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Biomedical subjects

R J Reiter

Publications and source records attributed to R J Reiter.

At least 127 records · Page 7Linked to original sources
PubMed1998

Oxidative damage in the central nervous system: protection by melatonin.

Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.

Animals↗
PubMed1998

Melatonin protects against lipid peroxidation induced by delta-aminolevulinic acid in rat cerebellum, cortex and hippocampus.

The in vitro and in vivo effect of melatonin on delta-aminolevulinic acid-induced lipid peroxidation in rat cerebellum, cortex and hippocampus was determined. The concentration of malonaldehyde and 4-hydroxyalkenals was assayed as an index of induced membrane oxidative damage. The rise in malonaldehyde+4-hydroxyalkenals concentrations induced by delta-aminolevulinic acid in cerebellar homogenates was concentration-dependent (P < 0.001) and also time-dependent in cerebellar, cortical and hippocampal homogenates (P < 0.01). In vitro melatonin and vitamin E protected, in a concentration-dependent manner, against delta-aminolevulinic acid-induced lipid peroxidation in cortical, cerebellar and hippocampal homogenates. In in vivo experiments it was demonstrated that delta-aminolevulinic acid-induced lipid peroxidation (40 mg/kg) in cerebellum and hippocampus was reduced by acute melatonin (10 mg/kg) treatment (P < 0.05). The results show that both in vitro and in vivo melatonin confers protection against delta-aminolevulinic acid-induced oxidative toxicity in brain regions. The findings suggest that melatonin may be useful in reducing neural damage in individuals suffering from acute intermittent porphyria.

Aminolevulinic Acid↗
PubMed1998

Cytoprotective properties of melatonin: presumed association with oxidative damage and aging.

For years melatonin, a molecule widely produced in both the plant and animal kingdom, was thought to function exclusively as a synchronizer of seasonal reproduction, adjuster of the biological clock, sleep-inducing agent, and immune system stimulator. More recently melatonin has also been found to be a free-radical scavenger and antioxidant. Although pharmacologic levels (higher than those normally present endogenously) of melatonin possess substantial protective activity against molecular damage inflicted by free radicals, its role as a physiologic antioxidant is currently under active investigation. Toxic free radicals have been implicated in a variety of age-associated degenerative diseases, as well as in aging itself. Because melatonin production falls substantially during aging, the loss of this antioxidant is theorized to be instrumental in the degenerative processes associated with advanced age. The exogenous administration of melatonin has been found to be effective in reducing macromolecular damage that is normally seen in experimental models of age-related disease. How effective melatonin will be in terms of deferring aging, however, must await the outcome on subsequent studies.

Aging↗
PubMed1998

Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain and liver of kainic acid-treated rats.

In the present study, the effect of melatonin on oxidative DNA damage induced by kainic acid (KA) treatment was investigated. 8-hydroxy-deoxyguanosine (8-OH-dG) is a main product of oxidatively damaged DNA and was used as the endpoint in these studies. The levels of 8-OH-dG were found to be elevated in the hippocampus and frontal cortex of rats treated with KA. These elevated levels were significantly reduced in animals that were co-treated with melatonin. Thus, there was no difference in 8-OH-dG levels in the brain of control rats compared to those treated with KA (10 mg/kg) plus melatonin (10 mg/kg). The levels of 8-OH-dG also increased in the liver of rats treated with KA. This rise in oxidatively damaged DNA was also prevented by melatonin administration. Melatonin's ability to reduce KA-induced increases in neural and hepatic 8-OH-dG levels presumably relates to its direct free radical scavenging ability and possibly to other antioxidative actions of melatonin.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

Physiological concentrations of melatonin inhibit the norepinephrine-induced activation of prostaglandin E2 and cyclic AMP production in rat hypothalamus: a mechanism involving inhibiton of nitric oxide synthase.

In this paper, we summarize the results of in vitro studies showing that physiological concentrations of melatonin inhibit the norepinephrine-induced activation of prostaglandin E2 (PGE2) and cyclic AMP production in rat medial basal hypothalamus (MBH). Interestingly, a concentration of melatonin as low as 1 nM, which is roughly equivalent to the nocturnal serum physiological concentration of the hormone in the rat, significantly inhibit PGE2 and cyclic AMP production in the MBH. The suppressive effect of melatonin may be mediated by an inhibition of nitric oxide synthase (NOS) activity, since the stimulatory effect of sodium nitroprusside (SNP), a spontaneous generator of NO, was not prevented by melatonin. Melatonin also inhibited NOS activity in rat MBH in a dose-dependent manner. The results suggest the existence of a new or an ancillary means by which melatonin may regulate the physiology of the hypothalamus-pituitary unit.

Animals↗
PubMed1998

Delta-aminolevulinic acid-induced lipid peroxidation in rat kidney and liver is attenuated by melatonin: an in vitro and in vivo study.

Acute intermittent porphyria (AIP) is a genetically inherited disease characterized by a partial block in liver heme biosynthesis and by increased urinary excretion of the delta-aminolevulinic acid (ALA). Recently, it has been proposed that the toxic effects of ALA are related to the generation of free radicals. In the present study the in vitro and in vivo effect of melatonin, a recently described antioxidative agent, on ALA-induced lipid peroxidation in rat liver and kidney was determined. The concentration of malonaldehyde (MDA) and 4-hydroxyalkenals (4-HDA) was assayed as an index of induced membrane oxidative damage. In vitro melatonin protected, in a concentration-dependent manner, against ALA-induced lipid peroxidation in liver and kidney homogenates. In in vivo experiments as well, it was demonstrated that ALA (40 mg/kg)-induced lipid peroxidation in liver and kidney was reduced by acute melatonin (10 mg/kg) treatment. The results support the involvement of free radicals in ALA toxicity and show that in vitro and in vivo melatonin confers protection against this toxicity, likely due to the antioxidative capability of the indole.

Aldehydes↗
PubMed1998

Pineal opioid receptors and analgesic action of melatonin.

Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In most species, including the humans, the circulating levels of melatonin, a substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at night, pinealectomy abolishes the analgesic effects of melatonin, and mu opioid receptor antagonists disrupt the day-night rhythm of nociception. It is believed that melatonin, with its sedative and analgesic effects, is capable of providing a pain free sleep so that the body may recuperate and restore itself to function again at its peak capacity. Moreover, in conditions when pain is associated with extensive tissue injury, melatonin's ability to scavenge free radicals and abort oxidative stress is yet another beneficial effect to be realized. Since melatonin may behave as a mixed opioid receptor agonist-antagonist, it is doubtful that a physician simply could potentiate the analgesic efficacy of narcotics such as morphine by coadministering melatonin. Therefore, future research may synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.

Analgesia↗
PubMed1998

The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates.

Free radical-induced oxidation can cause severe cell damage in biological systems. Melatonin, a pineal secretory product, is a recently identified antioxidant that protects cells from the damaging effects of free radicals. We compared the effect of melatonin and vitamin E, another antioxidant, against lipid peroxidation (LPO) in rat retinal homogenates. The aim was to characterize the antioxidative efficacy of melatonin in retina, a tissue highly susceptible to oxidative damage. The LPO product, malondialdehyde (MDA), was determined to provide an index of cell damage in vitro. After the incubation with iron(II) ions, the free radical scavenging effectiveness of four different concentrations (i.e., 0.5, 1.0, 2.0, and 4.0 mM) of vitamin E and melatonin were determined by comparing the final levels of MDA. Lipid peroxidation product levels were significantly reduced in a dose-response manner by all concentrations of vitamin E. Melatonin, in concentrations of either 2.0 or 4.0 mM, also significantly reduced LPO. Statistical analysis of the data showed that vitamin E treatment always yielded a lower level of LPO products than did the same concentration of melatonin. The concentrations of each agent required to inhibit 50% of the lipid damage (IC50) were 0.69 mM and 4.98 mM for vitamin E and melatonin, respectively. Both vitamin E and melatonin protect the retina against LPO in a dose-dependent manner. Although the IC50 value for melatonin is about 7.2 times higher than that of vitamin E, melatonin's pharmacological and physiological role in the treatment and/or prevention of certain retinal diseases in vivo should be further investigated.

Animals↗
PubMed1998

Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: prevention by melatonin.

Cardiac arrhythmias during ischemia/reperfusion are believed to be related to free radicals generated in the heart especially during the period of reperfusion. Since melatonin functions as a free radical scavenger and antioxidant, the ability of this molecule to influence cardiac arrhythmias was investigated. The pineal secretory product, melatonin, reduced the incidence and severity of arrhythmias induced by ischemia/reperfusion due to ligation of the anterior descending coronary artery in the isolated rat heart. Melatonin was either infused during both the ischemia and reperfusion periods or only late in the ischemia period and throughout reperfusion. The percentage of hearts that developed cardiac arrhythmias during reperfusion as indicated by the incidence of premature ventricular contraction (PVC) and ventricular fibrillation (VF) were recorded. Melatonin either infused during both the ischemia and reperfusion periods or during essentially the period of reperfusion greatly reduced PVC and VF due to occlusion and reopening the anterior descending coronary artery. Presumably melatonin's beneficial effect in reducing cardiac arrhythmias was due in part to its free radical scavenging activity, which is greatly assisted by the rapidity with which it is taken up into cells. Previous studies have shown that vitamin C is effective in reducing the severity of cardiac arrhythmias induced by ischemia/reperfusion; thus, we also compared the efficacy of melatonin with this well-known antioxidant. Melatonin was more potent than vitamin C in protecting against arrhythmias induced by ischemia/reperfusion. Besides melatonin's function as a broad spectrum free radical scavenger, melatonin may have also reduced cardiac arrhythmias due to its regulation of intracellular calcium levels, i.e., by preventing calcium overloading, or due to its ability to suppress sympathetic nerve function and reduce adrenergic receptor function in the myocardium. Additional studies into the mechanisms of melatonin's action in reducing cardiac arrhythmias due to ischemia/reperfusion or other causes are warranted because of the possible application of this information to humans with heart disease.

Animals↗
PubMed1998

Pharmacological analysis of sterol delta8-delta7 isomerase proteins with [3H]ifenprodil.

Sterol Delta8-Delta7 isomerases (SIs) catalyze the shift of the double bond from C8-9 to C7-8 in the B-ring of sterols. Surprisingly, the isoenzymes in fungi (ERG2p) and vertebrates [emopamil binding protein (EBP)] are structurally completely unrelated, whereas the sigma1 receptor, a mammalian protein of unknown function, bears significant similarity with the yeast ERG2p. Here, we compare the drug binding properties of SIs and related proteins with [3H]ifenprodil as a common high affinity radioligand (Kd = 1.4-19 nM), demonstrating an intimate pharmacological relationship among ERG2p, sigma1 receptor, and EBP. This renders SIs a remarkable example for structurally diverse enzymes with similar pharmacological profiles and the propensity to bind drugs from different chemical groups with high affinity. We identified a variety of experimental drugs with nanomolar affinity for the human EBP (Ki = 0.5-14 nM) such as MDL28815, AY9944, triparanol, and U18666A. These compounds, as well as the fungicide tridemorph and the clinically used drugs tamoxifen, clomiphene, amiodarone, and opipramol, inhibit the in vitro activity of the recombinant human EBP (IC50 = 0.015-54 microM). The high affinity of the human EBP for 3H-tamoxifen (Kd = 3 +/- 2 nM) implies that the EBP carries the previously described microsomal antiestrogen binding site. Interactions of the EBP with structurally diverse lipophilic amines suggest that novel compounds of related structure should be counterscreened for inhibition of the enzyme to avoid interference with sterol Delta8-Delta7 isomerization.

Adrenergic alpha-Antagonists↗
PubMed1998

Melatonin's role as an anticonvulsant and neuronal protector: experimental and clinical evidence.

The pineal gland classically has been considered as a vestigial and mystic organ. In the last decades, and with the incorporation of new methodologic procedures, it could be proved that it also has physiologic actions that vary depending on the level of the phylogenetic scale. Its best-known secretion, melatonin, has been related to many different actions, such as sleep promotion, control of biologic rhythms, hormonal inhibition, and an inhibiting action on central nervous system regulation mechanisms. In animal experimentation, there are papers even accepting an anticonvulsant effect. In humans, evidence is reduced to few experiences. In addition to this clinical experience, there is other evidence that clearly relates melatonin to convulsive phenomena. This relationship must be mediated by the following mechanisms attributed to melatonin: altered brain GABAergic neurotransmission, its known interaction with benzodiazepinic brain receptors, through tryptophan metabolite activity (kynurenine, kynurenic acid), or even by its efficacy as a free-radical scavenger.

Animals↗
PubMed1998

Melatonin, active oxygen species and neurological damage.

Recently described actions of melatonin and other antioxidants are currently of great interest in the clinical arena. The overall phenomenon by which oxygen destroys molecular integrity is referred to as oxidative stress, and the damage inflicted has been linked to a variety of diseases and to aging. In addition to its direct free radical-detoxifying activity, melatonin also functions as an indirect antioxidant by changing the activity of enzymes that metabolize active oxygen species to inactive products. Besides inhibiting the prooxidative enzyme NOS, melatonin-at least when given at pharmacological levels-stimulates the activity of several antioxidative enzymes. Melatonin was also recently shown to prevent membrane fluidity changes associated with lipid peroxidation. Melatonin has been shown to protect against a large number of models of neurodegeneration in animals that involve free radical damage; however, clinical studies using this molecule have yet to be performed. Considering the apparent virtual absence of either acute or chronic toxicity of melatonin, its use in humans to avert free radical damage should be considered.

Journal Article↗
PubMed1998

Melatonin and human reproduction.

In photoperiodic nonhuman mammals the secretion of melatonin from the pineal gland plays a major role in regulating reproductive physiology; in humans these relationships are less clear. The melatonin rhythm changes throughout life with the first substantial change in nocturnal melatonin secretion being reportedly associated with puberty. The transition from Tanner stage 1 to Tanner stage 5 of sexual maturation is associated with a significant reduction in nocturnal melatonin levels, but a cause-effect relationship has not been established. Menstrual cyclicity has been reported to be associated with fluctuations in melatonin production but whether they are related to, eg ovulation or menstruation is not established. At high latitudes the quantity of melatonin produced by the pineal gland varies with season (changes in the light-dark cycle), and there is some evidence that this changes reproductive efficiency accordingly. Menopause is associated with a reduction in melatonin which may relate to the changing gonadotropin levels. In males of the same age melatonin levels also drop with no significant alteration in reproductive physiology. While correlations between melatonin and the status of the reproductive system in humans have been noted, whether they are functionally related remains to be determined.

Adult↗
PubMed1998

Suppression of oxygen toxicity by melatonin.

Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. While most studies to date have used pharmacological quantities of melatonin to limit oxidative damage, physiologic concentrations of the indole which are present in aerobic organisms have also been shown to resist molecular damage inflicted by free radicals. Melatonin has several functions in terms of its antioxidative ability. It readily scavenges the most highly toxic free radical, the hydroxyl radical, and it directly detoxifies the peroxynitrite anion, nitric oxide, singlet oxygen, and the peroxyl radical. Precisely how efficient melatonin is in neutralizing each of these toxic agents remains to be determined. Melatonin also may stimulate several antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase as well as inhibiting the pro-oxidative enzyme, nitric-oxide synthase. Finally, melatonin chelates transition metal ions and prevents the deterioration of cellular membranes. This combination of actions may all contribute to melatonin's ability to reduce oxidative damage. Melatonin is highly effective in reducing nuclear DNA damage and membrane lipid destruction due to toxic free radicals in vivo. These findings have implications for disease processes, eg, neurodegenerative and cardiovascular diseases, which involve free radicals and for aging itself, which also is believed to be related to accumulated oxidative damage.

Alzheimer Disease↗
PubMed1998

Oxidative toxicity in models of neurodegeneration: responses to melatonin.

In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from beta-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury.

Journal Article↗
PubMed1997

Melatonin and vitamin E limit nitric oxide-induced lipid peroxidation in rat brain homogenates.

We have investigated the level of lipid peroxidation (LPO) in rat brain homogenates in the presence of nitric oxide (NO) which was released by the addition of sodium nitroprusside (SNP) and compared it with that induced by H2O2. We also examined the effect of melatonin and vitamin E on the NO-induced LPO. The concentration of malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HDA) was used as an index of LPO. While both H2O2 and SNP increased MDA + 4-HDA production in brain homogenates in a concentration-dependent manner, SNP was more potent than H2O2 at all concentrations tested. Both melatonin or vitamin E reduced NO-induced LPO in a dose-dependent manner in concentrations ranging from 10 microM to 10 mM. Under the in vitro conditions of this experiment, vitamin E was more efficient than melatonin in limiting NO-induced LPO in rat brain homogenates.

Animals↗