beta-Amyloid (Abeta) is strongly involved in the pathogenesis of Alzheimer's disease (AD), and mitochondria play an important role in neurodegenerative disorders. To determine whether any different effect of melatonin on cultured neurons treated with Abeta in vitro and which may be produced through its different action on mitochondria at different stages of culture, we investigated the damage of cultured rat hippocampal neurons mitochondrial function induced by Abeta in young neurons [days in vitro 10 (DIV 10)] and senescent neurons (DIV 25) and the protective effect of melatonin. Rat hippocampal neurons were incubated with amyloid-beta peptide 25-35 (Abeta25-35) alone or pretreatment with melatonin. Cell viability, mitochondrial membrane potential (Deltapsim), ATP and the activity of the respiratory chain complexes were measured. Data showed that Abeta25-35 caused a reduction in Deltapsim, inhibited the activity of the respiratory chain complexes and led to ATP depletion, melatonin attenuated Abeta25-35-induced mitochondrial impairment in young neurons, whereas melatonin had no effect on Abeta25-35-induced mitochondrial damage in senescent neurons. These results demonstrate that melatonin has differential effect on Abeta25-35-induced mitochondrial dysfunction at different stages of culture and suggest that melatonin is useful for the prevention of AD, rather than treatment. less...

The mechanisms responsible for the antihypertensive effect of melatonin are not completely understood. To elucidate the possible role of the nitric oxide (NO) pathway in the hemodynamic actions of melatonin, the effects of this indolamine on vascular function during hypertension induced by the NO-synthase (NOS) inhibitor, N(omega)-nitro-l-arginine-methyl ester (l-NAME) were investigated. Four groups of male adult Wistar rats were employed: control, L-NAME (40 mg/kg), melatonin (10 mg/kg) and l-NAME + melatonin for 5 wks. Systolic and diastolic blood pressure were measured invasively in the carotid artery. Conjugated dienes concentration (an oxidative load marker), NOS RNA expression and its activity and RNA expression of cyclooxygenase-(COX)-1 and COX-2 were determined in the aorta. Acetylcholine-induced responses and their NO-mediated component were evaluated in femoral and mesenteric artery. Moreover, endothelium-derived constricting factor (EDCF)-dependent vasoconstriction and inner diameter were determined in the femoral artery. Chronic l-NAME treatment induced hypertension, elevated the oxidative load and inhibited NOS activity. Moreover, impaired NO-dependent relaxation, augmented EDCF-constriction, increased COX-2 expression and reduced arterial inner diameter were observed. Melatonin added to l-NAME treatment completely prevented elevation of the oxidative load in the aorta. However, melatonin was not able to prevent NOS activity decline, elevation of COX-2 expression or the impairment of vascular responses (except moderate improvement in relaxation of small mesenteric arteries) and it exerted only slight antihypertensive effect. In conclusion, in addition to the reduction of the oxidative load, the restoration of the NO pathway seems to play an important role in the antihypertensive effect of melatonin. less...

In this study, we investigated whether calbindin-D9k (CaBP-9k) expression was regulated by melatonin during hydrogen peroxide (H(2)O(2))-induced cell death in rat pituitary GH3 cells. CaBP-9k expression was increased by melatonin in a dose- and time-dependent manner, indicating that CaBP-9k expression is regulated by melatonin. Cell survival was increased approximately 27-30% where H(2)O(2)-treated cells (0.25 or 0.5 mm) were also incubated with 1 mm melatonin, when compared with H(2)O(2) alone or H(2)O(2) plus 0.5 mm melatonin. This result was consistent with 4,6-diamidino-2-phenylindole staining. CaBP-9k expression was also augmented by co-treatment with H(2)O(2) and 1 mm melatonin, suggesting a functional relationship between increased cell death and melatonin-induced CaBP-9k expression during H(2)O(2)-mediated apoptosis. Bcl-2-associated protein expression increased following treatment with H(2)O(2) alone, whereas Bcl-2 expression was elevated following treatment with melatonin alone, or H(2)O(2) plus melatonin. The expression of p53 was depressed by treatment with melatonin alone, or co-treatment with H(2)O(2) plus melatonin. These results correlated with CaBP-9k expression levels and activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway. Knockdown of CaBP-9k expression using a small inhibitory RNA resulted in an elevation of H(2)O(2)-induced cell death, whereas cell survival was increased in cells that overexpressed CaBP-9k, providing additional evidence that the induction of CaBP-9k expression may be associated with survival signaling during H(2)O(2)-mediated oxidative cell death. CaBP-9k appears to interact with p53, suggesting a possible role for this interaction in cell proliferation and cell cycle progression. less...

The circadian production of melatonin by the pineal gland during the night provides an inhibitory signal to tissue-isolated steroid receptor SR+ and - MCF-7 human breast cancer xenografts in female nude rats. A pivotal mechanism for melatonin's anticancer effects in vivo involves a melatonin receptor-mediated inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE). Exposure of (SR-) xenograft-bearing rats to increasing intensities of polychromatic white light at night suppresses melatonin while increasing tumor growth rates, DNA content, [3H]thymidine incorporation into DNA, LA uptake, 13-HODE formation, cAMP levels and ERK1/2 activation a dose-dependent manner. Similar effects occur in SR- human breast cancer xenografts perfused in situ with melatonin-depleted blood from healthy female subjects after their exposure to a single bright intensity (2800 lux) of polychromatic light at night. Additionally, SR- human breast cancer xenografts exhibit robust circadian rhythms of LA uptake, 13-HODE formation and proliferative activity. Exposure of xenograft-bearing rats to dim light at night results in the complete elimination of these rhythms which culminates in unfettered, high rates of tumor metabolism and growth. The organization of tumor metabolism and growth within circadian time structure by the oncostatic melatonin signal helps create a balance between the cancer and its host that is disrupted by host exposure to light at night. This biological mechanism may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night. less...

In industrialized countries, certain types of cancer, most notably, breast and prostate, are more frequent than in poorly developed nations. This high cancer frequency is not explained by any of the conventional causes. Within the past decade, numerous reports have appeared that link light at night with an elevated cancer risk. The three major consequences of light at night are sleep deprivation, chronodisruption, and melatonin suppression. Each of these individually or in combination may contribute to the reported rise in certain types of cancer. In this article, the potential mechanisms underlying the basis of the elevated cancer risk are briefly discussed. Finally, if cancer is a consequence of excessive nighttime light, it is likely that other diseases/conditions may also be exaggerated by the widespread use of light after darkness onset. less...

Practical circadian therapy for the cancer patient involves 3 spheres of intervention-improving lifestyle, optimizing internal biochemical milieu, and adjusting treatment times. The potential value of improving overall circadian functioning is shown in the work of Mormont et al in which pronounced rest-activity rhythms were associated with better survival in colorectal cancer patients receiving chronomodulated chemotherapy. Lifestyle interventions that may improve circadian functioning involve diet, physical activity, and mind-body therapies. A diet that is anti-inflammatory and has appropriate carbohydrate intake, as well as regular meal timing, encourages normal circadian cycles. Adequate daytime physical activity encourages restful sleep, and morning light exposure during exercise may entrain melatonin rhythms. Meditation and other mind-body therapies can reduce anxiety and depression that may disrupt sleep. Aspects of the biochemical milieu that specifically disrupt circadian functioning are inflammation and stress hormones. Inflammation and cytokine disruption can be addressed with diet, herbs, and other natural substances. Chronomodulation of chemotherapy in a US clinical setting will be discussed. A series of 12 cases will be presented of patients who experienced grade 3 to 4 toxicities with various chemotherapy regimens for colorectal cancer. When rechallenged with the same regimens administered chronotherapeutically, none of the patients experienced grade 3 to 4 toxicity. Integrating all the above treatment modalities has the potential to improve both the quality of life and disease outcomes in cancer patients. less...

Effects of timed physical exercise were examined on the re-entrainment of sleep-wake cycle and circadian rhythms to an 8 hour phase-advanced sleep schedule. Seventeen male adults spent 12 days in a temporal isolation facility with dim light conditions (<10 lux). The sleep schedule was phase-advanced by 8 hours from their habitual sleep times for 4 days, which was followed by a free-run session for 6 days where the subjects were deprived of time cues. During the shift schedule, the exercise group (n=9) performed physical exercise with a bicycle ergometer in the early and middle waking period for 2 hours each. The control group (n=8) sat on a chair at those times. Their sleep-wake cycles were monitored everyday by polysomnography and/or weight sensor equipped with a bed. The circadian rhythm in plasma melatonin was measured on the baseline day before phase-shift, on the 4th day of shift schedule and the 5th day of free-run. As a result, the sleep-onset on the first day of free-run in the exercise group was significantly phase-advanced from that in the control and from the baseline. On the other hand, the circadian melatonin rhythm was significantly phase-delayed in the both groups, showing internal desynchronization of the circadian rhythms. The sleep-wake cycle resynchronized to the melatonin rhythm by either phase-advance or -delay shifts in the free-run session. These findings indicate that the re-entrainment of the sleep-wake cycle to a phase-advanced schedule occurs independent of the circadian pacemaker and is accelerated by timed physical exercise. Key words: physical exercise, sleep-wake cycle, plasma melatonin, circadian rhythms, humans. less...

BACKGROUND: Depression is a common problem in patients with Delayed Sleep Phase Syndrome (DSPS). This study used a randomized, double-blind, crossover, placebo-controlled approach to test the hypothesis that exogenous melatonin (5mg) can attenuate depressive symptomatology in DSPS patients. METHODS: Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms (Group I; n=8) and without depressive symptoms (Group II; n=12) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale (CES-D). Both groups received melatonin and placebo treatment for 4weeks with a 1-week washout period in between. Participants underwent a clinical interview and psychometric evaluation to assess depression, and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments. Furthermore, melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels. RESULTS: Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale - 17. Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions. Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals. CONCLUSION: Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology. less...

The authors have shown that, via activation of its MT1 receptor, melatonin modulates the transcriptional activity of various nuclear receptors and the proliferation of both ER alpha+ and ER alpha- human breast cancer cells. Employing dominant-negative (DN) and dominant-positive (DP) G proteins, it was demonstrated that G alpha i2 proteins mediate the suppression of estrogen-induced ER alpha transcriptional activity by melatonin, whereas the G alpha q proteins mediate the enhancement of retinoid-induced RAR alpha transcriptional activity by melatonin. In primary human breast tumors, the authors' studies demonstrate an inverse correlation between ER alpha and MT1 receptor expression, and confocal microscopic studies demonstrate that the MT1 receptor is localized to the caveoli and that its expression can be repressed by estrogen and melatonin. Melatonin, via activation of its MT1 receptor, suppresses the development and growth of breast cancer by regulation of growth factors, regulation of gene expression, regulation of clock genes, inhibition of tumor cell invasion and metastasis, and even regulation of mammary gland development. The authors have previously reported that the clock gene, Period 2 (Per2), is not expressed in human breast cancer cells but that its reexpression in breast cancer cells results in increased expression of p53 and induction of apoptosis. The authors demonstrate that melatonin, via repression of ROR alpha transcriptional activity, blocks the expression of the clock gene BMAL1. Melatonin's blockade of BMAL1 expression is associated with the decreased expression of SIRT1, a member of the Silencing Information Regulator family and a histone and protein deacetylase that inhibits the expression of DNA repair enzymes (p53, BRCA1 & 2, and Ku70) and the expression of apoptosis-associated genes. Finally, the authors developed an MMTV-MT1-flag mammary knock-in transgenic mouse that displays reduced ductal branching, ductal epithelium proliferation, and reduced terminal end bud formation during puberty and pregnancy. Lactating female MT1 transgenic mice show a dramatic reduction in the expression of beta-casein and whey acidic milk proteins. Further analyses showed significantly reduced ER alpha expression in mammary glands of MT1 transgenic mice. These results demonstrate that the MT1 receptor is a major transducer of melatonin's actions in the breast, suppressing mammary gland development and mediating the anticancer actions of melatonin through multiple pathways. less...

OBJECTIVE: To summarize the literature on the available pharmacotherapy for insomnia and the adverse cognitive effects of those options in persons with traumatic brain injury (TBI). DESIGN: Ovid/MEDLINE databases were searched by using the following key words: "brain injury," "sleep initiation and maintenance disorders," "hypnotics and sedatives," "benzodiazepines," "trazodone," and "neuronal plasticity." RESULTS: The reviewed literature consistently reported that benzodiazepines and atypical gamma-aminobutyric acid (GABA) agonists result in cognitive impairment when plasma levels are at their peak. Evidence of residual effects on cognition was reported for benzodiazepines but was seen less often in atypical GABA agonists. However, evidence has also been presented that GABA agonists have adverse effects on neuroplasticity, raising concerns about their use in patients recovering from TBI. CONCLUSIONS: Use of benzodiazepines in TBI has been discouraged and some authors also advocate caution in prescribingatypical GABA agonists. Alternate treatments including trazodone and a newer class of agents, melatonin agonists, are highlighted, along with the limited data available addressing the use of these medications in TBI. Finally, suggestions are offered for further research, especially on topic related to neural plasticity and functional recovery. less...