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.     

SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer’s and Parkinson’s disease

This was a small (~ 50 people) focused meeting on neurodegenerative disorders, with most of the speakers being from biotechnology or major pharmaceutical companies. The meeting covered a range of topics including introductions to Alzheimer’s disease and Parkinson’s disease, examples of targeting particular receptors/pathways, animal models and preclinical studies, clinical trial design and the use of biomarkers and imaging modalities. The major focus in the Alzheimer’s disease area was finding symptomatic treatments that are superior to acetylcholinesterase inhibitors and the extensive efforts that are ongoing to develop disease-modifying therapies. In terms of Parkinson’s disease there are now several reports examining the effects of dopamine agonists versus 3,4-dihydroxyphenylalanine on disease progression, and ongoing work with growth factors (e.g., glial cell line-derived neurotrophic factor) and mixed lineage/c-Jun N-terminal kinase inhibitors, such as CEP-1347. Small molecules that enhance endogenous signalling and repair pathways were also discussed.     

Antioxidants as treatment for neurodegenerative disorders

Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood-brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.     

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.     

Antioxidant strategies in protection against neurodegenerative disorders

The most common neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and stroke; they are devastating clinical problems which lack effective treatments. Although the aetiology of these diseases is not fully understood, oxidative stress is believed to be a contributing causative factor. In addition to conventional therapies, antioxidant strategies in protection against neurodegenerative conditions have been increasingly addressed, as evidenced by an increasing number of animal studies, clinical reports and patents regarding these processes in recent years. The effectiveness of antioxidants in protecting against neurodegenerative disorders lies mainly in their ability to cross the blood–brain barrier, their potential in terms of subcellular distribution occurring in membranes, in the cytoplasm and especially in mitochondria, and their multifunctional capacity as well as their synergistic actions. The naturally occurring antioxidants with different properties collaborate as an array to defend against oxidative stress. Single antioxidant supplementation would not then be expected to have a remarkable influence on neurodegenerative diseases, which may involve free radicals. Thus, using combinations of antioxidants with different subcellular distributions and different properties for prophylaxis or treatment would probably improve therapeutic outcomes. Based on their multifactoral aetiology, the development of novel antioxidants with anti-inflammatory and metal-chelating properties and the ability to improve metabolism, for example by increasing ATP production rate or a new formulation of antioxidants with other agents, which have different functions, will become the new strategies in protecting against neurodegenerative disorders.     

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.     

Multifunctional neuroprotective drugs targeting monoamine oxidase inhibition,iron chelation,adenosine receptors,and cholinergic and glutamatergic action for neurodegenerative diseases

A new paradigm is emerging in the targeting of multiple disease aetiologies that collectively lead to neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, post-stroke neurodegeneration and others. This paradigm challenges the widely held assumption that ‘silver bullet’ agents are superior to ‘dirty drugs’ when it comes to drug therapy. Accumulating evidence in the literature suggests that many neurodegenerative diseases have multiple mechanisms in their aetiologies, thus suggesting that a drug with at least two mechanisms of action targeted at multiple aetiologies of the same disease may offer more therapeutic benefit in certain disorders compared with a drug that only targets one disease aetiology. This review offers a synopsis of therapeutic strategies and novel investigative drugs developed in the authors’ own and other laboratories that modulate multiple disease targets associated with neurodegenerative diseases.     

帕金森病动物模型研究进展

帕金森病是老年期常见的慢性退行性疾病,其发病机制尚未明了,目前尚无有效根治或者逆转病情的药物.为了更好地了解帕金森病的病理机制并寻求更有效的治疗药物,建立帕金森病相关动物模型至关重要.目前常见的帕金森病动物模型有神经毒素模型、转基因模型和基因敲除模型,本文对此做一综述.     

Neuroinflammation: a potential therapeutic target

The increased appreciation of the importance of glial cell-propagated inflammation (termed ‘neuroinflammation’) in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer’s disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.     

Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease

Studies have implicated methamphetamine exposure as a contributor to the development of Parkinson’s disease. There is a significant degree of striatal dopamine depletion produced by methamphetamine, which makes the toxin useful in the creation of an animal model of Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. The immediate need is to understand the substances that increase the risk for this debilitating disorder as well as these substances’ neurodegenerative mechanisms. Currently, various approaches are being taken to develop a novel and cost-effective anti-Parkinson’s drug with minimal adverse effects and the added benefit of a neuroprotective effect to facilitate and improve the care of patients with Parkinson’s disease. A methamphetamine-treated animal model for Parkinson’s disease can help to further the understanding of the neurodegenerative processes that target the nigrostriatal system. Studies on widely used drugs of abuse, which are also dopaminergic toxicants, may aid in understanding the etiology, pathophysiology and progression of the disease process and increase awareness of the risks involved in such drug abuse. In addition, this review evaluates the possible neuroprotective mechanisms of certain drugs against methamphetamine-induced toxicity.     

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.     

Targeting protein aggregation in neurodegeneration – lessons from polyglutamine disorders

Polyglutamine diseases, such as Huntington’s disease, are among the most common inherited neurodegenerative disorders. They share salient clinical and pathological features with major sporadic neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotropic lateral sclerosis. Over the last decade, protein aggregation has emerged as a common pathological hallmark in neurodegenerative diseases and has, therefore, attracted considerable attention as a likely shared therapeutic target. Because of their clearly defined molecular genetic basis, polyglutamine diseases have allowed researchers to dissect the relationship between neurodegeneration and protein aggregation. In this review, the authors discuss recent progress in understanding polyglutamine-mediated neurotoxicity, and discuss the most promising therapeutic strategies being developed in the polyglutamine diseases and related neurodegenerative disorders.     

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

ABSTRACT

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.

Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.

Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.     

Therapeutic strategy at the crossroad of neuroinflammation and oxidative stress in age-related neurodegenerative diseases

Aging is the greatest risk factor for neurodegenerative diseases in the CNS, including two major age-related neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease. Understanding the biology of aging is pivotal in management of patients with neurodegenerative disorders. Genetically programmed aging and oxidative stress-elicited aging are two mechanisms of aging that are likely intertwined, leading to neurodegenerative damages. It is a commonly accepted that neurodegenerative diseases are the consequences of overproduction of oxidative stress or a result of compromised antioxidative mechanisms regardless of their aetiology. In aged brain, microglia increase in number and switch to a more pro-inflammatory state, providing a basis for greater inflammatory responses to inflammogens. Unfortunately, these unfavorable changes are often coupled with compromised capacity to remove oxidative products, allowing mutual perpetuation of inflammation and oxidative damage. This review highlights roles of microglia-mediated neuroinflammation and oxidative stress and association of these two. The possible novel therapeutic approaches are discussed in the context of focusing only on those possessing anti-inflammatory or antioxidative properties.     

Evaluation of memantine for neuroprotection in dementia

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer’s disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer’s disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.     

Neurotoxicity as a Mechanism for Neurodegenerative Disorders: Basic and Clinical Aspects

This three day meeting focused on chronic neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.     

芦丁神经保护作用的研究现状

芦丁是广泛存在于植物中的黄酮醇配体,具有抗氧化、抗炎、降压、维持血管弹性和神经保护等多种药理活性,在心脑血管疾病的治疗与预防起到至关重要的作用,有望可以改善或预防脑血管病、神经退行性病变及其他神经系统疾病。本文根据近年来的体内、外实验研究结果,综述了芦丁在缺血性脑卒中、阿尔茨海默病、帕金森病、抗癫痫和抗抑郁发挥脑神经保护作用机制。     

Repurposing small-molecule drugs for modulating toxic protein aggregates in neurodegenerative diseases

Neurodegenerative diseases (NDs) are often age-related disorders that can cause dementia in people, usually over 65 years old, are still lacking effective therapies. Some NDs have recently been linked to toxic protein aggregates, for example Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington disease; therefore, mulating toxic protein aggregates would be a promising therapeutic strategy. Moreover, drug repurposing, in other words exploiting drugs that are already in use for another indication, has been attracting mounting attention for potential therapeutic purposes in NDs. Thus, in this review, we focus on summarizing a series of repurposed small-molecule drugs for eliminating or inhibiting toxic protein aggregates and further discuss their intricate molecular mechanisms to improve the current ND treatment. Taken together, these findings will shed new light on exploiting more repurposed small-molecule drugs targeting different types of toxic proteins to fight NDs in the future.     

Apoptosis modulators in the therapy of neurodegenerative diseases

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer’s- (AD), Parkinson- (PD), or Huntington’s disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g., Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-β (TGF-β ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.     

Brain-targeted delivery of Tempol-loaded nanoparticles for neurological disorders

Brain-targeted Tempol-loaded poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) conjugated with a transferrin antibody (OX 26) were developed using the nanoprecipitation method. These NPs may have utility in treating neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Central to these diseases is an increased production of reactive oxygen and nitrogen species which may take part in the development of these conditions. As proof of principle, the NPs were loaded with Tempol, a free radical scavenger that has been shown to be protective against oxidative insults. To enhance the delivery of NPs to the central nervous system (CNS), we conjugated the transferrin receptor antibody covalently to PLGA NPs using the NHS-PEG3500-Maleimide crosslinker. The NPs showed a particle size suitable for blood brain barrier (BBB) permeation (particle size 80–110?nm) and demonstrated a sustained drug release behavior. A high cellular uptake of antibody-conjugated NPs was demonstrated in RG2 rat glioma cells. The ability of the Tempol-loaded NPs to prevent cell death by resveratrol in RG2 cells was determined using the MTT assay. The conjugated NPs containing Tempol were more effective in preventing cell viability by resveratrol when compared with unconjugated NPs or free Tempol in solution. Our findings suggest that transferrin-conjugated NPs containing antioxidants may be useful in the treatment of neurodegenerative diseases.