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.     

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.     

Poly(ADP-ribose) polymerase inhibitors in the prevention of neuronal cell death

Poly(ADP-ribose) polymerase is a nucleic enzyme that promotes energy-dependent repair of DNA, thus helping to protect against DNA fragmentation. Overactivation of PARP, for example in the context of apoptosis, may contribute to neuronal cell death. This article briefly reviews claims for PARP inhibitors as agents for the prevention of neuronal cell death, registered in the period 1998 – December 2001. Biological data are sparse in these patents, few claims are backed by in vitro biochemical data and fewer still with in vivo animal model data. The latter have used animal models of ischaemia rather than of neurodegeneration. The place of PARP inhibitors as a clinical therapy to prevent neuronal cell death remains to be determined.     

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.     

A review of pramipexole and its clinical utility in Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex^®, Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.     

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.     

P-糖蛋白在神经退行性疾病中的作用

神经退行性疾病( neurodegenerative disease)是一种以神经元退行性病变为基础的慢性进行性神经系统疾病,发病机制尚不明了,但一些内源性和外源性物质在脑部的异常聚集和沉积与其病因密切相关,且其往往是P糖蛋白的底物.近年来研究表明血脑屏障的p-糖蛋白在一些神经退行性疾病发展过程中表达会减少,这可能导致致病性内外源性物质的进一步聚集和沉积,恶化病情.本文对近年来有关P-糖蛋白在神经退行性疾病的发病和病情进展中的作用作一综述.     

The therapeutic potential of the cannabinoids in neuroprotection

After thousands of years of interest the last few decades have seen a huge increase in our knowledge of the cannabinoids and their mode of action. Their potential as medical therapeutics has long been known. However, very real concerns over their safety and efficacy have lead to caution and suspicion when applying the legislature of modern medicine to these compounds. The ability of this diverse family of compounds to modulate neurotransmission and act as anti-inflammatory and antioxidative agents has prompted researchers to investigate their potential as neuroprotective agents. Indeed, various cannabinoids rescue dying neurons in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury. Cannabinoids also provide symptomatic relief in experimental models of chronic neurodegenerative diseases, such as multiple sclerosis and Huntington’s disease. This preclinical evidence has provided the impetus for the launch of a number of clinical trials in various conditions of neurodegeneration and neuronal injury using compounds derived from the cannabis plant. Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential neuroprotective agents.     

Sphingosine kinase 1/sphingosine-1-phosphate receptors dependent signalling in neurodegenerative diseases. The promising target for neuroprotection in Parkinson’s disease

Parkinson’s disease (PD) is one of the most common serious neurodegenerative disorders in the world. The incidence of PD appears to be growing and this illness has an unknown pathogenesis. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra (SN), with an enigmatic cause in most individuals. Current pharmacotherapies and surgery provide symptomatic relief but their effects against the progressive degeneration of neuronal cells are strongly limited if present at all. Therefore, uncovering novel molecular mechanisms of DA cell death and new potentially disease-modifying pharmacological targets is an important task for basic research. Significant progress has been made in understanding the role of disturbed sphingolipid metabolism, particularly relating to ceramide and sphingosine-1-phosphate (S1P) in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative diseases. Additionally, the neuroprotective potential of an S1P receptors (S1PR) modulator, fingolimod (FTY720), in multiple sclerosis (MS) and numerous other diseases has been observed over the past decade. In this review, we briefly summarise recent achievements in defining intracellular S1PR-dependent actions, discuss their significance to therapeutic approaches, and explore their neuroprotective potential as a target in PD treatment.     

Inhibition of α-Synuclein contributes to the ameliorative effects of dietary flavonoids luteolin on arsenite-induced apoptotic cell death in the dopaminergic PC12 cells

Arsenite is a toxic metalloid that may increase the risk of Parkinson’s disease by inducing dopaminergic neuronal apoptosis. Luteolin, a common dietary flavonoid, possesses variety of biological functions, but potential effects of luteolin on arsenite toxicity remain elusive. In this study, we demonstrated that luteolin prevented arsenite-induced apoptosis in the dopaminergic PC12 cells. Administration of luteolin to cells attenuated arsenite-induced ROS production, enhanced caspase-3 activity and γ-H2AX expression. Our results further showed the expression of α-Synuclein (α-Syn) was significantly increased in arsenite-treated cells, but co-treatment with luteolin reversed the expression of α-Syn back toward normal level. Inhibition of α-Syn by siRNA remarkably enhanced the beneficial effect of luteolin against arsenite-induced apoptotic cell death. Taken together, these results demonstrate that the ameliorative effects of luteolin against arsenite in the dopaminergic cell may be modulated by α-Syn, and indicating that luteolin may be developed as a chemopreventive supplementary agent to ameliorate dopaminergic cell apoptosis resulting from arsenite exposure.     

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.     

Clinical trials in neuroprotection

Many common neurological and psychiatric disorders are accompanied by extensive neuronal loss, either acutely or chronically. These include stroke, head trauma, spinal cord injury, epilepsy, perinatal and perioperative hypoxia–ischaemia, Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis (ALS) and even some aspects of schizophrenia and depression. Despite considerable research effort, no agent has been found that can protect the brain from any of these neurodegenerative conditions. ‘Clinical Trials in Neuroprotection,’ sponsored by the University of Pennsylvania, was held to address this situation in a unique way. Rather than focus on one neurodegenerative condition, the conference brought together researchers from a variety of neuroprotection areas. They reviewed basic mechanisms of neuronal injury, the animal models used in a variety of paradigms and the design and results of clinical trials in many neuroprotection areas. The presentations and extensive discussions focused on common issues encountered and lessons learned, and on developing innovative strategies for clinical evaluation of potential neuroprotective agents. Conference participants came to a general consensus that some mechanisms were the same for all conditions, models need to be improved, new clinical trial paradigms should consider drug combinations and/or sequential administration of neuroprotective agents, new biomarkers should be developed and a ‘proof-of-principle’ trial would be widely valuable and should be developed.     

Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents

Increasing evidence suggests that mitochondrial dysfunction and oxidative stress play a crucial role in the majority of neurodegenerative diseases. Mitochondria are a major source of intracellular reactive oxygen species (ROS) and are particularly vulnerable to oxidative stress. Oxidative damage to mitochondria has been shown to impair mitochondrial function and lead to cell death via apoptosis and necrosis. Because dysfunctional mitochondria will produce more ROS, a feed-forward loop is set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation, resulting in a vicious cycle. It is now appreciated that reduction of mitochondrial oxidative stress may prevent or slow down the progression of these neurodegenerative disorders. However, if mitochondria are the major source of intracellular ROS and mitochondria are most vulnerable to oxidative damage, then it would be ideal to deliver the antioxidant therapy to mitochondria. This review will summarize the development of a novel class of mitochondria-targeted antioxidants that can protect mitochondria against oxidative stress and prevent neuronal cell death in animal models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis.     

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.     

Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other 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.     

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.     

New insights into the biological therapy of Crohn’s disease

Conventional treatment of Crohn’s disease (CD) has resulted in only a limited therapeutic benefit. Advancing knowledge of CD pathogenesis and recent advances in biotechnology have led to the development of biological agents that selectively target individual inflammatory pathways. Such agents may be divided in anti-TNF-α strategies, lymphocyte trafficking inhibitors, anti-inflammatory cytokines and pro-inflammatory cytokine inhibitors. Based on the early success of infliximab, humanised anti-TNF-α antibodies (CDP-571, CDP-870, adalimumab), soluble TNF-α receptors (etanercept, onercept), mitogen-activated protein kinase (MAPK) inhibitors and NF-κB inhibitors have been developed. To block lymphocyte migration, anti-integrin antibodies (natalizumab, MLN-02), antisense intercellular adhesion molecule-1, antinectin antibodies and chemotactic factors inhibitors have been engineered. Anti-inflammatory cytokines (IL-10, IL-11) have been tested with limited results in Crohn’s disease, but further improvement in delivery of these molecules has been achieved. Pro-inflammatory cytokine inhibitors, such as anti-IL-6 and anti-IL-12, have been shown to be effective in clinical trials; and new antibodies, as well as genetic manipulation, have been developed. The aim of this review is to provide an insight into the biological therapies already applied in human studies, and to the new patents potentially applicable in the forthcom-ing years.