Oxidative stress mediates tau-induced neurodegeneration in Drosophila

Markers of oxidative damage have been detected in brain tissue from patients with Alzheimer disease (AD) and other neurodegenerative disorders. These findings implicate oxidative injury in the neurodegenerative process, but whether oxidative stress is a cause or a consequence of neurotoxicity remains unclear. We used a Drosophila model of human tauopathies to investigate the role of oxidative stress in neurodegeneration. Genetic and pharmacological manipulation of antioxidant defense mechanisms significantly modified neurodegeneration in our model, suggesting that oxidative stress plays a causal role in neurotoxicity. We demonstrate that the JNK signaling pathway is activated in our model, which is in agreement with previous findings in AD tissue. Furthermore, we show that the extent of JNK activation correlates with the degree of tau-induced neurodegeneration. Finally, our findings suggest that oxidative stress acts not to promote tau phosphorylation, but to enhance tau-induced cell cycle activation. In summary, our study identifies oxidative stress as a causal factor in tau-induced neurodegeneration in Drosophila.     

Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics

Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.     

褪黑素与神经退行性疾病相关的研究进展

氧化应激和线粒体功能失调被认为是神经退行性疾病如阿尔茨海默病和帕金森病共同的病理生理机制。随着年龄的增加,褪黑素水平明显的降低可能是年老人体内氧化应激增加的原因之一,因此褪黑素的神经保护作用日益引起关注。本文就近年褪黑素抗神经退行性疾病的机制,包括自由基清除作用、抑制凋亡、神经保护作用、神经营养作用、抗β-淀粉样蛋白神经毒性、调节炎症反应和调节细胞骨架蛋白等方面作一综述。     

Oxidative stress,mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight

Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinson’s and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases.     

Role of iron in neurodegenerative disorders

Although the pathophysiology underlying a number of neurodegenerative diseases is complex and, in many aspects, only partly understood, increased iron levels in pathologically relevant brain areas and iron-mediated oxidative stress seem to play a central role in many of them. Much has been learned from monogenetically caused disturbances of brain iron metabolism including pantothenate kinase-associated neurodegeneration type 2, hereditary ferritinopathies affecting the basal ganglia, and aceruloplasminemia that may well be applied to the most common neurodegenerative disorders associated with brain iron accumulation including Parkinson disease and Alzheimer disease. Iron-mediated oxidative stress in neurodegenerative diseases caused by other genetic pathways like Huntington disease and Friedreich ataxia underscore the complex interaction of this trace metal and genetic variations. Therapeutical strategies derived from application of iron chelators in monogenetically caused disturbances of brain iron metabolism and new iron and oxidative stress diminishing substances in animal models of Parkinson disease are promising and warrant further investigational effort.     

Redox signaling regulated by electrophiles and reactive sulfur species

Redox signaling is a key modulator of oxidative stress induced by nonspecific insults of biological molecules generated by reactive oxygen species. Current redox biology is revisiting the traditional concept of oxidative stress, such that toxic effects of reactive oxygen species are protected by diverse antioxidant systems upregulated by oxidative stress responses that are physiologically mediated by redox-dependent cell signaling pathways. Redox signaling is thus precisely regulated by endogenous electrophilic substances that are generated from reactive oxygen species and nitric oxide and its derivative reactive species during stress responses. Among electrophiles formed endogenously, 8-nitroguanosine 3'',5''-cyclic monophosphate (8-nitro-cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signaling mechanism, and metabolism in cells have been clarified. Reactive sulfur species such as cysteine hydropersulfides that are abundant in cells are likely involved in 8-nitro-cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cell and stem cell biology; infectious diseases, cancer, metabolic syndrome, ageing, and neurodegenerative diseases; and other oxidative stress-related disorders. This review focuses on the most recent progress in the biosynthesis, cell signaling, and metabolism of 8-nitro-cGMP, which is a likely target for drug development and lead to discovery of novel therapeutics for many diseases.     

The protective effect of human platelet lysate in models of neurodegenerative disease: involvement of the Akt and MEK pathways

Neurodegenerative diseases have huge economic and societal impacts, and place an immense emotional burden on patients and caregivers. Given that platelets have an essential physiological role in wound healing and tissue repair, human platelet lysates (HPLs) are being developed as a novel, effective biotherapy for neurodegenerative diseases. HPLs constitute abundant, readily accessible sources of physiological mixtures of many growth factors (GFs), with demonstrable effects on neuron survival and thus the development, maintenance, function and plasticity of the vertebrate nervous system. Here, we found that HPLs had marked neuroprotective abilities in cell‐based models of Parkinson's disease and amyotrophic lateral sclerosis (the LUHMES and NSC‐34 cell lines, respectively). The HPLs protected against specific cell death pathways (apoptosis and ferroptosis) and specific oxidative stress inducers [1‐methyl‐4‐phenylpyridinium (MPP+) and menadione], and always afforded more protection than commonly used recombinant GFs (rGFs). The mechanism of protection of HPLs involved specific signalling pathways: whereas the Akt pathway was activated by HPLs under all conditions, the MEK pathway appeared to be more specifically involved in protection against MPP+ toxicity in LUHMES and, in a lesser extent, in staurosporine toxicity in NSC‐34. Our present results suggest that HPLs‐based therapies could be used to prevent neuronal loss in neurodegenerative diseases while overcoming the limitations currently associated with use of rGFs. Copyright © 2016 John Wiley & Sons, Ltd.     

Attenuated glutamate induced ROS production by antioxidative compounds in neural cell lines

Glutamate is an excitatory neurotransmitter involved in neural function. Excess accumulation of intercellular glutamate leads to increasing concentration of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in neuronal cells. In this study, we investigated the antioxidant activity of several typical superior compounds among four neuronal cells, and determined the scavenging activity of free radicals. The in vivo assay was also carried out to compare the protective effect of glutamate-induced cell damage. Hierarchical clustering analysis was used to identify the common properties. Glutamate induced neurotoxicity and ROS production, suggesting glutamate cytotoxicity was related to oxidative stress and widely exists in different cell lines. Those screening compounds exhibited strong antioxidant ability, but low cytotoxicity to neuronal cells, acting as agents against neurodegenerative diseases. Finally, a hierarchical clustering analysis assay indicated that hyperoside and rutin hydrate are the most effective compounds for attenuating intercellular ROS levels. The results suggested the activity more or less relies on structure, rather than residues. These data generate new supporting ideas to remove intracellular ROS and the identified compounds serve as potential therapeutic agents in multiple neurological diseases.

Glutamate is an excitatory neurotransmitter involved in neural function.     

The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol

Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome–ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.     

The novel neuroprotective action of sulfasalazine through blockade of NMDA receptors

Sulfasalazine is widely used to treat inflammatory diseases. Besides anti-inflammatory actions such as blockade of nuclear factor-kappaB and cyclooxygenases, we found that 30 to 1000 micro M sulfasalazine dose dependently blocked N-methyl-D-aspartate receptor-mediated excitotoxicity without intervening kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid neurotoxicity. The neuroprotective effects of sulfasalazine were attributable to prevention of Ca(2+) influx and accumulation through N-methyl-D-aspartate receptors as a low-affinity antagonist. The systemic administration of sulfasalazine reduced neuronal death following transient cerebral and retinal ischemia in adult rat. The present findings suggest that the neuroprotective action of sulfasalazine can be therapeutically applied to halt devastating neuronal death following hypoxic ischemia, trauma, and neurodegenerative diseases.     

Iron metabolism, free radicals, and oxidative injury.

Iron has the capacity to accept and donate electrons readily. This capability makes it physiologically essential, as a useful component of cytochromes and oxygen-binding molecules. However, iron is also biochemically dangerous; it can damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that attack cellular membranes, protein and DNA. This threat is reduced in the healthy state where, because of the fine iron metabolism regulation, there is never appreciable concentration of 'free iron'. Under pathological conditions, iron metabolism and superoxide metabolism are clearly interactive. Each can exacerbate the toxicity of the other. Iron overload may amplify the damaging effects of superoxide overproduction in a very broad spectrum of inflammatory, both acute and chronic, conditions. Furthermore, chronic oxidative stress may modulate iron uptake and storage, leading to a self-sustained and ever-increasing spiral of cytotoxic and mutagenic events. The iron chelator deferroxamine is able to chelate 'free iron' even inside the cell. Its regular clinical use is to promote the excretion of an iron overload, when phlebotomy is harmful, and the dosage varies between 2-10 g/d. In conditions where deferroxamine is used to prevent the iron-driven oxygen toxicity, i.e., acute or chronic inflammatory diseases with oxidative stress, the dosage can be extremely reduced and the addition of antioxidants could be useful.     

Antagonistic effects of Spirulina platensis against sub-acute deltamethrin toxicity in mice: Biochemical and histopathological studies

Spirulina platensis (SP); a microalga with high antioxidant and anti-inflammatory activities, acts as a food supplement in human and as many animal species. Deltamethrin (DLM) is a synthetic pyrethroid with broad spectrum activities against acaricides and insects and widely used for veterinary and agricultural purposes. Exposure to DLM leads to hepatotoxic, nephrotoxic and neurotoxic side effects for human and many species, including birds and fish. The present study was undertaken to examine the potential hepatoprotective, nephroprotective, neuroprotective and antioxidant effects of SP against sub-acute DLM toxicity in male mice. DLM intoxicated animals revealed a significant increase in serum hepatic and renal injury biomarkers as well as TNF-α level and AChE activity. Moreover, liver, kidney and brain lipid peroxidation and oxidative stress markers were altered due to DLM toxicity. Spirulina normalized the altered serum levels of AST, ALT, APL, LDH, γ-GT, cholesterol, uric acid, urea, creatinine AChE and TNF-α. Furthermore, it reduced DLM-induced tissue lipid peroxidation, nitric oxide and oxidative stress in a dose-dependent manner. Collectively, that Spirulina supplementation could overcome DLM-induced hepatotoxicty, nephrotoxicity and neurotoxicity by abolishing oxidative tissue injuries.     

Biopeptides with antioxidant and anti-inflammatory potential in the prevention and treatment of diabesity disease

Diabesity is the leading cause of modern, chronic disease. In 2012, diabetes killed 1.2 million people worldwide and its global prevalence exceeded 347 million people, and it is expected that it will increase to 540 million by 2030. Because of this health imperative, it is also linked to increasing obesity. The role of the inflammatory process and oxidative stress in the pathophysiology of these diseases is widely documented. This paper review, using data from major databases, the role of biopeptides with antioxidant and anti-inflammatory activity as a potential aid for the prevention and treatment of diabesity, since the mechanisms of action mentioned directly affect oxidative stress and the characteristic imbalance of the inflammatory process of this disease. Some of these studies have demonstrated beneficial results in relation to oxidative stress and proinflammatory markers. However, the role of biopeptides, in relation to oxidative stress and inflammatory biomarkers, remains unclear and represents a potentially fruitful area for further research in the health area.     

Atorvastatin suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells.

Hyperhomocysteinemia is regarded as an independent risk factor for vascular diseases, and homocysteine is supposed to contribute to oxidative stress and endothelial damage. Statin therapy is an established intervention to reduce the risk of acute events in patients suffering from cardiovascular diseases. Apart from their lipid-lowering capacity, statins also exert anti-inflammatory and antioxidant effects. As cellular immune activation and oxidative stress play a major role in the pathogenesis of cardiovascular diseases, the anti-inflammatory capacity of statins could partly be responsible for the beneficial effects observed in patients. Earlier we reported that stimulated peripheral blood mononuclear cells (PBMCs) release homocysteine. Here we studied the influence of atorvastatin on homocysteine production in stimulated PBMCs and compared changes in cysteine concentrations and in neopterin production, which is a sensitive indicator of cellular immune activation. Stimulation of human PBMCs with the mitogens concanavalin A and phytohemagglutinin induced significant homocysteine and neopterin production compared to unstimulated cells, whereas cysteine concentrations remained unchanged. Treatment of PBMCs with increasing doses of atorvastatin (10-100 microM) suppressed both biochemical pathways in a dose-dependent manner, and cell proliferation was inhibited in parallel. Again, cysteine levels were not influenced by any treatment. The down-regulating effect of atorvastatin on homocysteine formation in vitro indicates that statins may prevent homocysteine accumulation in the blood via immunosuppression.     

Low level lead exposure and oxidative stress: current opinions

Lead continues to pose a serious threat to the health of many children as well as adults. Concern about lead exposure as a significant public health problem has increased as evidence has mounted regarding adverse health effects at successively lower levels. This issue is complicated by the fact that there is no demonstrated biological function of lead in human. Lead potentially induces oxidative stress and evidence is accumulating to support the role of oxidative stress in the pathophysiology of lead toxicity. Lead is capable of inducing oxidative damage to brain, heart, kidneys, and reproductive organs. The mechanisms for lead-induced oxidative stress include the effects of lead on membranes, DNA, and antioxidant defense systems of cells. Recent epidemiological and toxicological studies have reported that lead exposure causes several diseases including hypertension, kidney disease, neurodegenerative disease and cognitive impairment. Although all these diseases include components of oxidative stress, the relevance of oxidative stress to lead-related diseases with low lead exposure has been criticized because most of the mechanistic studies have been conducted at moderate to higher dose levels. The association between low level lead exposure and oxidative stress has not been explored systematically. The present review focuses on mechanisms for lead-induced oxidative stress and relevance of oxidative stress to lead-related human disease with low lead exposure.     

Oxidative stress induced in pathologies: the role of antioxidants.

Exposure to oxidant molecules issued from the environment (pollution, radiation), nutrition, or pathologies can generate reactive oxygen species (ROS for example, H2O2, O2-, OH). These free radicals can alter DNA, proteins and/or membrane phospholipids. Depletion of intracellular antioxidants in acute oxidative stress or in various diseases increases intracellular ROS accumulation. This in turn is responsible for several chronic pathologies including cancer, neurodegenerative or cardiovascular pathologies. Thus, to prevent against cellular damages associated with oxidative stress it is important to balance the ratio of antioxidants to oxidants by supplementation or by cell induction of antioxidants.     

Regenerative therapy for hippocampal degenerative diseases: lessons from preclinical studies

Increase in life expectancy has put neurodegenerative diseases on the rise. Amongst these, degenerative diseases involving hippocampus like Alzheimer's disease (AD) and temporal lobe epilepsy (TLE) are ranked higher as it is vulnerable to excitotoxicity induced neuronal dysfunction and death resulting in cognitive impairment. Modern medicines have not succeeded in halting the progression of these diseases rendering them incurable and often fatal. Under such scenario, regenerative studies employing stem cells or their by‐products in animal models of AD and TLE have yielded encourageing results. This review focuses on the distinct cell types, such as hippocampal cell lines, neural precursor cells, embryonic stem cells derived neural precursor cells, induced pluripotent stem cells, induced neurons and mesenchymal stem cells, which can be employed to rescue hippocampal functions in neurodegenerative diseases like AD and TLE. Besides, the divergent mechanisms through which cell based therapy confer neuroprotection, current impediments and possible improvements in stem cell transplantation strategies are discussed. Authors are aware of the voluminous literature available on this issue and have made a sincere attempt to put forth the current status of research in the field of cell based therapy concurrently discussing the promise it holds for combating neurodegenerative diseases like AD and TLE in the near future. Copyright © 2015 John Wiley & Sons, Ltd.     

Cordycepin protects PC12 cells against 6-hydroxydopamine induced neurotoxicity via its antioxidant properties

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by degeneration and loss of dopaminergic neurons of the substantia nigra. Increasing evidence has indicated that oxidative stress plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). Therapeutic options that target the antioxidant machinery may have potential in the treatment of PD. Cordycepin, a nucleoside isolated from Cordyceps species displayed potent antioxidant, anti-inflammatory and anticancer properties. However, its neuroprotective effect against 6-OHDA neurotoxicity as well as underlying mechanisms is still unclear. In this present study, we investigated the protective effect of cordycepin against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity and its underlying mechanism. We observed that cordycepin effectively inhibited 6-OHDA-induced cell death, apoptosis and mitochondrial dysfunction. Cordycepin also inhibited cell apoptosis induced by 6-OHDA as observed in the reduction of cytochrome c release from the mitochondrial as well as the inhibition of caspase-3. In addition cordycepin markedly reduced cellular malondialdehyde (MDA) content and intracellular reactive oxygen species (ROS) level. Cordycepin also significantly increased the antioxidant enzymes; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in 6-OHDA-treated cells. The results obtained unambiguously demonstrated that cordycepin protects PC12 cells against 6-OHDA-induced neurotoxicity through its potent antioxidant activity.