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      Cellular and Biochemical Actions of Melatonin which Protect Against Free Radicals: Role in Neurodegenerative Disorders

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          Molecular oxygen is toxic for anaerobic organisms but it is also obvious that oxygen is poisonous to aerobic organisms as well, since oxygen plays an essential role for inducing molecular damage. Molecular oxygen is a triplet radical in its ground-stage (.O-O.) and has two unpaired electrons that can undergoes consecutive reductions of one electron and generates other more reactive forms of oxygen known as free radicals and reactive oxygen species. These reactants (including superoxide radicals, hydroxyl radicals) possess variable degrees of toxicity.

          Nitric oxide (NO•) contains one unpaired electron and is, therefore, a radical. NO• is generated in biological tissues by specific nitric oxide synthases and acts as an important biological signal. Excessive nitric oxide production, under pathological conditions, leads to detrimental effects of this molecule on tissues, which can be attributed to its diffusion-limited reaction with superoxide to form the powerful and toxic oxidant, peroxynitrite.

          Reactive oxygen and nitrogen species are molecular “renegades”; these highly unstable products tend to react rapidly with adjacent molecules, donating, abstracting, or even sharing their outer orbital electron(s). This reaction not only changes the target molecule, but often passes the unpaired electron along to the target, generating a second free radical, which can then go on to react with a new target amplifying their effects.

          This review describes the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases and the roles of melatonin as free radical scavenger and neurocytoskeletal protector.

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          Oxidants, antioxidants, and the degenerative diseases of aging.

          Metabolism, like other aspects of life, involves tradeoffs. Oxidant by-products of normal metabolism cause extensive damage to DNA, protein, and lipid. We argue that this damage (the same as that produced by radiation) is a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline, brain dysfunction, and cataracts. Antioxidant defenses against this damage include ascorbate, tocopherol, and carotenoids. Dietary fruits and vegetables are the principal source of ascorbate and carotenoids and are one source of tocopherol. Low dietary intake of fruits and vegetables doubles the risk of most types of cancer as compared to high intake and also markedly increases the risk of heart disease and cataracts. Since only 9% of Americans eat the recommended five servings of fruits and vegetables per day, the opportunity for improving health by improving diet is great.
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            Metals, toxicity and oxidative stress.

            Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link between vanadium and oxidative stress in the etiology of diabetes. The impact of zinc (Zn) on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiology of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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              Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

              Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.

                Author and article information

                Curr Neuropharmacol
                Current Neuropharmacology
                Bentham Science Publishers Ltd.
                September 2008
                : 6
                : 3
                : 203-214
                [1 ]Laboratorio de Desarrollo-Envejecimiento, Enfermedades Neurodegenerativas, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, IMSS, Sierra Mojada 800 C.P. 44340 Guadalajara, Jalisco, México
                [2 ]Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría, SSA. México, D.F.
                [3 ]Departamento de Química, Centro Universitario de Ciencias Exactas e Ingenierías (CUCEI), Universidad de Guadalajara, Guadalajara, Jalisco. México
                Author notes
                [* ]Address correspondence to this author at Laboratorio de Desarrollo-Envejecimiento, Enfermedades Neurodegenerativas, División de Neurociencias, CIBO-IMSS, Sierra Mojada 800 CP 44340. Guadalajara, Jalisco, México; Tel: (0133) 36-17-00-60 ext. 31951; Fax: (0133) 36175099; E-mail: genarogabriel@ 123456yahoo.com
                ©2008 Bentham Science Publishers Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.



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