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R J Reiter

Publications and source records attributed to R J Reiter.

At least 19 recordsLinked to original sources
PubMed2007

The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma.

Craniocerebral trauma (CCT) is the most frequent cause of morbidity-mortality as a result of an accident. The probable origins and etiologies are multifactorial and include free radical formation and oxidative stress, the suppression of nonspecific resistance, lymphocytopenia (disorder in the adhesion and activation of cells), opportunistic infections, regional macro and microcirculatory alterations, disruptive sleep-wake cycles and toxicity caused by therapeutic agents. These pathogenic factors contribute to the unfavorable development of clinical symptoms as the disease progresses. Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine endogenously produced in the pineal gland and in other organs and it is protective agent against damage following CCT. Some of the actions of melatonin that support its pharmacological use after CCT include its role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes (e.g. superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase), inhibition of pro-inflammatory cytokines and activation-adhesion molecules which consequently reduces lymphocytopenia and infections by opportunistic organisms. The chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness. Melatonin reduces the toxicity of the drugs used in the treatment of CCT and increases their efficacy. Finally, melatonin crosses the blood-brain barrier and reduces contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of CCT.

Craniocerebral Trauma↗
PubMed2006

Protective effect of melatonin and pinoline on nitric oxide-induced lipid and protein peroxidation in rat brain homogenates.

Nitric oxide (NO) is a physiological neurotransmitter, a mediator of the excitatory neurotransmitter glutamate pathways that regulates several neuroendocrine functions, but excessive NO is toxic by itself and it interacts with superoxide radical (O(2)(-)) to form the peroxynitrite anion (ONOO(-)). Using rat brain homogenates, we investigated the effects of melatonin and pinoline in preventing the level of lipid peroxidation (LPO) and carbonyl contents in proteins induced by nitric oxide (NO) which was released by the addition of sodium nitroprusside (SNP). Lipid and protein peroxidation were estimated by quantifying malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA) concentrations and carbonyl contents, respectively. SNP increased MDA+4-HDA and carbonyl contents production in brain homogenates in a time and concentration dependent manner. Both, melatonin and pinoline reduced NO-induced LPO and carbonyl contents in a dose-dependent manner in concentrations from 0.03 to 3 mM and 1 to 300 microM, respectively. Under the in vitro conditions of this experiment, both antioxidants were more efficient in limiting SNP protein oxidation than lipid damage.

Animals↗
PubMed2006

Melatonin directly scavenges free radicals generated in red blood cells and a cell-free system: chemiluminescence measurements and theoretical calculations.

Melatonin, a pineal secretory product, has properties of both direct and indirect powerful antioxidant. The aim of the present study was to compare the radical-scavenging, structural and electronic properties of melatonin and tryptophan, precursor of melatonin. Using the alkoxyl- and peroxyl radical-generating systems [the organic peroxide-treated human erythrocytes and a cell-free system containing the azo-initiator 2,2'-azobis(2-amidinopropane)dihydrochloride], we evaluated the radical-scavenging effects of melatonin and tryptophan. Melatonin rather than tryptophan at concentrations of 100-2000 microM markedly inhibited membrane lipid peroxidation in human erythrocytes treated with organic hydroperoxide as well as radical-induced generation of luminol-dependent chemiluminescence. The apparent Stern-Volmer constants for inhibition of membrane lipid peroxidation by melatonin and tryptophan were estimated to be (0.23+/-0.05) x 10(4) M(-1) and (0.02+/-0.005) x 10(4) M(-1), respectively. The apparent Stern-Volmer constants for inhibition of azo-initiator-derived peroxyl radical generation by melatonin and tryptophan were determined to be (0.42+/-0.05) x 10(4) M(-1) and (0.04+/-0.01) x 10(4) M(-1), respectively. The structural and electronic properties of melatonin and its precursor, tryptophan, were determined theoretically by performing semi-empirical and ab initio calculations. The high radical-scavenging properties of melatonin may be explained by the high surface area value and high dipole moment value. From the thermodynamic standpoint, based on our calculations, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), was the most stable end oxidative product of melatonin.

Cell-Free System↗
PubMed2006

Nocturnal secretion of melatonin in patients with upper digestive tract disorders.

Recently, the results of many experimental investigations have shown that melatonin possesses gastroprotective properties. On the other hand its role in pathogenesis of upper digestive tract diseases in man still remains unclear. The aim of the study was to investigate nocturnal secretion of melatonin in patients with functional and organic diseases of the upper part of digestive tract. The investigations were carried out in 149 persons, aged 21-51 years, including healthy subjects (group I, n=30), and patients with non-erosive gastroduodenal reflux (NERD, group II, n=24), with gastroesophageal reflux disease (GERD, group III, n=25), with functional dyspepsia (FD, according to the Rome III Criteria, group IV, n=36) and with recurrent duodenal ulcer (DUD, group V, n=34). Diagnoses were established on the basis of endoscopic imaging and histological examination, 24-hour pH-metry and laboratory tests. Melatonin serum concentration was measured with ELISA method. Blood samples were taken for examination in red-lighted room at 10 p.m. and on the following day at 2 and 6 a.m. The highest concentration of melatonin in all examined groups was determined at 2 a.m. The average melatonin concentration in healthy subjects was 34,7 +/- 4,8 pg/ml. In patients with GERD and DUD melatonin concentration was lower than in healthy subjects - 27,2 +/- 8,5 pg/ml and 25,5 +/- 6,2 pg/ml respectively (p < 0,05; p < 0,01). The highest concentration of melatonin was found in patients with NERD and FD - 43,2 +/- 10,8 pg/ml and 42,4 +/- 10,1 pg/ml (p < 0,01; p < 0,05). The findings of this study support the notion that melatonin exerts beneficial influences on the upper digestive tract. It is likely that high or relatively correct secretion of melatonin is sufficient to prevent peptic changes in esophageal and duodenal mucosa.

Adult↗
PubMed2005

Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and anti-apoptotic protein levels.

In the present study, we examined the molecular mechanism by which homocysteine causes neuronal cell apoptosis. We further investigated the mechanisms of melatonin's ability to reduce homocysteine-induced apoptosis. Consistent with its antioxidant properties, melatonin reduced homocysteine-induced lipid peroxidation and stimulated glutathione peroxidase enzyme activity in hippocampus of rats with hyperhomocysteinemia. Furthermore, melatonin treatment diminished cytochrome c release from mitochondria and reduced caspase 3 and caspase 9 activation induced by hyperhomocysteinemia. Chronic hyperhomocysteinemia also led to poly(ADP-ribose) polymerase cleavage and subsequently DNA fragmentation. Treatment with melatonin markedly inhibited poly(ADP-ribose) polymerase cleavage and reduced DNA damage. Hyperhomocysteinemia caused an elevation of pro-apoptotic Bax levels while reducing anti-apoptotic protein, Bcl-2, levels. Daily administration of melatonin up-regulated Bcl-2 and down-regulated Bax levels. We propose that, in addition to its antioxidant properties, melatonin has the ability to protect neuronal cells against apoptosis mediated homocysteine neurotoxicity by modulating apoptosis-regulatory proteins in the hippocampus of rats.

Animals↗
PubMed2005

Melatonin, lipid peroxidation, and age in heterophils from the ring dove (Streptopelia risoria).

Numerous recent studies have shown the ability of physiological as well as all pharmacological concentrations of melatonin to prevent oxidative stress. We have found that incubating avian heterophils from young birds with a pharmacological concentration of 100 microM (23x10(6) pg/ml) melatonin reduced superoxide anion levels by modulating the activity of superoxide dismutase while also enhancing phagocytosis. There was also a decline in lipid peroxidation levels with both physiological and pharmacological concentrations of this indolamine. In the present work, we evaluated malonaldehyde (MDA) levels as an indicator of lipid peroxidation (both basal and antigen-induced) in young and old animals (ring doves) at different times of day (16:00 and 00:00) and with two incubation times (15 and 60 min). The lipid peroxidation was also measured in heterophils from old animals, incubated with the physiological concentrations of melatonin measured in young animals (50 and 300 pg/ml, diurnal and nocturnal, respectively). The results, expressed as nmol MDA/mg protein, show that MDA levels were higher in heterophils of old animals than in the young birds in all the experimental groups studied at both 16:00 and 00:00 (00:00 is the time at which the lowest peroxidation levels were obtained). Incubation with melatonin was found to reduce MDA levels, with the maximum reduction being after the 60?min incubation time and the nocturnal melatonin concentration. At both concentrations (diurnal and nocturnal), melatonin also counteracted the enhancement of MDA levels caused by latex beads, with the effect being greater at the longer incubation time. In conclusion, the results are further evidence of the antioxidant effect of melatonin even at physiological concentrations, and suggest its utility as a therapeutic agent in some pathological processes associated with age.

Aging↗
PubMed2004

Elevated levels of oxidized low-density lipoprotein and impaired nocturnal synthesis of melatonin in patients with myocardial infarction.

This study was designed to investigate the relationship between nocturnal serum melatonin (MEL) levels and oxidized low-density lipoprotein (OxLDL) in patients with acute coronary syndrome (ACS). OxLDL plays a pivotal role in the development of atherosclerosis. Patients with coronary heart disease have an impaired nocturnal secretion of MEL. To date, there are no clinical human studies concerning the relationship of MEL to low-density lipoprotein (LDL) oxidation in patients with acute myocardial infarction (AMI). The study population contained 60 patients with AMI and 60 control subjects. Levels of circulating OxLDL were measured by a monoclonal antibody 4E6-based competition ELISA. Levels of circulating MEL were measured by an enzyme-immunoassay kit after chloroform extraction. Comparison of levels between AMI and controls, adjusted for age, revealed significantly higher nocturnal serum OxLDL levels (95.47+/-6.81 versus 68.35+/-4.07 U/l; p=0.004) in the AMI subjects. Nocturnal serum levels of MEL were lower in AMI than the control group (20.97+/-3.90 versus 53.19+/-7.80 pg/ml; p=0.009). Serum levels of total, high-density lipoprotein (HDL), and LDL cholesterol did not differ between the groups. Multiple regression analysis was performed on cases to study the association between AMI and serum levels of OxLDL and MEL (OR: 2.93; 95% CI, 2.89-2.98, p=0.01 and OR: 0.94; 95% CI, 0.89-0.97, p=0.02, respectively). This study demonstrates for the first time an independent association between nocturnal levels of OxLDL and MEL in patients with AMI. Additional population studies are necessary to further document these.

Adult↗
PubMed2004

Melatonin reduces oxidative stress in surgical neonates.

BACKGROUND/PURPOSE: Cytokines are inflammatory mediators found in the circulation after surgery. Newborns have less protection against oxidation and are very susceptible to free radical oxidative damage. Melatonin has been reported recently to reduce oxidative stress in neonates with sepsis, asphyxia, and respiratory distress. The aim of this study has been to determine if melatonin would lower interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-alpha) and nitrite/nitrate (NOx) levels and modify serum inflammation parameters, improving the clinical course of surgical neonates. METHODS: Ten newborns (group 1), 5 with surgical malformations and respiratory distress (group 1a) and 5 with isolated abdominal surgical malformations (group 1b) received a total of 10 doses of melatonin (10 mg/kg) at defined times interval for 72 hours. The treatment was started within 3 hours after the end of surgery. Ten surgical neonates (group 2), did not receive melatonin. Twenty healthy neonates (group 3) served as control. Blood samples were collected at the end of operation; before treatment with the antioxidant; and 24 hours 72 hours, and 7 days after start of treatment with melatonin or placebo, respectively. RESULTS: Postoperative value of cytokines and NOx levels of groups 1 and 2 were significantly higher than group 3. Compared with group 1b, group 2 displayed significantly higher cytokines and NOx levels at 24 hours, 72 hours, and at 7 days. In group 1a the immediate postoperative values of cytokines were significantly higher than group 1b and group 2, but a significant improvement was observed after administration of melatonin with significantly lower levels of IL-6 and IL-8 with respect to group 2. An improvement of clinical outcome was observed by progressive reduction of clinical parameters of inflammation. CONCLUSIONS: Melatonin reduces cytokines and NOx levels showing potent antioxidant properties with improvement in clinical outcome. Further studies are warranted to define, on larger numbers, the role of melatonin in surgical patients.

Female↗
PubMed2004

Scanning electron microscopy of the superficial pineal gland of the 15-day-old rat (Rattus norvegicus).

The presence of a cortex and medulla in the superficial pineal gland has been a controversial point in the morphology of this structure in mammals. The published reports indicate contradictory data especially in rodents. In this study the pineal gland of 15-day-old male rats (Rattus norvegicus) were studied, using scanning electron microscopy, in an attempt to determine whether or not a cortex and medulla are apparent in the pineal gland of young rats. The superficial pineal gland of the 15-day-old rat exhibited both a cortex and a medulla; these areas exhibited different structural organizations. The cortex had a thickness of 40-80 microm and the cells did not show a particular arrangement. The center of the gland was composed of a medulla, which had a width of 1000-1200 microm, and consisted of cells arranged in cords; its morphology was distinctly different from that of the cortex.

Animals↗
PubMed2004

Effects of melatonin on the nitric oxide treated retina.

AIMS: Nitric oxide (NO) is a free radical which reportedly causes damage to living cells. This study evaluated the damaging effect of NO and the protection of melatonin on the retina in vivo. METHODS: Female Wistar rats (230-250 g) received two intraperitoneal injections of either melatonin (5 mg/kg) or vehicle alone. After general anaesthesia, the animals received 1 microl intravitreal injections of 0.9% saline and 1 mM sodium nitroprusside (SNP) into the right eye and the left eye, respectively. The animals were divided into two groups and then sacrificed after 24 hours (day 1) and 96 hours (day 4). The mean inner retinal layer thickness (mIRLT), the number of retinas expressing hyperchromatic (HC) nuclei in the inner nuclear layer (INL) and the apoptotic ganglion cell detection were compared. RESULTS: After 1 day, SNP significantly increased the mIRLT by 45% (p = 0.004), initiated more INL nuclear HC expression (p = 0.01) and apoptotic nuclei (p<0.05) compared with the control eyes. Injection of melatonin ameliorated these changes. On day 4, SNP demonstrated similar effects in all parameters on the retina. After the injection of melatonin, both INL HC expression and apoptotic ganglion nuclei in the SNP treated eyes were similar to the controls but the mIRLT was significantly greater than in controls (p = 0.006). CONCLUSION: Uncontrolled NO elevation caused morphological and nuclear changes in the retina. Melatonin significantly suppressed the NO induced increase in mIRLT, INL HC expression, and apoptotic ganglion cells on day 1, but not after day 4. Melatonin may have a protective role in the NO elevated retina.

Animals↗
PubMed2003

Apoptosis in primary lymphoid organs with aging.

Age-associated changes in the immune system are responsible for an increased likelihood of infection, autoimmune diseases, and cancer in the elderly. Immunosenescence is characterized by reduced levels of the peripheral naive T cell pool derived from thymus and the loss of immature B lineage cells in the bone marrow. Primary lymphoid organs, i.e., bone marrow and thymus, exhibit a loss of cellularity with age, which is especially dramatic in the thymus. A summary of major changes associated with aging in primary lymphoid organs is described in this article. The participation of apoptosis in cell loss in the immune system, a change associated with age, as well as a description of molecular machinery involved, is presented. Finally, the involvement of different hormonal and non-hormonal agents in counteracting apoptosis in thymus and bone marrow during aging is explained. Here, we underlie the important role of glucocorticoids as immunodepressors and melatonin as an immunostimulatory agent.

Aging↗
PubMed2003

Protection against oxidative protein damage induced by metal-catalyzed reaction or alkylperoxyl radicals: comparative effects of melatonin and other antioxidants.

Melatonin is a well-known hydroxyl radical (*OH) scavenger that protects DNA and lipids from free radical attack. In this paper, we studied the ability of melatonin to prevent oxidative damage to bovine serum albumin (BSA) induced by two different paradigms: the metal-catalyzed oxidation (MCO) induced by Cu(2+)/H(2)O(2) and the alkoxyl and alkylperoxyl radicals formed by the azo initiator 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH, 40 mM). The protective effects of melatonin were compared with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), glutathione (GSH), ascorbate, 3,4',5-trihydroxy-trans-stilbene (resveratrol, 0.1 microM-4 mM) and mannitol (50 microM-100 mM). Melatonin efficiently prevented protein modification induced by both models, as assayed by polyacrylamide gel electrophoresis and carbonyl content. Both trolox and ascorbate had an obvious pro-oxidant effect in the Cu(2+)/H(2)O(2) model, whereas both prevented BSA damage induced by AAPH. In the MCO model, the efficacy of GSH in terms of protein protection was higher than melatonin at relatively high concentrations (250 microM-4 mM); however, at lower concentrations (50-250 microM), the efficacy of melatonin was superior to GSH. D-Mannitol (50 microM-100 mM) and resveratrol did not protect BSA from the site-specific damage induced by Cu(2+)/H(2)O(2). On the other hand, the relative protective efficiency in the AAPH model was melatonin approximately trolox>GSH>ascorbate.

Amidines↗
PubMed2003

Melatonin and cell death: differential actions on apoptosis in normal and cancer cells.

Melatonin is a natural compound synthesized by a variety of organs. It has been shown to function as a cell-protective agent. Since 1994, when the first paper was published documenting the role of melatonin in apoptosis, the number of reports in this area has increased rapidly. Much of the research conducted falls into three major categories: first, the role of melatonin in inhibiting apoptosis in immune cells; second, the role of melatonin in preventing neuronal apoptosis and finally, the role of melatonin in increasing apoptotic cell death in cancer cells. The mechanisms whereby melatonin influences apoptosis have not clarified, although a number of mechanistic options have been suggested. Apoptotic cell death is a physiological phenomenon related to homeostasis and proper functioning of tissues and organs; however, a failure in the apoptotic program is related to a number of diseases. The participation of melatonin in apoptosis in numerous cell types and its potential importance in a variety of diseases such as immunodeficiency, neurodegeneration and cancer is summarized in this review.

Animals↗
PubMed2003

The chemistry of melatonin's interaction with reactive species.

Melatonin has been shown to be an effective antioxidant in a number of experimental models both in vitro and in vivo. Considering the data available, it is now clear that the indoleamine is involved in antioxidative mechanisms more complex than originally envisaged. These range from the direct radical scavenging of a variety of radicals and reactive species to the control and/or modulation of a number of processes which may trigger a redox imbalance between antioxidant and prooxidant species. This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions. These actions likely account for at least some of the protective actions of melatonin under conditions of high oxidative stress.

Animals↗
PubMed2003

Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract.

Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.

Animals↗
PubMed2002

A novel role for melatonin: regulation of the expression of cell adhesion molecules in the rat hippocampus and cortex.

Neural cell adhesion molecules (NCAMs) are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. There are three major NCAM forms: NCAM 180, NCAM 140 and NCAM 120. Several studies report that NCAMs play a central role in memory. In the present study we investigated the effects of melatonin on the expression of NCAMs in the hippocampus, cortex and cerebellum. The levels of NCAMs were determined by Western blotting. After administration of melatonin for 7 days, NCAM 180 expression increased both in the hippocampus and in the cortex as compared to controls. On the contrary, in rats exposed to the constant light for 7 days (which inhibits endogenous production of melatonin), NCAM 180 levels decreased in the hippocampus and became undetectable in cortex and cerebellum. NCAM 140 levels were also diminished in the hippocampus of constant light-exposed rats. There was no change in NCAM 120 expression in any brain regions. This is the first report indicating that melatonin has a modulatory effect on the expression of NCAM in brain areas concerned with cognitive function. Melatonin may be involved in structural remodeling of synaptic connections during memory and learning processes.

Animals↗
PubMed2002

Melatonin improves deferoxamine antioxidant activity in protecting against lipid peroxidation caused by hydrogen peroxide in rat brain homogenates.

Deferoxamine (DF) is an antioxidant molecule because of its ability to chelate iron. This study compared the ability of DF alone or in combination with melatonin, 5-methoxytryptophol or pinoline in preventing lipid peroxidation due to hydrogen peroxide (H(2)O(2)) in rat brain homogenates. Malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) in the homogenates were measured as indices of lipid peroxidation. Incubation of homogenates with DF reduced, in a dose-dependent manner, MDA+4-HDA formation due to H(2)O(2). When melatonin, 5-methoxytryptophol or pinoline were added to the incubation medium, the efficacy of DF in preventing lipid peroxidation was enhanced. These cooperative effects between DF, melatonin, and related pineal products may be important in protecting tissues from the oxidative stress due to iron overload.

Animals↗