6-Hydroxymelatonin protects against quinolinic-acid-induced oxidative neurotoxicity in the rat hippocampus (original) (raw)
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6-Hydroxymelatonin protects against cyanide induced oxidative stress in rat brain homogenates
Journal of Chemical Neuroanatomy, 2003
Both 6-hydroxymelatonin and N-acetyl-N-formyl-5-methoxykynurenamine are photodegradants and enzymatic metabolites of melatonin and are known to retain equipotent activity against potassium cyanide-induced superoxide generation compared to melatonin. It is not clear whether one or both of these metabolites is responsible for this effect. The present study therefore investigates the possible manner in which 6hydroxymelatonin protects against oxidative stress induced by cyanide in rat brain homogenates. We examined the ability of 6-hydroxymelatonin to scavenge KCN-induced superoxide anion generation as well as lipid peroxidation. In addition, we also examined the effect of this indole on lactate dehydrogenase activity (LDH) as well as mitochondrial electron transport using dichlorophenol-indophenol as an electron acceptor. The results of this study show that 6-hydroxymelatonin significantly reduces KCN-induced superoxide anion generation, which is accompanied by a commensurate reduction in lipid peroxidation. Partial reversal of the KCN-induced reduction in mitochondrial electron transport is accompanied by a similar reversal of mitochondrial LDH activity blunted by KCN. It can thus be proposed that 6-hydroxymelatonin is potentially neuroprotective against KCN-induced neurotoxicity.
Melatonin reduces oxidative neurotoxicity due to quinolinic acid
Neuropharmacology, 2000
The in vivo and in vitro effects of melatonin on quinolinic acid-induced oxidative damage in rat brain were determined. The concentrations of malonaldehyde and 4-hydroxyalkenals were assayed as an index of oxidatively damaged lipid. In in vitro experiments, the increase in malonaldehyde and 4-hydroxyalkenals concentrations induced by quinolinic acid were concentration-dependent and time-dependent. The accumulation of products of lipid peroxidation induced by quinolinic acid were very significantly reduced by melatonin in a concentration-dependent manner. Additionally, at the highest concentrations of melatonin used in quinolinic acid treated homogenates, it reduced the levels of oxidatively damaged lipid products below those measured in control homogenates (no quinolinic acid or melatonin). When quinolinic acid (200 mg/kg) was intraperitonally injected into 11-day-old rats, lipid peroxidation in the brain was significantly increased 24 hours later compared to levels in control rats. When melatonin (10 mg/kg) was injected ip 30 min before and 4 and 20 hours after the administration of quinolinic acid, the increased lipid peroxidation induced by quinolinic acid was significantly reduced. Likewise, neurobehavioral signs associated with quinolinate administration were attenuated by melatonin. These results show that both in vitro and in vivo pharmacological levels of melatonin confer protection against quinolinic acid-induced oxidative toxicity in the brain. The findings also indicate that melatonin may be pharmacologically useful in combatting quinolinic neurotoxicity which is associated with several acute and chronic neurodegenerative neurological diseases.
Melatonin reduces oxidative neurotoxicity due to quinolinic acid:: in vitro and in vivo findings
2000
The in vivo and in vitro effects of melatonin on quinolinic acid-induced oxidative damage in rat brain were determined. The concentrations of malonaldehyde and 4-hydroxyalkenals were assayed as an index of oxidatively damaged lipid. In in vitro experiments, the increase in malonaldehyde and 4-hydroxyalkenals concentrations induced by quinolinic acid were concentration-dependent and time-dependent. The accumulation of products of lipid peroxidation induced by quinolinic acid were very significantly reduced by melatonin in a concentration-dependent manner. Additionally, at the highest concentrations of melatonin used in quinolinic acid treated homogenates, it reduced the levels of oxidatively damaged lipid products below those measured in control homogenates (no quinolinic acid or melatonin). When quinolinic acid (200 mg/kg) was intraperitonally injected into 11-day-old rats, lipid peroxidation in the brain was significantly increased 24 hours later compared to levels in control rats. When melatonin (10 mg/kg) was injected ip 30 min before and 4 and 20 hours after the administration of quinolinic acid, the increased lipid peroxidation induced by quinolinic acid was significantly reduced. Likewise, neurobehavioral signs associated with quinolinate administration were attenuated by melatonin. These results show that both in vitro and in vivo pharmacological levels of melatonin confer protection against quinolinic acid-induced oxidative toxicity in the brain. The findings also indicate that melatonin may be pharmacologically useful in combatting quinolinic neurotoxicity which is associated with several acute and chronic neurodegenerative neurological diseases.
Melatonin neutralizes neurotoxicity induced by quinolinic acid in brain tissue culture
Journal of Pineal Research, 2005
Abstract: Quinolinic acid is a well-known excitotoxin that induces oxidative stress and damage. In the present study, oxidative damage to biomolecules was followed by measuring lipid peroxidation and protein carbonyl formation in rat brain tissue culture over a period of 24 hr of exposure to this prooxidant agent at a concentration of 0.5 mm. Quinolinic acid enhanced lipid peroxidation in an early stage of tissue culture, and protein carbonyl at a later stage. These data confirm and extend previous studies demonstrating that quinolinic acid can induce significant oxidative damage. Melatonin, an antioxidant and neuroprotective agent with multiple actions as a radical scavenger and signaling molecule, completely prevented these prooxidant actions of quinolinic acid at a concentration of 1 mm. Morphological lesions and neurotoxicity induced by quinolinic acid were evaluated by light microscopy. Quinolinic acid produced extensive apoptosis/necrosis which was significantly attenuated by melatonin. Cotreatment with melatonin exerted a profound protective effect antagonizing the neurotoxicity induced by quinolinic acid. Glutathione reductase and catalase activities were increased by quinolinic acid and these effects were antagonized by melatonin. Furthermore, melatonin induced superoxide dismutase activity. Quinolinic acid and melatonin acted independently and by different mechanisms in modulating antioxidant enzyme activities. Our findings using quinolinic acid and melatonin clearly demonstrate that such changes should always be seen in the context of oxidative neurotoxicity and antioxidant neuroprotection.
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.
Neurotoxins: Free Radical Mechanisms and Melatonin Protection
Current Neuropharmacology, 2010
Toxins that pass through the blood-brain barrier put neurons and glia in peril. The damage inflicted is usually a consequence of the ability of these toxic agents to induce free radical generation within cells but especially at the level of the mitochondria. The elevated production of oxygen and nitrogen-based radicals and related non-radical products leads to the oxidation of essential macromolecules including lipids, proteins and DNA. The resultant damage is referred to as oxidative and nitrosative stress and, when the molecular destruction is sufficiently severe, it causes apoptosis or necrosis of neurons and glia. Loss of brain cells compromises the functions of the central nervous system expressed as motor, sensory and cognitive deficits and psychological alterations. In this survey we summarize the publications related to the following neurotoxins and the protective actions of melatonin: aminolevulinic acid, cyanide, domoic acid, kainic acid, metals, methamphetamine, polychlorinated biphenyls, rotenone, toluene and 6-hydroxydopamine. Given the potent direct free radical scavenging activities of melatonin and its metabolites, their ability to indirectly stimulate antioxidative enzymes and their efficacy in reducing electron leakage from mitochondria, it would be expected that these molecules would protect the brain from oxidative and nitrosative molecular mutilation. The studies summarized in this review indicate that this is indeed the case, an action that is obviously assisted by the fact that melatonin readily crosses the blood brain barrier.
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.
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