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Antioxidants and treatment of diseases

What are antioxidants?

An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves.

As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect any benefit for the formulations tested, and excess supplementation may be harmful. In addition to these uses in medicine, antioxidants have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline.

Organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).

The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,while damage to proteins causes enzyme inhibition, denaturation and protein degradation.

Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. These compounds may be synthesized in the body or obtained from the diet.The different antioxidants are present at a wide range of concentrations in body fluids and tissues, with some such as glutathione or ubiquinone mostly present within cells, while others such as uric acid are more evenly distributed.

Ascorbic acid

Ascorbic acid or “vitamin C” is a monosaccharide antioxidant found in both animals and plants. As it cannot be synthesised in humans and must be obtained from the diet, it is a vitamin. Most other animals are able to produce this compound in their bodies and do not require it in their diets. In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins. Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide. In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the antioxidant enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants.

Glutathione

Glutathione is a cysteine-containing peptide found in most forms of aerobic life.It is not required in the diet and is instead synthesized in cells from its constituent amino acids. Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants. Due to its high concentration and its central role in maintaining the cell’s redox state, glutathione is one of the most important cellular antioxidants.

Melatonin

Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.

Pro-oxidant activities

Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide, however, it will also reduce metal ions that generate free radicals through the Fenton reaction.

2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate
2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH−

The relative importance of the antioxidant and prooxidant activities of antioxidants are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.However, less data is available for other dietary antioxidants, such as vitamin E.

Health effects

The brain is uniquely vulnerable to oxidative injury, due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation. Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Here, superoxide dismutase mimetics,sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury,while the experimental drug NXY-059 and ebselen are being applied in the treatment of stroke. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis,and as a way to prevent noise-induced hearing loss.

Therapeutic Antioxidants

The use of naturally occutring antioxidants (with or without structural modifications) or completely synthetic molecules. Any antioxidant proposed for therapeutic use must be non-toxic. A 1st step in evaluating putative therapeutic antioxidants is to establish what they are capable of doing.

Superoxide Dismutases and Catalases
Antioxidant enzymerapeues available for therapeutic use include Human SODs (CuZnSOD,MnSOD and EC-SOD). But if SODs are injected into animals they have short plasma half-lives. To avoid this problem a variety of longer–lived SOD conjugatesclu are available,including PEG-SOD,Ficoll-SOD,lecitinized-SOD,poluamine-canjugated SOD,cationized-SOD,genetically engeenered SOD polymers an albumin SOD complexes.

Some animal studies show that intravenous administration of PEG-SOD and PEG-catalase decrases ischemia reperfusion injury to the CNS. Dismutases with heparin binding domains can bind to endothelial cells. Galarosylated or PEG modified catalase decreased metastasis in mice. Administration of recombinant human CuZnSOD to premature babies decreased inflammation in later life.

Viral Vectors
An alternative approach is to deliver not the antioxidant enzymes but the genes encoding them using viral vectors. In one study genes encoding MnSOD or CuZnSOD attached to an adenoviral vector were injected into rats 3 days before bile duct ligation.The activity of both enzymes icreased in the liver but the MnSOD gene offered more protection againist liver damage than that encoding CuZnSOD.

SOD/CATALASE mimetics

Several low-molecular-mass compounds that react with rO2 and H2O2 have been described. Most contain transition ions.Examples include a complex of Manganase ions with desferrioxamine and Cu ions chelated to amino acids or to anti-inflammatory drugs. SOD mimetics have been shown to protect againist oxidative damage in a wide range of cell and animal model systems (table 10.12) and EUK-8 increased the lifespan of C.elegans in some studies.

SPIN TRAPS/NITROXIDES

Spin traps are used to detect free radicals in vivo and in vitro.If spin trap intercepts a biologically damaging radical in vivo then it ought to protect againist injury. The idea of using spin traps as therapeutic antioxidants arose from studies showing that alpha phenyl-tert-butylnitrone(PBN) could protect rats againist death from shock induced by gut ischemia-reperfusion or endotoxin injection. Later study demonstrated that PBN can protect againist myocardial ischemia-reoxygenation injury and heart transplant rejection in animals.

Several derivatives of PBN have been developed as potential therapeutic agents such as CPI-1429. A promising one is NXY-059 also called Cerovive.It has been shown to improve outcome in a primate stroke model even when therapy was begun as late as 4 h after ischemia and is under test in humans.

The PBN molecule is a nitrone and reacts with radicals to give a nitroxide.Indeed some nitroxides have been proposed as antioxidants such as OXANO and TEMPO.They reacts with rO2. N-t-butyl hydroxylamine formed during the spontaneous decomposition of PBN is a better antioxidant than PBN itself. Nitroxides have radioprotective effects and can decrease tissue damage in some animl models of shock,ischemia-reperfusion and inflammation.

Vitamin C& E and their derivatives

Several strutural analogues of alpha tocopherol some with improved antioxidant activity have been described. One is BO-653 which has shown antiatherosclerotic effects in animal and unlike probucol does not lower HDL levels. A water soluble analogue of alpha tocopherol ,Trolox C is widely used in vitro as an antioxidant. Glitazone is an antidiabetic agent with antioxidant properties is being used on patients.

Raxofelast has been reported to improve vascular endothelial dysfunction in diabetes.It is hydrolysed to the antioxidant IRF1005 in vivo.Vitamin E succinate has been claimed to have anticancer properties. Various esters of ascorbic acid,for example ascorbyl palmitate and 2-octadecylascorbate have been synthesized as lipophilic versions as ascorbate. They have been used as food preservativesand tested as antioxidants in some animal models. EPC-K1 is a combined phosphate ester of vitamins E and c that has been reported as protective in a rat stroke model.

Other chain-breaking antioxidants

Coenzyme Q has an antiatherosclerotic effects in some animals and limited beneficial effects in human neurodegenerative diseases. The modified CoQ Idebenone has also been used with positive effects.By contrast the phenolic compound OPC-14117 show some beneficial effects in animal models of neurodegenerative diseases. BN82451 increased survival in a transgenic mouse model of Huntingtons disease.

The Lazaroids

The original aim to develop lazaroids as neuroprotective agents was to add antioxidant activity to a steroid nucleus since high doses of methylprednisalone had been claimed as effective in diminishing brain lipid peroxidation after trauma and improving clinical outcome.

The lazaroids inhibit iron-dependent lipid peroxidation in brain homogenates in vitro and exerted neuroprotective effects in various of animal models traumatic injury to the CNS. The most studied was U-74006F (Freedox), sometimes called tirilazad mesylate which underwent several cinical trials for the treatment of stroke and traumatic injury to the nervous system.

Tirilazad seems to accumulate in the BBB,perhaps protecting the microvascular endothelium. An allternative is the pyrrolopyrimidines,antioxidants which appear to enter the brain more readily.Another drug being tested on stroke patients is edaravone. Edaravone has also been suggested to be beneficial in animal models of cardiac and joint inflammation.

Thiol Compounds

Thiols scavenge numerous RS but can also be cytotoxic at least in part by generating oxygen and sulphur radicals. Cysteine oxidizes much faster than either GSH or N-acetylamine and is correspondingly more cytotoxic. Penicillamine and bucillamine may exert side effects in rhematoid arthritis patients by forming sulphur radicals that bind to proteins and create new antigens.

Glutathione

GSH is often suggested as potentially therapeutically ueful. Areas of interest include tthe preservation of organs for transplantation. GSH is added to UW solutions and protection againist tissue damage by cytotoxic drugs such as cyclophohphamide. Glutathione is not easily taken up by cells.However methyl,isopropyl and ethyl monoesters can cross membranes and be hydrolized to GSH with in the cell.

N-acetylcysteine

N-acetylcysteine is used as an antioxidant in many laboratory experiments and is efefctive in treating paracetamol overdosage.It can protect by entering cells and being hydrolized to cysteine,as a prcursor of GSH. It has been widely used in humans for treatment of respiratory disorders in babies and ARDS and in HIV. More positive effects have been obtained in its use to prevent cardiovascular problems in patients with kidney failure. N acetylcysteine amide(AD4) has been reported to crooss the BBB and showedprotective effects againist MOG-induced auimmune encephalomyelitis.

Other Thiols

Mercaptoethylguanine is a powerful scavenger and inhibits iNOS. It has beneficial effects on inflammation in animal models. Lipoic acid can act as an antioxidant in vitro and has been used in diabetes.In rats it prevented falls in GSH level with age.

Many thiols have been tested for their ability to protect cells from ionizing radiation.They include GSH,cysteine, dimercaprol, cysteamine and mesna. MPG decreases ROS production and protects againist ischemia-reperfusion injury in animal models of myocardial stunning and infarction.

The results of recent study showed an evident tendency to a decrease in chemically-induced cough after exposure to hyperoxia, although this effect was somewhat less than that shown in previous reports. Therefore, the intensity of hyperoxia-induced airway inflammation was strong enough to affect nerve endings in the airways responsible for mediation and modulation of cough.. Studies related to the interactions “hyperoxia – cough reflex” and “antioxidants – hyperoxia – cough reflex” are limited.

Morphological changes accompanying hyperoxia, manifesting in airway and lung damage, can contribute to decreased cough. ROS overproduction is liable to be involved in cough attenuation by hyperoxia. At the present state of knowledge, however, it is unknown what level of ROS or any other components of oxidative stress attenuates the intensity of cough. That oxidative stress is at play in the hyperoxia-induced cough attenuation may be inferred from the reversal of this effect on the background of antioxidant vitamin supplementation observed in the present study.

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