Glutamate induces oxidative stress not mediated by glutamate receptors or cystine transporters: protective effect of melatonin and other antioxidants (original) (raw)
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Prophylactic Actions of Melatonin in Oxidative Neurotoxicity
Annals of The New York Academy of Sciences, 1997
The central nervous system frequently suffers badly from oxidative damage, and a variety of specific neurological diseases, especially in the aged, are at least in part related to the destructive effects of free radicals.' Neural tissue incurs damage more frequently than other organs because of its high susceptibility to free radical damage and oxidative attack. The reasons for this are severalfold. Firstly, the utilization of molecular oxygen (dioxygen or 02), a molecule that gives rise to many of the most damaging free radicals,2 by the brain is far greater than that for any other organ and the polyunsaturated fatty acid (PUFA) concentration of neural tissue is high? the susceptibility of PUFA to oxidative damage is well known to be high! Additionally, the brain contains elevated concentrations of iron and ascorbic acid, both of which can favor the production of free radicals. Any chemical that increases free radical generation is obviously prooxidative even when the molecule may, under other conditions, have antioxidative properties, e.g., ascorbic acid.5
Beneficial Neurobiological Effects of Melatonin Under Conditions of Increased Oxidative Stress
Current Medicinal Chemistry-Central Nervous System Agents, 2002
Aerobic organisms consistently sustain molecular abuse because of oxidative stress. Oxidative stress is a consequence of oxygen (O 2) being converted to semi-reduced toxic species including the superoxide anion radical (O 2-•), hydrogen peroxide (H 2 O 2) and the hydroxyl radical (•OH). Besides these oxygen-based reactive species, the O 2-• also rapidly combines with nitric oxide (NO•) to produce the peroxynitrite anion (ONOO-), an agent with well defined neurotoxic actions. Furthermore, ONOOis converted to peroxynitrous acid (ONOOH) which can degrade into the •OH or an agent with similar toxicity. How much of the O 2 used by aerobes is actually converted to reactive species is unknown, but the general consensus is on the order of 2-4% of the total O 2 inhaled. Once formed the toxic species may or may not be neutralized by a complex antioxidative defense system. Those that are not detoxified can mutilate essential macromolecules within brain cells, the re by diminishing the ir func tiona l e ff icienc y, or , in extr e me c a se s, killing the ce lls via eithe r nec rosis or a poptosis. Despite its importance for essential organismal functions as well as for survival, the central nervous system is unexpectedly highly susceptible to oxidative insults. One reason for this is that the brain, although constituting roughly 2% of the body weight in humans, utilizes 20% of the total O 2 inhaled. Thus, proportionally it generates a large number to toxic radicals. Other reasons for the brain's high susceptibility to free radical damage include the fact that it contains large quantities of polyunsatu rated fatty acids (PUFA) which are easily damaged (oxidized) by reactive species and, regionally at least, the nervous system contains high levels of iron and ascorbic acid both of which, under the some circumstances, can be strongly prooxidant. Thus, the brain, perhaps more than any other organ, is subjected to excessive oxidative damage over the course of a life time. This persistent bludgeoning of essential molecules in brain cells is believed to contribute to a variety of neurodegenerative diseases. This review briefly describes the role of free radicals in several models of neurodegeneration and summarizes the actions of a newly discovered antioxidant, melatonin, in reducing the damage done by toxic oxygen and nitrogen derivatives.
Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity
2002
Objectives. Stroke is a major cause of brain injury in Alaska. Since antioxidant levels are decreased in aged brain, the greater predisposition to neuronal death in stroke leading to subsequent neurodegeneration in aged individuals may be related to changes in oxidant balance. We studied the effect of the endogenous antioxidant melatonin on excitotoxic injury resulting from N-methyl-D-aspartate (NMDA)-induced damage by developing an organotypic mouse brain slice model. Our objective was to inhibit the effects of oxidative stress induced by NMDA in mouse brain slices, using melatonin. Methods. An organotypic mouse brain slice culture was established at PO 2 levels maintained between 80 -100 mm Hg. NMDA, melatonin or both were added to the slices and antioxidant function was determined using the redox active iron assay as well as 8-OHG and HO-1 immunoassays. Results. This slice system allows for better regulation of both NMDA and melatonin concentrations than can be achieved by in vivo studies. Supporting an antioxidant function, melatonin (100 µM) significantly decreased redox active iron, heme-oxygenase (HO-1) induction and 8-hydroxyguanosine (8-OHG) following NMDA (50-100 µM) insult. However, somewhat surprisingly, high concentrations of melatonin alone (1mM), increased redox active iron levels and HO-1 induction. Conclusions. These results support the hypothesis that melatonin is a neuroprotective antioxidant. Our data also suggest that 1mM melatonin may have detrimental effects. (Int J Circumpolar Health 2002; 61: 32-40)
Current Neuropharmacology, 2008
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.
Journal of Pineal Research, 2000
Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. J. Pineal Res. 2000; 2:100 -107. © Munksgaard, Copenhagen Abstract: Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical ( OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an OH scavenger, was used to detect the in vitro generation of OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.
Preventive effect of several antioxidants after oxidative stress on rat brain homogenates
General physiology and biophysics, 2000
Brain homogenate was used as a model system to study antioxidant properties of several natural and synthetic antioxidants under oxidative stress. Oxidative stress was induced by Fe/ascorbate system and lipid peroxidation as well as protein modification were studied. Thiobarbituric acid reactive substances (TBARS) were used as a marker of lipid peroxidation. The preventive effect concerning lipid peroxidation decreased in the order: buthylated hydroxytoluene (BHT) (3.5), stobadine (ST) (35), serotonin (54), trolox (98), U 74389G (160), melatonin (3100), (the numbers in the brackets represent IC50 in micromol/l). Methylprednisolone had no effect, and spin traps interfered with TBARS determination. Concerning creatine kinase (CK) activity as a selected marker of oxidative modification of proteins, the preventive effect of antioxidants (30 micromol/l) decreased in the order: BHT (30), trolox (75), stobadine (ST) (77), alpha-phenyl-N-tert-buthylnitrone (PBN) (87), sodium salt of N-tert-b...
Melatonin Reduces Oxidative Catastrophe in Neurons and Glia
2010
Melatonin, the chief secretory product of the pineal gland, is an uncommonly effective direct free radical scavenger and indirect antioxidant. It detoxifies both reactive oxygen (ROS) and reactive nitrogen species (RNS), both groups of which are abundantly produced in the brain. Endogenously-generated melatonin is discharged from pinealocytes into the rich capillary plexus in the gland and may also be released directly into the cerebrospinal fluid (CSF). In the few species where it has been investigated, CSF levels of melatonin greatly exceed its concentrations in the blood. From both the CSF and the blood melatonin readily enters the brain to protect neurons and glia from molecular damage induced by ROS/RNS. Melatonin's efficacy in reducing molecular damage resulting from toxic oxygen and nitrogen derivatives in both the brain and spinal cord supports the notion that this non-toxic molecule may have utility in forestalling and/or delaying the development and progression of neurodegenerative diseases that have a massive free radical component. The disease models of interest and in which melatonin has been most thoroughly tested include Alzheimer disease, Parkinson disease and to a lesser extent Huntington disease and amyotrophic lateral sclerosis. The experimental findings summarized herein clearly document that melatonin readily prevents oxidative damage to both neurons and glia. In doing so, it greatly reduces apoptosis of critical cells within the central nervous system.