NADPH Oxidase and Neurodegeneration

NADPH oxidase (Nox) is a unique, multi-protein, electron transport system that produces large amounts of superoxide via the reduction of molecular oxygen. Nox-derived reactive oxygen species (ROS) are known to be involved in a variety of physiological processes, including host defense and signal transduction. However, over the past decade, the involvement of (Nox)-dependent oxidative stress in the pathophysiology of several neurodegenerative diseases has been increasingly recognized. ROS produced by Nox proteins contribute to neurodegenerative diseases through distinct mechanisms, such as oxidation of DNA, proteins, lipids, amino acids and metals, in addition to activation of redox-sensitive signaling pathways. In this review, we discuss the recent literature on Nox involvement in neurodegeneration, focusing on Parkinson and Alzheimer diseases.     

Mitochondrial Biology and Neurological Diseases

Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondriaMutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases.     

Association of Oxidative Stress with Neurological Disorders

Backgorund: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson’s, Alzheimer’s, and Huntington’s diseases.Objectives: In this study, we explored the involvement of OS in neurodegenerative diseases.Methods: We used different search terms like “oxidative stress and neurological disorders” “free radicals and neurodegenerative disorders” “oxidative stress, free radicals, and neurological disorders” and “association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS.Results: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress.Conclusion: More elaborated studies in the future will certainly help in understanding the exact mechanism involved in neurological diseases and provide insight into revelation of therapeutic targets.     

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

Much attention has been devoted to neurodegenerative diseases involving redox processes. This review comprises an update involving redox processes reported in the considerable literature in recent years. The mechanism involves reactive oxygen species and oxidative stress, usually in the brain. There are many examples including Parkinson’s, Huntington’s, Alzheimer’s, prions, Down’s syndrome, ataxia, multiple sclerosis, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis, schizophrenia, and Tardive Dyskinesia. Evidence indicates a protective role for antioxidants, which may have clinical implications. A multifaceted approach to mode of action appears reasonable.     

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

Alzheimer''s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-β (Aβ) protein by GO. Both in vivo and in vitro models were induced using Aβ_1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aβ_1-42-induced AD. This proved that GO loaded with Dau could protect against Aβ_1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.     

H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria

This review is focused on the mechanistic aspects of the insulin-induced H₂O₂ signalling pathway in neurons and the molecules affecting it, which act as risk factors for developing central insulin resistance. Insulin-induced H₂O₂ promotes insulin receptor activation and the mitochondria act as the insulin-sensitive H₂O₂ source, providing a direct molecular link between mitochondrial dysfunction and irregular insulin receptor activation. In this view, the accumulation of dysfunctional mitochondria during chronological ageing and Alzheimer’s disease (AD) is a risk factor that may contribute to the development of dysfunctional cerebral insulin receptor signalling and insulin resistance. Due to the high significance of insulin-induced H₂O₂ for insulin receptor activation, oxidative stress-induced upregulation of antioxidant enzymes, e.g., in AD brains, may represent another risk factor contributing to the development of insulin resistance. As insulin-induced H₂O₂ signalling requires fully functional mitochondria, pharmacological strategies based on activating mitochondria biogenesis in the brain are central to the treatment of diseases associated with dysfunctional insulin receptor signalling in this organ.     

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.     

Ginkgo Biloba Extract in an Animal Model of Parkinson’s Disease: A Systematic Review

Although the exact cause of neuronal loss in Parkinson’s disease is not known, evidence points to oxidative stress and the production of reactive oxygen species as the main events that occur in the substantia nigra pars compacta of the brain of parkinsonians. EGb761 is an extract of the leaves from the Ginkgo biloba tree that has been reported as an antioxidant and neuroprotective agent. The objective of this work was to perform a systematic review of the studies that analysed the effect of Ginkgo biloba extract on Parkinson’s disease or Parkinsonism. This research was conducted using the following databases: Medline, PsycInfo, Cinahl, Sigle, Lilacs, Scielo, Cochrane Library, and Embase. Initially, we selected 32 articles. After a more detailed analysis, only 10 articles remained. One of the hypotheses for the positive effect of EGb761 on Parkinson’s disease is the reduction or inhibition of monoamine-oxidase activity. This enzyme metabolises dopamine, inducing the formation of free radicals, which in turn damage nigrostriatal neurons. Another hypothesis is that the neuroprotective effect of EGb761 against 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and MPP+ toxins. As there are few studies on the effect of EGb761 on humans, this review could contribute new data to further the discussion of this issue.     

Role of Nitric Oxide in Neurodegeneration: Function,Regulation, and Inhibition

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of L-arginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.     

Antineuroinflammatory Effects of 7,3’,4’-Trihydroxyisoflavone in Lipopolysaccharide-Stimulated BV2 Microglial Cells through MAPK and NF-κB Signaling Suppression

Neuroinflammation—a common pathological feature of neurodegenerative disorders such as Alzheimer’s disease—is mediated by microglial activation. Thus, inhibiting microglial activation is vital for treating various neurological disorders. 7,3’,4’-Trihydroxyisoflavone (THIF)—a secondary metabolite of the soybean compound daidzein—possesses antioxidant and anticancer properties. However, the effects of 7,3’,4’-THIF on microglial activation have not been explored. In this study, antineuroinflammatory effects of 7,3’,4’-THIF in lipopolysaccharide (LPS)-stimulated BV2 microglial cells were examined. 7,3’,4’-THIF significantly suppressed the production of the proinflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as of the proinflammatory cytokine interleukin-6 (IL-6) in LPS-stimulated BV2 microglial cells. Moreover, 7,3’,4’-THIF markedly inhibited reactive oxygen species (ROS) generation. Western blotting revealed that 7,3’,4’-THIF diminished LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β), and nuclear factor kappa B (NF-κB). Overall, 7,3’,4’-THIF exerts antineuroinflammatory effects against LPS-induced microglial activation by suppressing mitogen-activated protein kinase (MAPK) and NF-κB signaling, ultimately reducing proinflammatory responses. Therefore, these antineuroinflammatory effects of 7,3’,4’-THIF suggest its potential as a therapeutic agent for neurodegenerative disorders.     

Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways

The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H₂O₂)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H₂O₂ induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H₂O₂ induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.     

Recent Evidence in Epigenomics and Proteomics Biomarkers for Early and Minimally Invasive Diagnosis of Alzheimer’s and Parkinson’s Diseases

Background: Alzheimer’s (AD) and Parkinson’s diseases (PD) show deposits of improperly folded modified proteins. Protein expression mechanisms are involved since the early stages. Several studies evaluated epigenomics and proteomics profiles in these patients, with promising results. In general, they focused on early, specific, and minimally invasive biomarkers for the diagnosis and prognosis of AD and PD.Objectives This review aimed at summarizing results to find the most reliable evidence in the field.Results Among epigenomics studies, there is a focus on microRNAs (miRNAs) as candidate diagnostic biomarkers for AD or PD from blood samples like miR-342-3p, miR-107, miR-106a-5p, miR-106b-5p, miR-195, and miR-19b. In addition, DNA methylation has been tested in a few works, obtaining significant differences in some genes (NCAPH2/LMF2 COASY, SPINT1, BDNFTREM1, TREM2, NPAS2, PDE4D), which could be useful for evaluating the disease progression as well as potential risk factors. Regarding proteomics, most of the studies were untargeted and used plasma or serum samples. In general, they highlighted the importance of coagulation, inflammation pathways, and oxidative stress. Among targeted studies, some proteins (phosphorylated tau, C reactive protein (CRP), interleukins, necrosis factors, transferrin, glial fibrillary acidic protein (GFAP), and neurofilaments) showed different plasma levels in AD and PD patients in comparison with healthy participants. Finally, a few studies have identified specific-AD and PD epigenetic and proteomic biomarkers (ApoE and oxidized DJ-1) in comparison with other similar pathologies.Conclusion In general, there is a common lack of clinical validation of these potential biomarkers because of which its use in clinical practice is still limited.     

Matrix Metalloproteinases,New Insights into the Understanding of Neurodegenerative Disorders

Matrix metalloproteinases (MMPs) are a subfamily of zinc-dependent proteases that are responsible for degradation and remodeling of extracellular matrix proteins. The activity of MMPs is tightly regulated at several levels including cleavage of prodomain, allosteric activation, compartmentalization and complex formation with tissue inhibitor of metalloproteinases (TIMPs). In the central nervous system (CNS), MMPs play a wide variety of roles ranging from brain development, synaptic plasticity and repair after injury to the pathogenesis of various brain disorders. Following general discussion on the domain structure and the regulation of activity of MMPs, we emphasize their implication in various brain disorder conditions such as Alzheimer’s disease, multiple sclerosis, ischemia/reperfusion and Parkinson’s disease. We further highlight accumulating evidence that MMPs might be the culprit in Parkinson’s disease (PD). Among them, MMP-3 appears to be involved in a range of pathogenesis processes in PD including neuroinflammation, apoptosis and degradation of α-synuclein and DJ-1. MMP inhibitors could represent potential novel therapeutic strategies for treatments of neurodegenerative diseases.     

Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease

Parkinson’s disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients’ brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials.     

Quality control gone wrong: mitochondria,lysosomal storage disorders and neurodegeneration

The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson''s disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be ‘recycled.’ Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson''s and Gaucher diseases in which defective quality control is a defining factor.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington’s disease via suppressing MAPKs and NF-κB pathways in the striatum

Huntington’s disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg⁻¹, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.     

C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside

Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person’s mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington’s disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.     

Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.