Manual Oxidative Stress and Neurodegenerative Disorders

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Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS).
Table of contents

Ermak G, Davies K J. Calcium and oxidative stress: Ferrari C K B. Free radicals, lipid peroxidation and antioxidants in apoptosis: Free radical damage to protein and DNA: Mechanism involved and relevant observations on brain undergoing oxidative stress. Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Protective action of nitrone-based free radical traps against oxidative damage to the central nervous system.

Complexes of iron III with ligands of biological interest: Oxidative stress induced-neurodegenerative diseases: Iron overload in Africa. Interaction between a gene and dietary iron content. Neuroprotective effects of estrogens: Guido K, John CR. Mitochondrial control of cell death. Free radicals, antioxidants, and human disease: Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: American Psychiatric Association; Molecular Cell Biology; pp. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study.

Huie RE, Padmaja S. The reaction of NO with superoxide. Visions of an emerging subspecialty. Enols and Enolates- The Michael Additions. Emerit M, Edeas F B. Neurodegenerative diseases and oxidative stress.

Oxidative Stress and Neurodegenerative Disorders | ScienceDirect

Jayalakshmi M Sairam, S. Singh SK Sharma, G. Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal culture. Klaus A, Heribert H. Metabolism, oxidative stress, and signal transduction. Dietary flavonoid and cancer prevention: Glial cells under physiologic and pathologic conditions. Quenching of the tyrosyl free radical of ribonucleotide reductase by nitric oxide. Fruits and vegetables in the prevention of cancer: Folate pathway gene variants in cancer: Transworld Research Network; Lotharius J, Brundin P.

Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative Disorders. Role of asbestos and active oxygen species in activation and expression of ornithine decarboxylase in hamster tracheal epithelial cells. Excitotoxic and excitoprotective mechanisms: Will caloric restriction and folate protect against AD and PD? The evolution of free radicals and oxidative stress. Changes in hepatic glutathione metabolism in diabetes.

Mitscher LA, Telikepalli Natural antimutagenic agents. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Retinyl palmitate and ascorbic acid inhibit pulmonary neoplasms in mice exposed to fiberglass dust. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H 2 O 2.

S, Khachaturian S, V. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements-The Cache County Study. Role of oxidative DNA damage in cancer initiation and promotion. The free-radical theory of aging revisited: A critique and a suggested disease-specific theory. Eds Modern Biological Theories of Aging. Biochemical indices of peroxidation in Alzheimer's and control brains.

The origin of the hydroxyl radical oxygen in the Fenton Reaction. Anti-inflammatory and antioxidant properties of Helichrysum italicum. The benefits and hazards of antioxidants: Impaired antioxidant status in diabetic rat liver. Activated neutrophils induce prolonged DNA damage in neighboring cells. Targeting antioxidants to mitochondria: A new therapeutic direction. Biochimica et Biophysica Acta.

Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid and total bile acids in gastric juice of patients with and without precancerous conditions of the stomach. Biochemistry of nitric oxide and its redox-activated forms. Antioxidant and antiproliferative activities of common fruits. Age related changes in the concentrations of major and trace elements in the brain of rats and mice.

Free radical generation in the brain precedes hyperbaric oxygen-induced convulsions. Torben M, Evan HM. The metabolism of neuronal iron and its pathogenic role in neurological disease: Oxidative damage and pathogenesis. Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. The structure of neuromelanin as studied by chemical degradative methods. Winblad B, Jelic V. Treating the full spectrum of dementia with memantine.

Macrophage-mediated induction of drug-resistant variants in a mouse mammary tumor cell line. Inhibition of carcinogenesis by dietary polyphenolic compounds. The Ginkgo biloba extract EGb rescues the PC12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-derived diffusible neurotoxic ligands. Youdim MBH, lavie L. Free radicals and their scavengers in Parkinson's disease. The effects of desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat.

Cellular defenses against damage from reactive oxygen species. Free radicals, antioxidants, and nutrition. Regional lipid peroxidation in rat brain in vitro: Zheng M, Storz G. Redox sensing by prokaryotic transcription factors. Zheng W, Wang SY. Antioxidant activity and phenolic compounds in selected herbs. Support Center Support Center. Please review our privacy policy.

Aryl amines and indoles-carotene, lycopene Polyenes- carotene, lycopene, retinol Selenium containing compounds ebselen. Amino oxidase inhibitors, calcium antagonists, dopamine receptor agonists, glutamate receptor antagonists, ion chelators, nitric oxide synthase inhibitors. Prevent excitotoxicity, ROS and free radical generation targeting inhibitors and receptors dysregulating metal homeostasis.

N-acetyl-cysteine, glutathione, 2-oxo-thiazolidinecarboxylate, and other thiol-delivering compounds N-butyl- -phenylnitrone. Living cells continually generate reactive oxygen species ROS through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious.

The central nervous system CNS is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system PNS of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well.

Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.

Oxygen is required for energy metabolism for the survival and normal functions of most eukaryotic organisms. Along the respiratory chain, oxygen is also partially reduced, at low ratio, into superoxide, a basic free radical that can be converted eventually into other forms of reactive oxygen species ROS. Cell metabolism could generate other free radicals from nitrogen, classified into the family of reactive nitrogen species RNS.

ROS and RNS at physiological concentrations have recently been demonstrated to mediate a variety of normal functions, such as regulation of signal transduction, induction of mitogenic response, and involvement in defense against infectious agents, etc. ROS are balanced with antioxidant systems to keep their level constant in living organisms. These antioxidant systems are both enzymatic and non-enzymatic. In its lifespan, a living organism could be exposed to a number of oxidative damage-causing exogenous factors, such as irradiation by UV light, X-rays, gamma-rays, heavy metals, and atmospheric pollutants.

Amongst the different organs in the body, the brain is particularly vulnerable to oxidative stress due to its high oxygen utilization, weaker antioxidant enzymes, high content of easily oxidized polyunsaturated fatty acids, and the terminal-differentiation characteristic of neurons.

This review focuses on the role of oxidative stress on neurodegenerative diseases. To aid the understanding of toxic targets in neurodegenerative diseases, this review begins with the essential characteristics of ROS, including its generation, regulation and physiological functions. Then, the mechanisms for ROS underlying neurodegeneration are highlighted with a focus on the causal relationship between ROS and protein misfolding and aggregation which can serve as a key to distinguish one neurodegenerative disease from another.

In addition, the role of ROS in artificial event-induced neuronal disorders, such as chemotherapy-induced cognitive impairment colloquially known as chemobrain and chemotherapy-induced peripheral neuropathy CIPN is assessed. The review further comments on drug developmental strategies for the therapy of neurodegenerative diseases, as well as prevention of anticancer drug-induced neuronal disorders.

Mitochondria, Apoptosis, and Oxidative Stress

Since reactive nitrogen intermediates RNI are involved in the regulation of apoptotic or necrotic cell death, they are also recognized as important radicals. ROS can be generated in the mitochondria, endoplasmic reticulum ER , plasma membrane and cytoplasm Figure 1. Cells constantly generate ROS in mitochondria during aerobic metabolism. ROS generations and antioxidant systems in cells. Reactive oxygen species ROS can be generated from various sites in a cell.

To limit over-accumulation of ROS in the body, there exists both enzymatic and non-enzymatic systems to maintain ROS balance. In addition to the enzymatic defense systems, the human body also uses non-enzymatic antioxidants to limit over-accumulation of ROS. Vitamin C is a potent antioxidant that neutralizes free radicals by donating an electron. Vitamin E is a fat-soluble vitamin whose main antioxidant function is protection against lipid peroxidation, providing a high efficiency antioxidant effect by stopping ROS from forming in membranes undergoing lipid peroxidation.

GSH is highly abundant in the cytoplasm, nuclei and mitochondria. GSH reacts with a radical and becomes a thiyl radical itself. The newly-generated thiyl radicals dimerize to form the non-radical product oxidized glutathione GSSG. GSH in the nucleus maintains the redox state of sulfhydryls of critical proteins for DNA repair and gene expression. Flavonoids constitute the most important single group of polyphenols, acting as antioxidants by terminating free radical chain reactions. Flavonoids stop the oxidation of lipids and other molecules by the rapid donation of hydrogen atoms to radicals, becoming the phenoxy radical intermediates by themselves.

The intermediates are relatively stable, and thus do not initiate further radical reaction. There are also many other non-enzymatic antioxidants in the body, such as selenium, carotenoids, lipoic acid, coenzyme Q, melatonin, etc , which are detailed in recent reviews [ 10 , 13 ]. ROS involves a number of cellular signaling pathways in controlling cell survival, migration and proliferation.

H 2 O 2 can inactivate PP2A at the cysteine site and therefore activate the Akt pathway to facilitate cell survival [ 14 — 16 ]. Among them, the extracellular signal-regulated kinase ERK pathway has most commonly been associated with the regulation of cell proliferation. The negative regulation of this pathway is fulfilled by dephosphorylation of MAPKs by phosphatases.

Oxygen radicals elicit phosphorylation of these receptors, resulting in activation of the ERK pathway in relation to mitogenic signaling [ 17 — 19 ]. In fact, the activation of the ERK pathway is not limited to receptor levels. ROS actively mediates cell differentiation. Myogenic differentiation is an essential process for myogenesis in response to various extracellular stimuli, including ROS.

An array of stresses such as oxidative stress can activate ASK1 and initiate the differentiation process of myoblasts [ 23 ]. As a signaling molecule, ROS has been shown to mediate the function of angiogenic factors like VEGF or angiopoietin-1 in directing cell migration [ 24 ]. In addition to the regulation of cellular signaling pathways as secondary messengers, ROS are also involved in cell defense against infectious agents.

Oxidative stress contributes to physiological functions of the CNS, including the process of learning and memory Figure 2. Long-term potentiation LTP is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. As memories are thought to be encoded by modification of synaptic strength, LTP is widely considered as one of the major cellular mechanisms that underlie learning and memory.

Contribution of ROS to the process of learning and memory. Long-term potentiation LTP is considered one of the major cellular mechanisms for learning and memory. The activation of these receptors results in calcium influx, which then activates different kinases in the cascade to facilitate LTP formation.

The pathways to activate LTP are different, depending on the hippocampal regions. In other brain regions, metabotropic glutamate receptor mGluR -dependent LTP presents in the cerebellar cortex at parallel fibers to Purkinje cell synapses [ 27 ]. These enzymes in active condition further activate downstream ERK. Upon activation, ERK may phosphorylate a number of cytoplasmic and nuclear molecules that ultimately result in the protein synthesis and morphological changes necessary for formation of LTP [ 39 ]. ERK-mediated changes in transcription factor activity may trigger the synthesis of proteins that underlie the maintenance of LTP.

Considerable evidence has also shown that certain forms of LTP induction at excitatory synapses are dependent on activation of mGluRs that are widespread in different brain regions such as the neocortex, hippocampus, striatum and nucleus accumbens. Scavenging superoxide in hippocampal slices blocks high-frequency stimulation-induced LTP [ 45 ].

In addition, ROS can also induce LTP through suppression of the activity of a number of protein phosphatases, such as protein tyrosine phosphatase, protein phosphatase 2A and calcineurin [ 48 ]. As shown above, ROS under normal and controlled conditions mediate and regulate physiological functions of the body. However, ROS over-accumulation caused by losing the balance between the generation and elimination of ROS results in severe deleterious effects to the cells, organs and body, a phenomenon known as oxidative stress.

Oxidative stress can result from over generation of ROS in various conditions, such as injury, inflammation, aging, chronic diseases, etc. Alternatively, ROS accumulation and oxidative stress could be due to the diminished abilities in the elimination of ROS. Free radicals can pass freely through cell and nucleus membranes, and oxidize biomacromolecules. Lipid peroxidation caused by ROS leads to membrane leakage [ 54 ]. The oxidation of amino acid residues especially cysteine residues results in the formation of protein-protein cross-links, leading to dysfunction of these proteins.

In addition, oxidation of kinase and phosphatase dysregulates the signal pathways as well. The oxidant-damaged DNA leads to gene mutations, microsatellite instability, and effects on transcription factor binding [ 56 ]. RNA may be more vulnerable to oxidative insults than DNA given its generally single-stranded state and accessibility to the oxidant-producing mitochondria.

The most commonly quantified nucleotide adducts include 8-hydroxyguanine 8-OHG , 8-hydroxyadenine 8-OHA , 5-hydroxycytosine 5-OHC , 2,6-diaminohydroxyformamidopyrimidine fapyguanine , and 4,6-diaminoformamidopyrimidine fapyadenine [ 57 ], all of which are found in both DNA and RNA.

Excessive ROS result in a number of chronic diseases typified by neurodegenerative diseases and also mediate therapeutic side effects, such as chemotherapy-induced cognitive impairment or chemobrain. Neurodegenerative diseases are disorders in which the nervous system progressively and irreversibly deteriorates.

AD is an age-dependent, chronic neurodegenerative disease, the leading cause of dementia amongst older people and the fourth most common cause of death in the Western world [ 59 — 61 ]. Characteristic neurofibrillary tangles and neural plaques are seen post mortem. PD is another CNS neurodegenerative disease afflicting millions of the older population, with most cases occurring after the age of Early on in the course of the disease, the most obvious symptoms are movement-related, including tremor, rigidity, slowness of movement and difficulty with walking and gait.

The motor symptoms of PD result from the slow degeneration of dopamine-generating neurons in the substantia nigra of the basal ganglia, a region of the midbrain, leading to progressive loss of muscular co-ordination and balance [ 62 ].

Oxidative Medicine and Cellular Longevity

Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. HD characterized with abnormal involuntary writhing movements called chorea is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. Although physical symptoms of HD can begin at any age from infancy to old age, it usually begins between 35 and 44 years of age.

Medical imaging techniques such as computerized tomography CT and magnetic resonance imaging MRI can show atrophy of the caudate nuclei and striatal volume in the disease [ 63 , 64 ]. ALS is a fatal chronic neurodegenerative disease with a prevalence of 1—2 per , [ 65 ]. In ALS pathogenesis, it has been assumed that damage to motor neurons in the primary motor cortex, corticospinal tracts, brain stem, and spinal cord leads to the muscle weakness that typifies ALS.

In addition, phosphorylation of Tau protein results in abnormal aggregation and dysfunction of this protein in AD. All humans have two copies of the huntingtin gene htt , which codes for the protein huntingtin Htt. The mutant huntingtin protein mHtt is an aggregate-prone protein.

During the natural clearance process of cells, these proteins are retrogradely transported to the cell body for destruction by lysosomes. Under pathological conditions, these mutant proteins aggregate and damage the retrograde transport of important molecules such as BDNF by damaging molecular motors as well as microtubules [ 74 ], causing pathological changes and disease symptoms.

Prior to the destruction in ALS, motor neurons develop proteinaceous inclusions in their cell bodies and axons. These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: Protein degradation pathways play a crucial role in removing misfolded proteins and preventing protein aggregation. Accumulation of ALS-specific proteinaceous inclusions may be partly due to defects in protein degradation [ 75 ]. NFT are composed of bundles of paired helical filaments PHF , the major component of which is the microtubule-associated protein Tau. Tau hyperphosphorylation appears to be a critical event leading to abnormal aggregation and disrupted function of this protein in the affected neurons in AD.

ROS are actively involved in Tau phosphorylation. Acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of Tau at the site recognized by antibody to PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons [ 77 ]. In addition, increased activities of c-Jun N -terminal kinases JNK and p38 and decreased activity of PP2A under chronic oxidative stress condition are likely involved in tau phosphorylation as well [ 54 ] Figure 3. The causal relationship between ROS and misfolded proteins underlying neurodegenerative diseases.

ROS mediate neurotoxicity in each of these diseases through modifying the hallmark protein by oxidation. Once phosphorylated, Tau and other cytoskeletal proteins are vulnerable to modification by carbonyl products of oxidative stress [ 78 , 79 ] and consequent aggregation into fibrils [ 78 ]. Modifications of Tau by 4-hydroxynonenal HNE are found to promote and contribute to the generation of the major conformational properties defining neurofibrillary tangles [ 80 ].

Oxidative stress actively regulates protein aggregation in PD. Aggregation of mHtt plays an important role in the pathogenesis of HD.

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The mHtt can aggregate at distinctive conformations that have different neurotoxicity, and different conformations of mHtt exist in different brain regions in HD mice [ 86 ]. Oxidative modification of the aggregated mHtt facilitates an increase in the size of aggregates and changes the conformation of aggregated mHtt [ 87 ]. Oxidative stimuli have been found to enhance the polyglutamine-expanded truncated N -terminal Huntingtin aggregation and mHtt-induced cell death [ 88 ].

Oxidation of cysteines in the RNA recognition motif of TDP induces conformational changes that subsequently result in protein aggregation and loss of nucleic acid-binding activity to facilitate disease progression [ 90 , 91 ]. There is a causal relationship between ROS imbalance and misfolded proteins.

Oxidative Stress and Neurodegenerative Disorders

In contrast to the phenomena, as described above, that oxidative stress results in generation and aggregation of misfolded proteins, misfolded proteins can also lead to excessive ROS causing neurotoxicity. On the other hand, mHtt decreases the expression of the antioxidant protein Prx 1, while overexpression of wildtype Prx1 suppresses mHtt-induced toxicity [ ]. TDPexpressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis in yeast [ ].

In a motor neuron-like cell system that was stable-transfected with wild type and mutant TDP, mutant TDP induced mitochondrial dysfunction and oxidative damage that was indicated by an increase in lipid peroxidation [ ]. Under a pathological condition, such as in PD, the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress so that a decreased clearance rate results in the accumulation of alpha-synuclein [ , ]. Extracellular clearance pathways include interaction of neurons with astrocytes and microglia [ ].

Oxidative stress can result in microglial senescence in response to intracellular accumulation of iron. Although there is a great deal of scientific literature that describes the debilitating effects of ROS, oxidative stress may not readily contribute directly to cell death. For example, a downstream response of oxidative stress-caused misfolded proteins, named ER stress, has recently attracted extensive attention for its role in cell death. The ER is an organelle that crucially controls, in addition to calcium and redox homeostasis, protein synthesis, folding and trafficking.

Protein folding is fulfilled in the lumen of the ER where related proteins and enzymes are located, including immunoglobulin binding protein BiP , GRP94, protein disulfide isomerase PDI , calnexin, calreticulin, etc. Only properly folded proteins can export to the Golgi apparatus for further modification. In contrast, misfolded or incompletely folded proteins are retained in the ER, leading to a cell adaptive response, named the unfolded protein response UPR or ER stress response.

ER stress is a physiological adaption to accumulated folded protein in the ER by attenuation of protein synthesis to reduce protein load, transcriptional induction of ER chaperone genes to accelerate protein folding, and degradation of misfolded proteins by the ER-associated degradation ERAD machinery to remove these proteins [ ]. However, if ER stress is prolonged or excessive in a disturbance, such as hypoxia, glucose deprivation or oxidative stress, the cells will elicit apoptotic processes to remove over-stressed cells.

The key role of ER stress in mediation of neurodegenerative diseases has been well documented recently [ , ]. In addition to the ROS-mediated neurodegenerative diseases, ROS also mediates chemotherapy-induced neurotoxicity in both the central and peripheral nervous systems. Side effects of anticancer drugs in the CNS and PNS can sometimes be too severe to continue chemotherapy treatment for cancer patients. Chemotherapy has improved survival rates in patients with many of the common cancers.

However, one of the most common complications of chemotherapeutic drugs is toxicity to the CNS, termed chemotherapy-induced cognitive impairment, chemotherapy-induced cognitive dysfunction, post-chemotherapy cognitive impairment PCCI , chemo fog, or chemobrain. Chemobrain can be very frustrating both for those who are living with cancer, and their loved ones who are trying to support them.

Chemobrain can seriously affect quality of life and life itself in cancer patients. This toxicity can manifest itself in many ways, including encephalopathy syndromes and confusional states, seizure activity, headache, cerebrovascular complications and stroke, visual loss, cerebellar dysfunction, and spinal cord damage with myelopathy [ ].

There is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years following the completion of chemotherapy. These include attention deficits, memory loss, and confused thought processes. Longitudinal studies have shown that, in a subset of survivors, cognitive difficulties can persist for between 1 and 2 years following the completion of chemotherapy [ , ]. Cross-sectional studies have found cognitive impairments lasting between 4 and 10 years following chemotherapy [ , ].

Healthy rodents that are given chemotherapy show increase in cell death in the CNS [ ], increase in oxidative stress [ , ], increase in microglia activity [ ], suppression of hippocampal neurogenesis [ ], decreases in levels of neurotrophic factors [ ], and decreases in levels of hippocampal catecholamines [ ], as compared to baseline values. The etiology of chemotherapy-induced cognitive impairment is largely unknown, but several candidate mechanisms have been suggested, including oxidative stress, impaired blood-brain barrier BBB , neuroinflammation, and decreased neurogenesis, etc [ ].

Oxidative stress plays a key role in cognitive disorders caused by certain types of anticancer drugs, such as antimetabolites, mitotic inhibitors, topoisomerase inhibitors and microtubule stabilizers, etc. These chemotherapeutic agents are not known to rely on oxidative mechanisms for their anticancer effects. Among the antimetabolite drugs, methotrexate MTX , 5-fluorouracil 5-FU, a widely used chemotherapeutic agent , and cytosine arabinoside are most likely to cause CNS toxicity [ ].

Acute neurotoxicity manifests itself as encephalopathy cerebellar syndrome or as seizures. Acute neurotoxicity due to 5-FU is dose-related and generally self-limiting [ ]. Clinically relevant concentrations of 5-FU are toxic for both CNS progenitor cells and non-dividing oligodendrocytes in vitro and in vivo [ ].

Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology [ ]. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment [ ].

1. Introduction

Delayed neurotoxicity has been reported when fluorouracil was given in combination with levamisole; this form of subacute multifocal leukoencephalopathy is immune-mediated [ ]. Although there is no report yet of 5-FU increasing CNS oxidative stress, it has been shown to induce apoptosis in rat cardiocytes through intracellular oxidative stress [ ], to increase oxidative stress in the plasma of liver cancer patients [ ], and to decrease glutathione in bone marrow cells [ ]. Evidence for the involvement of ROS in 5-FU-induced neurotoxicity comes from our latest research, in which 5-FU elicits cell death of embryonic cerebral neurons only under the condition where antioxidants in the culture medium are reduced to a certain level Figure 4.

Another antimetabolite, MTX, can cross the blood-brain barrier as well [ ]. It causes an increase of oxidative stress in cerebral spinal fluid and results in dysfunction of the CNS in MTX-treated patients with pediatric acute lymphoblastic leukemia [ , ]. A recent observation also indicates that genetic polymorphism for methionine is a potent risk factor for MTX-induced CNS toxicity [ ].

This process did not elicit cell death by itself comparison of Non-Insult groups under higher and lower AO conditions. However, 5-FU at the same concentration resulted in severe cell death when AO concentration was reduced to The graph shows that the neurons under reduced AO condition were vulnerable to 5-FU. CIPN is one of the most common and serious side effects of chemotherapy, and it can result in dose reductions or early discontinuation of chemotherapy, which reduces the efficacy of cancer treatments.

An estimated 30 to 40 percent of cancer patients treated with chemotherapy experience CIPN [ ]. The peripheral nervous system PNS consists of sensory neurons running from stimulus receptors that inform the CNS of the stimuli, and motor neurons running from the spinal cord to the effectors that take action. In CIPN, an anticancer drug could impair both sensory and motor functions. It can include sharp, stabbing pain. CIPN can make it difficult to perform normal day-to-day tasks like buttoning a shirt, sorting coins in a purse, or walking.

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  5. In addition, the motor neuron dysfunction manifests itself as cramps, difficulty with fine motor activities e. The chemotherapeutic drugs that most commonly elicit CIPN include platinum compounds cisplatin, carboplatin, oxaliplatin , vincristine, taxanes docetaxel, paclitaxel , epothilones ixabepilone , bortezomib Velcade , thalidomide Thalomid and lenalidomide. Many other chemotherapeutic agents, such as Ixabepilone, arsenic trioxide, cytarabine, etoposide, hexamethylmelamine, Ifosfamide, methotrexate, and procarbazine can also induce CIPN.

    The underlying causes for CIPN on the cellular and tissue level are still largely a matter of speculation. Oxidative stress may play a key role in CIPN. It was found that antioxidant machinery e. Oxidative stress was found as an important mediator in a rat model of painful oxaliplatin-induced neuropathy, since the increases of carbonylated protein and thiobarbituric acid reactive substances in the plasma of oxaliplatin-treated rats were indicative of the resultant protein oxidation and lipoperoxidation, respectively.

    The same pattern of oxidation was also revealed in the sciatic nerve and the spinal cord where the damage reached the DNA level [ ]. In addition, oxidative imbalance was also indicated to mediate inflammatory pain [ ]. Oxidative stress was also found to impair the autonomic nervous system, such as hearing loss [ , ]. Since ROS mediates neurotoxicity in a number of neurodegenerative disorders, one strategy in disease control has been focused on development of antioxidants as preventive and therapeutic molecules.

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