development.     

Potential Compensatory Responses Through Autophagic/Lysosomal Pathways in Neurodegenerative Diseases

Intracellular protein degradation decreases with age, altering the important balance between protein synthesis and breakdown. Slowly, protein accumulation events increase causing axonopathy, synaptic deterioration, and subsequent cell death. As toxic species accumulate, autophagy–lysosomal protein degradation pathways are activated. Responses include autophagic vacuoles that degrade damaged cellular components and long-lived proteins, as well as enhanced levels of lysosomal hydrolases. Although such changes correlate with neuronal atrophy in age-related neurodegenerative disorders and in related models of protein accumulation, the autophagic/lysosomal responses appear to be compensatory reactions. Recent studies indicate that protein oligomerization/aggregation induces autophagy and activates lysosomal protein degradation in an attempt to clear toxic accumulations. Such compensatory responses may delay cell death and account for the gradual nature of protein deposition pathology that can extend over months/years in model systems and years/decades in the human diseases. Correspondingly, enhancement of compensatory pathways shifts the balance from pathogenesis to protection. Positive modulation of protein degradation processes represents a strategy to promote clearance of toxic accumulations and to slow the synaptopathogenesis and associated cognitive decline in aging-related dementias.

Addendum to:

Cellular Responses to Protein Accumulation Involve Autophagy and Lysosomal Enzyme Activation

D. Butler, Q.B. Brown, D.J. Chin, L. Batey, S. Karim, M.S. Mutneja, D.A. Karanian and B.A. Bahr

Rejuvenation Res 2005; 8:227-37     

Rho激酶抑制剂在神经退化性疾病上的应用

Rho激酶,又称Rho相关的卷曲蛋白激酶,是一类丝氨酸/苏氨酸蛋白激酶,被发现为小G蛋白Rho的下游作用底物。由于Rho激酶活性涉及神经细胞的功能,而且越来越多的研究表明抑制Rho激酶的活性在数种神经退行性疾病包括帕金森病、阿尔茨海默病、亨廷顿病、多发性硬化症,和肌萎缩性侧索硬化症等的实验模式中都有明显的效果。因此,Rho激酶已成为针对治疗神经性退化性疾病的一个热门标靶蛋白。本文探讨Rho激酶抑制剂在神经退化性疾病上的应用及发展,使神经退行性疾病能进一步提升治疗和在应用上的水平。     

Mitochondria-ER Tethering in Neurodegenerative Diseases

Cellular and Molecular Neurobiology - Organelles juxtaposition has been detected for decades, although only recently gained importance due to a pivotal role in the regulation of cellular processes...     

Mitochondrial Dysfunction in Neurodegenerative Diseases

Mitochondria play a pivotal role in mammalian cell metabolism, hosting a number of important biochemical pathways including oxidative phosphorylation. As might be expected from this fundamental contribution to cell function, abnormalities of mitochondrial metabolism are a common cause of human disease. Primary mutations of mitochondrial DNA result in a diverse group of disorders often collectively referred to as the mitochondrial encephalomyopathies. Perhaps more importantly in numerical terms are those neurodegenerative diseases caused by mutations of nuclear genes encoding mitochondrial proteins. Finally there are mitochondrial abnormalities induced by secondary events e.g. oxidative stress that may contribute to senescence, and environmental toxins that may cause disease either alone or in combination with a genetic predisposition. Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.     

线粒体与神经系统退行性疾病

现在普遍认为线粒体是控制凋亡的中心 ,线粒体功能的失调可以导致许多神经系统退行性疾病的发生。神经元死亡是一些神经系统退行性疾病的共同特征 ,其中包括帕金森氏病 (ＰＤ)、阿尔茨海默病(ＡＤ)、亨廷顿舞蹈病 (ＨＤ)以及肌萎缩型侧索硬化症(ＡＬＳ)等 ,这些疾病的遗传因素和环境因素现已得到确认 ,其中包括氧化应激 ,Ｃａ2 平衡失调 ,线粒体的功能失调以及胱天蛋白酶 (ｃａｓｐａｓｅ)的激活。研究促进或抑制神经元凋亡的机制可以为预防和治疗神经系统退行性疾病提供新的思路和方法。在一些哺乳动物不同类型的衰老细胞中已发现线粒体膜…     

神经退行性疾病的表观遗传学

研究发现多种疾病的发生与表观遗传学相关.有证据显示表观遗传学信号在大脑中起着重要调节作用,在哺乳动物中枢神经系统中DNA甲基化动力学被发现是表观遗传学调节的主要组成,染色质修饰药物的快速发展显示出对神经系统中范围广泛的退行性功能紊乱出人意料的治疗作用,促进了人们对神经退行性疾病的表观遗传学机制研究.其中,研究得比较多的是DNA甲基化、组蛋白修饰及染色质重塑.这些研究为神经退行性疾病的治疗提供了潜在靶点,并为开发相关药物提供了线索.对疾病表观遗传学机制及药物的作用机制的进一步研究将为疾病治疗提供更多靶点,为神经退行性疾病提供确切的有效治疗途径,具有积极意义.     

Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling

Background

Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicals with pharmacologically desirable properties.

Methodology/Principal Findings

Using an automated cell-based assay, we screened a collection of >3,500 chemicals and identified three approved drugs (perhexiline, niclosamide, amiodarone) and one pharmacological reagent (rottlerin) capable of rapidly increasing autophagosome content. Biochemical assays showed that the four compounds stimulate autophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibit signaling to mTORC1. mTORC1 inhibition and autophagosome accumulation induced by perhexiline, niclosamide or rottlerin were rapidly reversed upon drug withdrawal whereas amiodarone inhibited mTORC1 essentially irreversibly. TSC2, a negative regulator of mTORC1, was required for inhibition of mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone. Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein TSC2, an upstream regulator of mTORC1. By contrast, transient exposure to the mTORC1 inhibitor rapamycin caused essentially irreversible mTORC1 inhibition, sustained inhibition of cell growth and no selective cell killing in starvation.

Conclusion/Significance

The observation that drugs already approved for human use can reversibly inhibit mTORC1 and stimulate autophagy should greatly facilitate the preclinical and clinical testing of mTORC1 inhibition for indications such as tuberous sclerosis, diabetes, cardiovascular disease and cancer.     

Neurogenesis in the Diseased Adult Human Brain: New Therapeutic Strategies for Neurodegenerative Diseases

No abstract available.     

MicroRNA，lncRNA与神经退行性疾病

综述了microRNA和lncRNA在一些神经退行性疾病病理生理中的作用机制．随着社会生产的发展,人类文明的进步,人口日益老年化,神经退行性疾病正在全球范围内流行,严重地危害着人类的健康．尽管长期的研究使人们对神经退行性疾病有了比较全面和深入的了解,但是其背后隐藏的发病机制仍然是个谜．人类基因组约98%的转录产物为非编码RNA(ncRNA),在生命活动中有着许多鲜为人知的广泛而多样性的生物功能．小分子RNA(microRNA)是研究得相对比较深入的一类小ncRNA,最近2～3年,长非编码RNA(lncRNA)受到人们的重视,已积累了一些相关研究成果．     

Role of Microbiota in Neurodegenerative Diseases

Russian Journal of Developmental Biology - Functional interaction of the gastrointestinal tract (GI) and the central nervous system (CNS) is due to various relationships, which includes autonomic...     

Astroglial Vesicular Trafficking in Neurodegenerative Diseases

The neocortex represents one of the largest estates of the human brain. This structure comprises ~30–40 billions of neurones and even more of non-neuronal cells. Astrocytes, highly heterogeneous homoeostatic glial cells, are fundamental for housekeeping of the brain and contribute to information processing in neuronal networks. Gray matter astrocytes tightly enwrap synapses, contact blood vessels and, naturally, are also in contact with the extracellular space, where convection of fluid takes place. Thus astrocytes receive signals from several distinct extracellular domains and can get excited by numerous mechanisms, which regulate cytosolic concentration of second messengers, such as Ca²⁺ and cAMP. Excited astrocytes often secrete diverse substances (generally referred to as gliosignalling molecules) that include classical neurotransmitters such as glutamate and ATP or neuromodulators such as d-serine or neuropeptides. Astrocytic secretion occurs through several mechanisms: by diffusion through membrane channels, by translocation via plasmalemmal transporters or by vesicular exocytosis. Vesicular release of gliosignalling molecules appears fundamentally similar to that operating in neurones, since it depends on the SNARE proteins-dependent merger of the vesicle membrane with the plasmalemma. However, the coupling between the stimulus and astroglial vesicular secretion is at least one order of magnitude slower than that in neurones. Here we review mechanisms of astrocytic excitability and the molecular, anatomical and physiological properties of vesicular apparatus mediating the release of gliosignalling molecules in health and in the neurodegenerative pathology.     

Coenzyme Q 10 as a Possible Treatment for Neurodegenerative Diseases

Coenzyme Q 10 (CoQ 10 ) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q 10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ 10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ 10 significantly extended survival in a transgenic mouse model of ALS. CoQ 10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N -methyl- d -aspartate (NMDA) receptor antagonist, remacemide. CoQ 10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.