Biomedical subjects

L C Manchester

Publications and source records attributed to L C Manchester.

41 records · Page 3Linked to original sources

PubMed1993

Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis.

Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.

Aging↗

PubMed1993

In vivo and in vitro effects of the pineal gland and melatonin on [Ca(2+) + Mg2+]-dependent ATPase in cardiac sarcolemma.

The possible diurnal variation in cardiac [Ca(2+) + Mg2+]-dependent ATPase (Ca2+ pump) activity and the influence of pinealectomy and melatonin on this enzyme in rat heart have been studied. Lowest levels of cardiac sarcolemmal membrane [Ca(2+) + Mg2+]-dependent ATPase activity were measured in late afternoon in rats kept under a 14:10 light:dark cycle. Late in the dark phase the enzyme activity began to increase with the rise continuing until 0900, 3 hr after light onset. These time-dependent changes in [Ca(2+) + Mg2+]-dependent ATPase activity did not occur in either pinealectomized or light-exposed rats suggesting that melatonin, secreted from the pineal gland during the night, induces the change in [Ca(2+) + Mg2+]-dependent ATPase activity, In vitro studies in which cardiac tissue was incubated in the presence of melatonin over a wide range of doses showed that this indole stimulated the Ca2+ pump. The half-maximal effect of melatonin was observed at a melatonin concentration of 28 ng/ml. These findings suggest that the daily change in [Ca(2+) + Mg2+]-dependent ATPase activity in the sarcolemma of heart tissue is a result of the circadian rhythm in pineal melatonin production and secretion. These findings may be applicable to normal cardiac physiology.

Animals↗

PubMedDate not supplied

Cyclic 3-hydroxymelatonin: a melatonin metabolite generated as a result of hydroxyl radical scavenging.

The pineal secretory product, melatonin, is a potent, endogenous hydroxyl radical (HO.) scavenger. When melatonin was incubated in different in vitro cell-free HO.-generating systems, a novel melatonin adduct was formed. The molecular weight of this new compound is 248. Its structure was found to be cyclic 3-hydroxymelatonin (3-OHM). A proposed reaction pathway suggests that 3-OHM is the footprint product of the interaction between melatonin with HO. 3-OHM was also detected in the urine of both rats and humans. This urinary metabolite is identical to the compound generated in the in vitro chemical reaction between HO. and melatonin. This provides direct evidence that melatonin, under physiological conditions, functions as an antioxidant to detoxify the most reactive and cytotoxic endogenous HO. When exogenous melatonin was administered to young rats, urinary 3-OHM levels increased significantly in the treated rats compared to those in controls. This indicates that even in young animals there is insufficient endogenously produced melatonin to detoxify the basal levels of the toxic HO. The accumulated damage induced by the escaped HO. that results when the HO. avoids detoxification over the course of a life time may directly or indirectly accelerate aging and aging-related diseases.

Aging↗

PubMedDate not supplied

Significance of melatonin in antioxidative defense system: reactions and products.

Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(.)), nitric oxide (NO(.)), peroxynitrite anion (ONOO(-)), hypochlorous acid (HOCl), singlet oxygen ((1)O(2)), superoxide anion (O(2)(-).) and peroxyl radical (LOO(.)), although the validity of its ability to scavenge O(2)(-). and LOO(.) is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO. Also, its secondary and tertiary metabolites, for example, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.

Animals↗

PubMedDate not supplied

Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo.

This brief resume summarizes the evidence which shows that melatonin is a significant free radical scavenger and antioxidant at both physiological and pharmacological concentrations in vivo. Surgical removal of the pineal gland, a procedure which lowers endogenous melatonin levels in the blood, exaggerates molecular damage due to free radicals during an oxidative challenge. Likewise, providing supplemental melatonin during periods of massive free radical production greatly lowers the resulting tissue damage and dysfunction. In the current review, these findings are considered in terms of neurodegenerative diseases, cancer, ischemia/reperfusion injury and aging. Besides being a highly effective direct free radical scavenger and indirect antioxidant, melatonin has several features that make it of clinical interest. Thus, melatonin is readily absorbed when it is administered via any route, it crosses all morphophysiological barriers, e.g., blood-brain barrier and placenta, with ease, it seems to enter all parts of every cell where it prevents oxidative damage, it preserves mitochondrial function, and it has low toxicity. While blood melatonin levels are normally low, tissue levels of the indoleamine can be considerably higher and at some sites, e.g., in bone marrow cells and bile, melatonin concentrations exceed those in the blood by several orders of magnitude. What constitutes a physiological level of melatonin must be redefined in terms of the bodily fluid, tissue and subcellular compartment being examined.

Aging↗