File Name: oxidative stress and neurodegenerative disorders .zip
A growing body of evidence suggests the alteration of the reduction-oxidation redox homeostasis in the brain grown with the increasing of the age.
- Oxidative Stress, Antioxidants and Neurodegenerative Diseases
- Oxidative Stress and Neurodegenerative Disorders
- Oxidative stress and neurodegenerative disorders
- Apoptosis and Oxidative Stress in Neurodegenerative Diseases
Oxidative insults, whether over-excitation, excessive release of glutamate or ATP caused by stroke, ischemia or inflammation, exposure to ionizing radiation, heavy-metal ions or oxidized lipoproteins may initiate various signaling cascades leading to apoptotic cell death and neurodegenerative disorders. Among the various reactive oxygen species ROS generated in the living organism, hydroxyl and peroxynitrite are the most potent and can damage proteins, lipids and nucleic acids. It appears that some natural antioxidants tocopherol, ascorbic acid and glutathione and defense enzyme systems superoxide dismutase, catalase and glutathione peroxidase may provide some protection against oxidative damage.
Author s : I. Casetta , V. Govoni , E.
Oxidative Stress, Antioxidants and Neurodegenerative Diseases
Author contributions: Xueping Chen is responsible for designing and writing the manuscript. Chunyan Guo helps to revise the manuscript. Jiming Kong is responsible for manuscript oversight and instruction. The mitochondrial respiratory chain and enzymatic reactions by various enzymes are endogenous sources of reactive oxygen species. Exogenous reactive oxygen species -inducing stressors include ionizing radiation, ultraviolet light, and divergent oxidizing chemicals.
At low concentrations, reactive oxygen species serve as an important second messenger in cell signaling; however, at higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death.
Biochemical alterations in these macromolecular components can lead to various pathological conditions and human diseases, especially neurodegenerative diseases. Deposition of abnormal aggregated proteins and disruption of metal ions homeostasis are highly associated with oxidative stress. The main aim of this review is to present as much detailed information as possible that is available on various neurodegenerative disorders and their connection with oxidative stress.
A variety of therapeutic strategies designed to address these pathological processes are also described. For the future therapeutic direction, one specific pathway that involves the transcription factor nuclear factor erythroid 2-related factor 2 is receiving considerable attention.
Free radicals are molecules with at least one unpaired electron in the outermost shell; they are highly reactive due to the presence of unpaired electron. Any free radical involving oxygen can be referred to as a reactive oxygen species ROS [ 1 ].
Since ROS are common outcome of normal aerobic cellular metabolism, in-built antioxidant system of body plays its decisive role in prevention of any loss due to ROS overproduction. Oxidative stress arises as a result of an imbalance between the production of ROS and the biological system's ability to detoxify the reactive intermediates[ 2 ].
Oxidative stress has been implicated in the progression of Alzheimer's disease AD , Parkinson's disease PD and other neurodegenerative diseases. Oxidative stress leading to free radical attack on neural cells contributes calamitous role to neurodegeneration.
Toxicity of ROS contributes to protein misfolding, glia cell activation, mitochondrial dysfunction and subsequent cellular apoptosis[ 3 ]. However, the systems in place to cope with biochemistry of oxidative stress are complex, and this complexity provides a number of therapeutic targets.
Recognition of upstream and downstream antioxidant therapy has been proved an effective tool in alteration of neuronal damage as well as novel metal-protein attenuating compound MPAC. Furthermore, therapeutic approaches aiming at nuclear factor erythroid 2-related factor 2 Nrf2 transcriptional pathway have shown promise in clinical studies.
This review presents detailed information on oxidative stress and its connection with neurodegenerative diseases. The therapeutic strategies designed to address these diseases are also described. Free radicals, with at least one unpaired electron in the outermost shell, is highly reactive[ 4 ]. Cells exposed to environment fortified with oxygen continuously generate oxygen free radicals. ROS includes oxygen-related free radicals and reactive species[ 6 ], and they are produced as a result of aerobic metabolism.
Formation of ROS can occur in two ways: enzymatic and non-enzymatic reactions. Enzymatic reactions generating free radicals include those involved in the mitochondrial respiratory chain, phagocytosis, prostaglandin synthesis and the cytochrome P system[ 7 ].
For example, the superoxide radical is generated via several cellular oxidase systems such as 5,methylenetetrahydrofolate reductase oxidase, xanthine oxidase, peroxidases.
ROS can also be produced from non-enzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing radiations.
The non-enzymatic process can also occur during oxidative phosphorylation i. ROS is generated from either endogenous or exogenous sources. Endogenous free radicals are generated from immune cell activation, inflammation, mental stress, excessive exercise, ischemia, infection, cancer and aging.
Exogenous ROS result from air and water pollution, cigarette smoke, alcohol, heavy or transition metals Cd, Hg, Pb, Fe, As , certain drugs cyclosporine, tacrolimus, gentamycin, bleomycin , industrial solvents, cooking smoked meat, used oil, fat and radiation[ 9 , 10 , 11 , 12 ]. After penetrated into the body by different routes, these exogenous compounds are decomposed or metabolized into free radicals. The generation of mitochondrial ROS is a consequence of oxidative phosphorylation, a process that occurs in the inner mitochondrial membrane and involves the oxidation of reduced form of nicotinamide-adenine dinucleotid to produce energy.
Mitochondrial electron transport involves four-electron reduction of O 2 to H 2 O. Superoxide anion is detoxified by the mitochondrial manganese superoxide dismutase to yield H 2 O 2 , and H 2 O 2 in the presence of reduced transition metals can also be converted to hydroxyl radical OH -.
This reaction generates H 2 O 2 as a by-product. Peroxisomes are organelles responsible for degrading fatty acids as well as other molecules[ 14 ].
Phagocytic cells are another important source of oxidants; these cells defend the central nervous system CNS against invading microorganisms and clear the debris from damaged cells by an oxidative burst of nitric oxide, H 2 O 2 , and O 2 -. Finally, cytochrome P enzymes in animals are one of the first defenses against natural toxic chemicals from plants. In addition, the generation of ROS in living systems is closely linked with the participation of redox-active metals such as iron and copper.
As a general principle, the chemical origin of the majority of ROS is the direct interactions between redox-active metals and oxygen species via reactions such as the fenton and haber-weiss reaction.
Apart from direct ROS generation, indirect pathway involves calcium activation with metallo-enzymes such as phospholipases, nitric oxide synthase. Calcium stimulates the tricarboxylic acid cycle and enhances electron flow into the respiratory chain; it also stimulates the nitric oxide synthase and subsequently promotes nitric oxide generation, which would inhibit respiration at complex IV.
These events would enhance ROS generation from Q cycle. Calcium is an important signaling molecule and it is required for many cellular responses and cell-cell communication. Thus, any disruption of calcium homeostasis may disrupt the cellular physiology[ 16 ]. At low or moderate concentrations, ROS are necessary for the maturation process of cellular structures and can act as weapons for the host defense system, supporting cell proliferation and survival pathways.
Indeed, phagocytes neutrophils, macrophages, monocytes release free radicals to destroy invading pathogenic microbes as part of the body's defense mechanism against disease[ 7 ]. Other beneficial effects of ROS involve their physiological roles in the function of a number of cellular signaling systems. ROS signaling can affect cellular energetics by acutely regulating adenosine-triphosphate production via activation of uncoupling proteins[ 17 ].
Moreover, ROS are required for transduction growth signals via certain receptor tyrosine kinases[ 18 ]. Specific example includes nitric oxide, which is an intercellular messenger for modulating blood flow, thrombosis, and neural activity[ 19 ].
Nitric oxide is also important for nonspecific host defense, and for killing intracellular pathogens and tumors. Another beneficial activity of free radicals is the induction of a mitogenic response[ 19 ]. In brief, ROS at low or moderate levels are vital to human health. When produced in excess, these highly reactive radicals can start a pathological chain reaction, like dominoes[ 20 ], damaging all components of the cells, and leading to a progressive decline in physiological function[ 21 ].
This will generate a phenomenon called oxidative stress. Oxidative stress is a deleterious process that can seriously alter the cell membranes and other structures such as proteins, lipids, lipoproteins, and deoxyribonucleic acid DNA [ 3 , 6 ]. Oxidative stress can arise when cells cannot adequately destroy the excess of free radicals formed. In other words, oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to detoxify the reactive intermediates.
For example, ROS overproduction within mitochondria can lead to oxidative damage to mitochondrial proteins, membranes, and mitochondrial DNA, finally resulting in mitochondrial injury[ 23 ]. Mitochondrial oxidative damage leads to the release of cytochrome c into the cytosol resulting in apoptosis. Increased permeability makes the inner membrane permeable to small molecules. Despite a large amount of scientific evidence supporting oxidative stress as a pathogenic factor in these diseases, human also experience with antioxidant neuroprotectants[ 2 ].
The body counteracts oxidative stress by producing antioxidants, either naturally generated in situ endogenous antioxidants , or externally supplied through foods exogenous antioxidants. The role of antioxidants is to neutralize excess of free radicals, protecting the cells against their toxic effects, and to contribute to disease prevention. However, overproduction of ROS which could not be fully neutralized can cause oxidative damage to biomolecules, and eventually leading to many chronic diseases, such as atherosclerosis, cancer, diabetics, rheumatoid arthritis and degenerative diseases.
Neurodegenerative diseases are clinically characterized by their insidious onset and chronic progression, and are pathologically characterized by progressive dysfunction and death of cells that frequently affect specific neural system.
While many brain neurons can cope with a rise in oxidative stress, there are selected populations of neurons that are vulnerable to increase oxidative stress, this phenomenon in neurodegenerative conditions is called selective neuronal vulnerability[ 25 ].
Selective neuronal vulnerability refers to the differential sensitivity of neuronal populations in the CNS to stresses that cause cell injury or death and lead to neurodegeneration. For example, neurons in the entorhinal cortex, hippocampal CA1 region, frontal cortex, and amygdala are the populations of neurons most sensitive to the neurodegeneration associated with AD.
In PD, dopaminergic neurons of the substantia nigra are the primary neurons undergoing cell death[ 26 ]. Amyotrophic lateral sclerosis is characterized by the degeneration of, primarily, spinal motor neurons, but also cortical and brain stem neurons[ 27 ].
The fact that specific brain regions exhibit differential vulnerabilities to oxidative stress in various neurodegenerative diseases is a reflection of the specificity in the etiology of each disease, and it is possible that the selected cells involved in the pathology of neurodegenerative diseases may share a common increased vulnerability to the detrimental effects of oxidative stress.
Under normal conditions, cells are capable of counteracting the oxidant insults by regulating their homeostatic balance. However, during the progression of age-related neurodegenerative conditions, the capacity of cells to maintain the redox balance decreases, leading to the accumulation of free radicals, mitochondrial dysfunction, and neuronal injury.
It is widely accepted that oxidative stress increases during aging[ 29 ], and it can be considered as an important age-dependent factor making the neuronal systems more susceptible to several neurodegenerative diseases such as AD and PD. Oxidative overload in the neuronal microenvironment causes oxidation of lipids[ 30 ], proteins[ 31 ] and DNA[ 32 ] and generates many by-products such as peroxides, alcohols, aldehydes, ketones and cholesterol oxide[ 33 ].
Unsaturated lipids are particularly susceptible to oxidative modification and lipid peroxidation is a sensitive marker of oxidative stress. Lipid peroxidation is the result of attack by radicals on the double bond of unsaturated fatty acids to generate highly reactive lipid peroxy radicals that initiate a chain reaction of further attacks on other unsaturated fatty acids.
The chain reaction leads to the formation of breakdown products including 4-hydroxy-2, 3-nonenal HNE and F2-isoprostanes[ 34 , 35 , 36 , 37 ]. These findings, together with the recent demonstration that HNE is cytotoxic to neurons and that it impairs the function of membrane proteins including the neuronal glucose transporter 3, indicate that HNE is a characteristic marker and a toxin leading to neurodegeneration[ 41 ]. ROS mediated oxidation of protein side-chains and resulted in the introduction of hydroxyl groups or in the generation of protein based carbonyls[ 42 ].
Carbonyl groups are introduced in proteins by oxidizing amino acid residue side-chain hydroxyls into ketone or aldehyde derivatives[ 43 ]. Measurement of protein carbonylation is thought to be a good estimate for the extent of oxidative damage of proteins associated with various conditions of oxidative stress[ 45 , 46 , 47 ]. DNA bases are vulnerable to oxidative stress damage involving hydroxylation, carbonylation and nitration[ 48 , 49 , 50 ].
DNA and RNA oxidation is marked by increased levels of 8-hydroxydeoxyguanosine and 8-hydroxyguanosine[ 51 , 52 , 53 ]. It is now widely accepted that oxidative damage is responsible for DNA strand breaks and this is consistent with the increased free carbonyls in the nuclei of neuronal cells in neurodegenerative diseases.
Advanced glycation end products AGEs , which are formed by a non-enzymatic reaction of sugars with long lived protein deposits, are also potent neurotoxins and proinflammatory molecules. A cascade of reactions results thereafter in the formation of AGEs, which are composed of irreversibly cross-linked heterogeneous protein aggregates[ 54 ]. Abnormal interactions between proteins that result in aberrant intracellular and extracellular deposition of self aggregating misfolded proteins with formation of high-ordered insoluble fibrils are common pathological hallmarks of multiple neurodegenerative disorders.
Although the pathogenicity of protein aggregates remains uncertain[ 56 ], a causative link between the formation of protein aggregates and neurodegeneration has been established, which may occur as a result of the toxic action of substances produced during early phases, and soluble oligomers and protofibrillar derivatives of misfolded proteins may play a pathogenic role[ 57 , 58 ]. The exact mechanisms of abnormal folding are not fully understood; however, speculations lead to the presumption that genetic and environmental factors especially oxidative stress are involved[ 59 ].
Aberrant proteins, the result of inherited or acquired amino acid substitution or damage, especially oxidative modification, cannot fold correctly and will be trapped in misfolded conformations. Growing evidence supports the hypothesis that oxidative stress, combined with protein aggregation, triggers a cascade of events leading to cell death in multiple neurodegenerative diseases. Because proteins modified by oxidative reactive species tend to form aggregates, and highly oxidized and cross-linked proteins may act as endogenous inhibitors of proteasomal activity.
Oxidative Stress and Neurodegenerative Disorders
Author contributions: Xueping Chen is responsible for designing and writing the manuscript. Chunyan Guo helps to revise the manuscript. Jiming Kong is responsible for manuscript oversight and instruction. The mitochondrial respiratory chain and enzymatic reactions by various enzymes are endogenous sources of reactive oxygen species. Exogenous reactive oxygen species -inducing stressors include ionizing radiation, ultraviolet light, and divergent oxidizing chemicals. At low concentrations, reactive oxygen species serve as an important second messenger in cell signaling; however, at higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death.
Oxidative stress and neurodegenerative disorders
Introduction: The incidence and prevalence of neurodegenerative diseases increase with life expectancy. Brain, for physiological and biochemical reasons, has a high sensitivity to oxidative stress. Therefore, maintaining the redox homeostasis is essential for brain cells. In addition, brain antioxidant levels are limited compared to other tissues.
DNA is a potential target for oxidative damage, and genomic damage can contribute to neuropathogenesis. It is important therefore to identify tools for the quantitative analysis of DNA damage in models on neurological disorders. This book presents detailed information on various neurodegenerative disorders and their connection with oxidative stress. This information will provide clinicians with directions to treat these disorders with appropriate therapy and is also of vital importance for the drug industries for the design of new drugs for treatment of degenerative disorders. Researchers, clinicians and students in the fields of neuroscience, neurology, biochemistry and drug discovery who are interested in neurodegenerative disorders.
Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration.
Apoptosis and Oxidative Stress in Neurodegenerative Diseases
Perspective Free access Address correspondence to: Susan L. Phone: ; Fax: ; E-mail: sla jax. Find articles by Klein, J. Find articles by Ackerman, S.
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Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and.
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