Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease

The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer's disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients’ cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer's disease, and the treatment approaches they provide. A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.     

Antipsychotic drug use in neurodegenerative disease in the elderly: problems and potential from a pharmacological perspective

The past decade has seen the introduction of several new antipsychotics for the treatment of schizophrenia. These drugs demonstrate substantially lower levels of extrapyramidal side effects (EPS) than the classical antipsychotics, as well as having (often poorly supported) claims of increased efficacy at ameliorating certain schizophrenic syndromes. Increasingly, these ‘atypical’ drugs are being used in the treatment of psychotic or related behavioural disturbances in patients with neurodegenerative disease. Thus, some newer antipsychotics are particularly valuable in ameliorating the L-dopa-induced psychosis in Parkinson’s disease, while behavioural problems in dementing disorders, such as those occurring in Alzheimer’s disease, are also frequently treated by antipsychotic drugs. The relationship between drug pharmacology and neurotransmitter pathology is essential to understanding the relative efficacy of individual antipsychotic drugs in treating the psychotic and behavioural disturbances of neurodegenerative disorders.     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) [Parkinson's disease (PD)/dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA). The involvement of neuroinflammation and microglial activation has been emphasized in the pathogenesis of PD. Recent epidemiological studies have revealed that therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing PD. Here, we examined the effects of NSAIDs, such as ibuprofen, aspirin, acetaminophen, meclofenamic acid sodium salt, sulindac sulfide, ketoprofen, flurbiprofen, diclofenac sodium salt, naproxen, and indomethacin, on the formation and destabilization of alphaS fibrils (falphaS) at pH 7.5 and 37 degrees C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. All examined NSAIDs, except for naproxen and indomethacin, inhibited the formation of falphaS in a dose-dependent manner. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity was in the order: ibuprofen approximately aspirin approximately acetaminophen approximately meclofenamic acid sodium salt approximately sulindac sulfide>ketoprofen approximately flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. These findings indicate that NSAIDs could be key molecules for the development of therapeutic or preventive agents for LBD and MSA.     

Paraquat and Parkinson's disease: an overview of the epidemiology and a review of two recent studies

Objective

This paper reviews and evaluates two recent epidemiologic studies focused on pesticides, and in particular, paraquat as a cause of PD. Both studies are derived primarily from the Agricultural Health Study (AHS). A review and evaluation is also provided on the AHS and several additional studies of paraquat and PD.

Methods

The methods used to design and conduct the studies and analyze the data are described and evaluated.

Results

Studies were inadequately designed and often underpowered with very few exposed individuals. They were not population-based, failed to distinguish incident from prevalent cases, relied on multiple comparisons, and may have reported results selectively. The results across the studies are inconsistent.

Conclusions

The inherent difficulties of studying Parkinson’s disease in relation to paraquat or other pesticides are well illustrated by these studies. A conclusion regarding these relationships cannot be reached based on the current literature. Further research with higher methodological standards is needed to reach a definitive conclusion.     

Neuronal apoptosis as a therapeutic target in neurodegenerative disease

Apoptosis is a form of physiological or programmed cell death. It has been speculated that this process might account for the death of selective neuronal populations in certain progressive neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) and some circumstantial evidence to support this view has been forthcoming. Increased understanding of the molecular pathophysiology of neuronal apoptosis may therefore present significant new therapeutic targets, to slow or halt neurodegeneration. This article reviews patents from the last five years which claim the use of apoptotic modulators in neurodegenerative disease. Although there are a significant number of claims, very few are buttressed with strong experimental evidence; this is usually from cell culture studies, rather than animal models of neurodegenerative disease; only a single human clinical study was identified. Thus, although treatment of neurodegenerative disease by means of manipulating apoptosis is an area of much activity and holds promise for the future, clinical application of current patents is unlikely in the near future. Extant medications may conceivably exert some of their action through effects on apoptosis.     

mTOR信号通路与神经退行性疾病研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamy-cin,mTOR)是进化上十分保守的丝氨酸/苏氨酸蛋白激酶,是自噬的关键调节位点。自噬体是神经退行性疾病内某些聚集蛋白清除的主要途径之一,近年的研究显示,神经退行性疾病如阿尔采末病、帕金森病、亨廷顿病等疾病模型或患者表现出mTOR通路异常,伴随着自噬功能的紊乱,而抑制mTOR的活性可以正向调节自噬。该文对当前mTOR信号转导通路与神经退行性疾病的研究进行综述。     

Targeting α-synuclein as a therapeutic strategy for Parkinson’s disease

Introduction: α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients’ quality of life.

Areas covered: The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease.

Expert opinion: The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD.     

Microglial dysfunction in brain aging and Alzheimer's disease

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.     

乙二醛酶Ⅰ的结构、功能及其与阿尔采末病的关系

胞质中的乙二醛酶系能有效去除胞内α-羰基醛类化合物的细胞毒性,对细胞具有重要的保护作用,乙二醛酶Ⅰ是该酶系的关键酶。α-羰基醛是体内形成晚期糖基化终末产物(AGEs)的主要活性中间体。α-羰基醛和AGEs都能促进阿尔采末病(AD)的发生和发展。因此乙二醛酶Ⅰ的表达和酶活性水平与AD病变具有非常重要的关系。     

Targeting striatal cholinergic interneurons in Parkinson's disease: focus on metabotropic glutamate receptors

In the early sixties, anticholinergic drugs were introduced in the pharmacological treatment of Parkinson's disease (PD). The rationale behind their utilisation in the treatment of the disease was based on the evidence of an imbalance between the dopaminergic inputs and the intrinsic cholinergic innervation within the striatum. Metabotropic glutamate (mGlu) receptors have been shown to play a key role in striatal function both in physiological conditions and in experimental models of diseases affecting this brain area. Indeed, compelling electrophysiological and morphological evidence shows that mGlu receptors are highly expressed at cellular level and exert a profound modulatory role on cholinergic interneurons excitability. This review will provide a brief survey of studies on the localization and function of mGlu receptors in cholinergic interneurons. The potential relevance of these findings in the control of motor function and in the treatment of PD will be discussed.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP

The long-term effects of permethrin (PM) and its interaction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopaminergic pathways were investigated in C57BL/6 mice. In a 3-month exposure, technical PM (1.5mg/kg) was administered once per week, with MPTP (20mg/kg) given once on either the 7th week or 11th week. In a 6-month exposure, PM (0.8mg/kg or 1.5mg/kg) was administered once per week for 26 weeks, with MPTP (20mg/kg) given once, on week 24. Alterations in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and alpha-synuclein proteins were analyzed 1 day after the last PM treatment using western blot assay. PM had no significant effect on striatal dopaminergic pathways by itself, whereas MPTP significantly reduced the expression of TH and DAT proteins. In both exposure paradigms, weekly 1.5mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression (p<0.05). There was no significant alteration of alpha-synuclein expression following any exposure to PM and/or MPTP. [(3)H]Tetrabenazine (TBZ) binding assay for expression of striatal vesicular monoamine transporter (VMAT) showed no effect of PM, but the reduction in this protein caused by MPTP was attenuated by PM, consistent with effects on other dopaminergic biomarkers. The overall findings demonstrate that long-term, low-dose exposure to PM alone did not cause signs of neurotoxicity to striatal dopaminergic neural terminals, or enhance the effects of MPTP. We conclude that under typical use conditions, PM poses little Parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies.     

Oxidative stress,redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2

Chronic oxidative stress and oxidative damage of the cerebral microvasculature and brain cells has become one of the most convincing theories in neurodegenerative pathology. Controlled oxidative metabolism and redox signalling in the central nervous system are crucial for maintaining brain function; however, excessive production of reactive oxygen species and enhanced redox signalling damage neurons. While several enzymes and metabolic processes can generate intracellular reactive oxygen species in the brain, recently an O₂⁻-generating enzyme, NADPH oxidase 2 (Nox2), has emerged as a major source of oxidative stress in ageing-related vascular endothelial dysfunction and neurodegenerative diseases. The currently available inhibitors of Nox2 are not specific, and general antioxidant therapy is not effective in the clinic; therefore, insights into the mechanism of Nox2 activation and its signalling pathways are needed for the discovery of novel drug targets to prevent or treat these neurodegenerative diseases. This review summarizes the recent developments in understanding the mechanisms of Nox2 activation and redox-sensitive signalling pathways and biomarkers involved in the pathophysiology of the most common neurodegenerative diseases, such as ageing-related mild cognitive impairment, Alzheimer’s disease and Parkinson’s disease.     

Gene expression profiling and therapeutic interventions in neurodegenerative diseases: a comprehensive study on potentiality and limits

Introduction: Neurodegenerative diseases are incurable debilitating disorders of the nervous system that affect approximately 30 million people worldwide. Despite profuse efforts attempting to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. The novelty of their mechanisms represents a challenge to biology, to their related biomarkers identification and drug discovery. Because of their multifactorial aspects and complexity, gene expression analysis platforms have been extensively used to investigate altered pathways during degeneration and to identify potential biomarkers and drug targets.

Areas covered: This work offers an overview of the gene expression profiling studies carried out on Alzheimer's disease, Huntington's disease, Parkinson's disease and prion disease specimens. Therapeutic approaches are also discussed.

Expert opinion: Although many therapeutic approaches have been tested, some of them acting on several altered cellular pathways, no effective cures for these neurodegenerative diseases have been identified. Microarray technology must be associated with functional proteomics and physiology in an effort to identify specific and selective biomarkers and druggable targets, thus allowing the successful discovery of disease-modifying therapeutic treatments.     

Part I: parkin-associated proteins and Parkinson's disease

Parkin is an E3 ligase that plays an important role in the ubiquitin/proteosome pathway responsible for protein degradation events. Mutations in parkin result in a loss-of-function and lead to Parkinson's disease, a progressive neurological disorder of movement. Presumably, this occurs due to the toxic build-up of proteins that are no longer effectively cleared/degraded by the parkin-dependent ubiqutin/proteosome pathway. To date, three types of proteins have been shown to interact with parkin. Firstly, the E2 ubiquitin conjugating proteins called UbcH7 and UbcH8 interact with parkin. Secondly, putative substrates interacting with parkin include a synaptic vesicle associated GTPase named CDCrel-1; a G protein-coupled receptor named Pael; a novel from of alpha-synuclein; and an alpha-synuclein interacting protein synphilin-1. Thirdly and more recently, a PDZ domain containing scaffolding protein CASK/Lin2 has been shown to interact with the PDZ binding motif of parkin. A network of PDZ-interacting proteins has potential to form a complex web of molecules that surround parkin and regulate its subcellular localisation and function.     

Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila

Introduction: Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms.

Areas covered: The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models.

Expert opinion: Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.     

Chlorzoxazone exhibits neuroprotection against Alzheimer’s disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo

Alzheimer’s disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (Aβ) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using Aβ. We found that Aβ caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β). Aβ deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by Aβ led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. Aβ accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-α, IL-1β and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.     

沙利度胺治疗葡聚糖硫酸钠诱导小鼠炎症性肠病及其机制研究

目的考察沙利度胺对葡聚糖硫酸钠诱导小鼠炎症性肠病的治疗作用,并探讨其可能的作用机制。方法 60只Balb/c小鼠按体质量随机分为对照组、模型组、柳氮磺吡啶(200 mg/kg)组以及沙利度胺30、60、120 mg/kg剂量组,每组10只。试验当天为第1天,试验期间葡聚糖硫酸钠诱导组饮用2.5%葡聚糖硫酸钠饮用水,对照组则饮用纯净水。从试验第5天开始,各给药组开始ig给予相应药物,给药容积10 m L/kg,1次/d,对照组和模型组则给予相应体积的0.5%MC,直至第12天结束试验。试验期间,每天记录各动物体质量变化。试验结束后,测量各动物结肠长度,观察各组结肠组织病理学改变和评分,ELISA法检测结肠组织肿瘤坏死因子-α(TNF-α)含量。结果沙利度胺在120 mg/kg剂量下改善葡聚糖硫酸钠诱导小鼠体质量下降症状,改善小鼠的结肠缩短,降低结肠组织TNF-α含量,减少炎症细胞对结肠组织的浸润。结论沙利度胺对葡聚糖硫酸钠诱导小鼠炎症性肠病呈现较好治疗作用,该作用可能与沙利度胺对TNF-α的调节作用有关。     

Alzheimer's disease and oxygen radicals: new insights

Alzheimer's disease (AD) is the most common form of neurodegenerative disease, with dementia, in the elderly. In addition to the presence of senile plaques and neurofibrillary tangles, the AD brain exhibits evidence for oxygen radical-mediated damage, a situation commonly known as oxidative stress. However, the ability to directly implicate this mechanism in AD has been a difficult task for several reasons. First, most of the analytical approaches used to investigate oxidative stress turned out to be unreliable. Second, the majority of the published studies have been performed in post-mortem tissues with advanced disease, leaving open the question as to whether oxidative stress is an early event or a common final step secondary to the degenerative process. The discovery of the isoprostanes, recent studies performed in living patients, and the development of transgenic animal models of AD-amyloidosis are three important factors that are helping us to better understand and define the role that oxygen radicals might play in AD pathogenesis. Here we review some of the most recent works that have supported the importance of oxygen radical-mediated damage in AD. The accumulated information points toward an earlier involvement than previously thought of oxidative stress in the pathogenesis of the disease, making this a potential target for therapeutic intervention, especially in subjects at high risk for developing AD.