Biomedical subjects

Nava Zisapel

Publications and source records attributed to Nava Zisapel.

13 recordsLinked to original sources

PubMed2006

Sleep-anticipating effects of melatonin in the human brain.

Melatonin, the hormone produced nocturnally by the pineal gland, is an endogenous regulator of the sleep-wake cycle. The effects of melatonin on brain activities and their relation to induction of sleepiness were studied in a randomized, double-blind, placebo controlled functional magnetic resonance imaging (fMRI) study. Melatonin, but not placebo, reduced task-related activity in the rostro-medial aspect of the occipital cortex during a visual-search task and in the auditory cortex during a music task. These effects correlated with subjective measurements of fatigue. In addition, melatonin enhanced the activation in the left parahippocampus in an autobiographic memory task. Results demonstrate that melatonin modulates brain activity in a manner resembling actual sleep although subjects are fully awake. Furthermore, the fatigue inducing effect of melatonin on brain activity is essentially different from that of sleep deprivation thus revealing differences between fatigues related to the circadian sleep regulation as opposed to increased homeostatic sleep need. Our findings highlight the role of melatonin in priming sleep-associated brain activation patterns in anticipation of sleep.

Adult↗

PubMed2006

Melatonin reduces night blood pressure in patients with nocturnal hypertension.

PURPOSE: Nocturnal hypertension is associated with a high risk of morbidity and mortality. A blunted nocturnal surge in melatonin excretion has been described in nondipping hypertensive patients. We therefore studied the potency of melatonin to reduce nighttime blood pressure (BP) in treated hypertensive patients with nocturnal hypertension. PATIENTS AND METHODS: Thirty-eight treated hypertensive patients (22 males, mean age 64+/-11 years) with confirmed nocturnal hypertension (mean nighttime systolic BP >125 mm Hg), according to repeated 24-hour ambulatory blood pressure monitoring (ABPM), were randomized in a double-blind fashion to receive either controlled release (CR)-melatonin 2 mg or placebo 2 hours before bedtime for 4 weeks. A 24-hour ABPM was then performed. RESULTS: Melatonin treatment reduced nocturnal systolic BP significantly from 136+/-9 to 130+/-10 mm Hg (P=.011), and diastolic BP from 72+/-11 to 69+/-9 mm Hg (P=.002), whereas placebo had no effect on nocturnal BP. The reduction in nocturnal systolic BP was significantly greater with melatonin than with placebo (P=.01), and was most prominent between 2:00 AM and 5:00 AM (P=.002). CONCLUSIONS: Evening CR-melatonin 2 mg treatment for 4 weeks significantly reduced nocturnal systolic BP in patients with nocturnal hypertension. Thus, an addition of melatonin 2 mg at night to stable antihypertensive treatment may improve nocturnal BP control in treated patients with nocturnal hypertension.

Adult↗

PubMed2006

Differential effects of melatonin and its downstream effector PKCalpha on subcellular localization of RGS proteins.

Regulators of G protein signaling (RGS) are proteins that bind specifically to activated Galpha subunits of heterotrimeric G proteins to terminate signaling by both Galpha and Gbetagamma subunits. Signal-induced RGS redistribution may affect their activity in G protein-mediated signaling. We have previously shown that melatonin and the cell permeable cGMP analog 8-bromo cGMP, which lead to protein kinase C (PKC) activation, enhanced cytoplasmic distribution of RGS10 and RGS2 in prostate carcinoma PC3-AR cells. In the present study, we transfected PC3-AR cells with myc-tagged Galphai/Galphaq specific RGS proteins RGS2, RGS4 and RGS10 and examined the effects of melatonin, 8-bromo cGMP and PKC inhibitors on their nuclear-cytoplasmic partitioning. RGS10 and RGS2 were predominantly localized in the nucleus and perinuclear regions whereas RGS4 was mostly cytoplasmic in the PC3-AR cells. Melatonin and the cell permeable cGMP analog 8-bromo cGMP, previously found to activate PKCalpha in the PC3-AR cells, enhanced cytoplasmic localization of RGS10 and RGS2 but induced nuclear accumulation of RGS4. The isozyme specific PKC inhibitor GO6976 (PKCalpha and PKCbeta1) but not hispidin (PKCbeta) negated the effects of melatonin on RGS10, RGS2 and RGS4 localization. These findings indicate that PKCalpha, a downstream effector of the melatonin receptor, differentially affects nuclear/cytoplasmic localization of both Galphai and Galphaq specific RGS proteins. These observations provide further insight into melatonin's ability to fine-tune multiple membrane G-proteins signaling in cells.

Animals↗

PubMed2005

Nocturnal patterns and up-regulated excretion of the melatonin metabolite 6-sulfatoxymelatonin in the diurnal rodent Psammomys obesus post-weaning under a short photoperiod.

The ontogeny of daily rhythms in body temperature (T(b)) oxygen intake (VO(2)) and urinary excretion of the major melatonin metabolite, 6-sulfatoxymelatonin (6SMT) was studied in the day-active rodent, Psammomys obesus. Generally, T(b) and VO2 were high during the light phase in this diurnal species. However, after weaning, and only under the short photoperiod, P. obesus individuals display elevated T(b) and VO2 levels during the dark phase, as in nocturnally active species. In parallel, 6SMT and nocturnal activity of pineal arylalkylamine N-acetyltransferase (AANAT) were greatly enhanced. The cDNA encoding P. obesus pineal AANAT was cloned and found to share 90.2% homology with rat and 83.8% with human AANAT, and based on homology modeling, to structurally resemble the ovine enzyme. A robust diurnal rhythm in P. obesus pineal AANAT-mRNA was found, with maximal levels at night. AANAT-mRNA levels were not enhanced in the post-weaning phase, suggesting post-transcriptional up-regulation of pineal AANAT activity. The photoperiod-dependent post-weaning change into nocturnal behavior and up-regulation melatonin production (as evidenced from the increase in both 6SMT and AANAT activity) represent a hitherto unobserved pattern of transition of a diurnal mammal into independent life. Possibly, this pattern may be physiologically important to facilitate T(b) maintenance in the cold nights of winter in the desert.

Amino Acid Sequence↗

PubMed2004

Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy.

PURPOSE: Melatonin, which is produced by the pineal gland at night, is an endogenous sleep regulator. Both sleep disorders and impaired melatonin production are common among the elderly. We examined the excretion of the major melatonin metabolite 6-sulfatoxymelatonin in insomnia patients aged >or=55 years and its relation with the subsequent response to melatonin therapy. METHODS: We studied 517 insomnia patients, along with 29 age-matched and 30 younger healthy volunteers. Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed between 10 pm and 10 am. Three hundred and ninety-six of the insomnia patients were treated for 2 weeks with placebo and for 3 weeks with 2 mg per night of controlled-release melatonin, of which 372 provided complete datasets. Clinical response, assessed with the Leeds Sleep Evaluation Questionnaire, was defined as an improvement of 10 mm or more on the visual analog scales. RESULTS: Mean (+/- SD) 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 +/- 8.3 microg per night) than in volunteers of the same age (18.1 +/- 12.7 microg per night, P <0.05) and in younger volunteers (24.2 +/- 11.9 microg per night, P <0.05). About 30% of patients (112/372) excreted <or=3.5 microg of sulfatoxymelatonin per night, which is considered to be lower than normal for this age group. These "low excretors" had a significantly higher response to melatonin replacement therapy (58% [65/112] vs. 47% [122/260], P <0.05). CONCLUSION: Low nocturnal melatonin production is associated with insomnia in patients aged 55 years or older, and identifies patients who are somewhat more likely to respond to melatonin replacement.

Aged↗

PubMed2003

Cross-cultural validation of the Leeds sleep evaluation questionnaire (LSEQ) in insomnia patients.

The Leeds sleep evaluation questionnaire (LSEQ) is a standardized self-reporting instrument comprising ten 100 mm visual analogue scales that pertain to the ease of getting to sleep (GTS), quality of sleep (QOS), ease of awakening from sleep (AFS) and alertness and behaviour following wakefulness (BFW). Although the LSEQ has been used in a variety of populations, published psychometric data on insomnia patients are limited. The LSEQ reliability and construct validity was evaluated in 396 French insomnia patients aged 55 years and over, who were treated with placebo (2 weeks) and melatonin (3 weeks). The results supported LSEQ internal consistency, reliability and construct validity with minor differences from those of the original English version. Then the internal consistency of the LSEQ was evaluated in 257 insomnia patients (age 20-80 years) in France and Israel who, following a 1 week placebo baseline, were randomized to placebo or melatonin treatment for 3 weeks. Cronbach's alpha and Pearson's r correlation coefficients for placebo and drug treatment conditions (p<0.001 for all) supported LSEQ internal consistency in different treatment and age groups and in different languages. It is concluded that the consistency, reliability and validity of the four LSEQ domains allows them to be singled out as independent outcome variables in cross cultural sleep research and clinical practice in adult and elderly patients with insomnia.

Aged↗

PubMed2003

Determination of the minimal clinically significant difference on a patient visual analog sleep quality scale.

The amount of change in quality of sleep (QOS), as measured by a 100-mm visual analog scale (VAS), that constitutes a minimum clinically significant difference was determined. A total of 428 patients with insomnia aged 55 years and older received placebo (2 weeks), prolonged release melatonin 2 mg (3 weeks) and then placebo (2 weeks). Sleep quality was assessed by the end of each period using the Leeds Sleep Evaluation Questionnaire (LSEQ) QOS variable and a five-point severity-rating scale. The mean difference between current and preceding VAS scores in patients improving or worsening by 1 point was 13 mm (95% CI 11-16). Correlation analysis indicated that a change of 1 point was associated with a mean change of 10.3 mm on the VAS. In conclusion, a change of 10 mm change in the 100-mm VAS QOS variable of the LSEQ, signifies an important change in patients' sleep quality.

Adult↗

PubMed2003

Impaired nocturnal melatonin secretion in non-dipper hypertensive patients.

BACKGROUND: Melatonin plays a role in the biologic regulation of circadian rhythms, including sleep. Melatonin has also been shown to modulate vascular smooth muscle tone and to induce hemodynamic effects in humans. OBJECTIVE: To evaluate whether melatonin plays a role in the circadian rhythm of blood pressure in hypertensive patients. METHODS: Sixteen elderly patients with essential hypertension were evaluated. Patients were defined as either dippers (DIP, n = 8) or non-dippers (NDIP, n = 8) according to the nocturnal change in the mean arterial pressure (MAP). 6-Sulfatoxymelatonin (6-SMT), the main melatonin metabolite, was determined by enzyme-linked immunosorbent assay (ELISA) in two separate urine collections, one in the daytime and one during the night. RESULTS: Both groups of DIP and NDIP hypertensives were comparable in regard to age and sex. During the night, the mean arterial pressure decreased by 10.3 +/- 2.2% in the DIP and increased by 7.5 +/- 1.7% in the NDIP group (p < 0.01). Daily 6-SMT was comparable in DIP (3.28 +/- 0.87 microg/12 h) and NDIP (2.31 +/- 0.68 microg/12 h) (p = 0.39). However, while the DIP presented the physiological nocturnal increase in urinary 6-SMT (mean 8.19 +/- 1.68 microg/ 12 h), this surge of melatonin production was missing in NDIP in whom nocturnal urinary 6-SMT concentrations were not significantly different from daily levels (mean 2.56 +/- 0.79 microg/12 h). The nocturnal change in urinary 6-SMT excretion was positively correlated to the nocturnal change in MAP (R = 0.54; p = 0.031). CONCLUSIONS: NDIP hypertensive patients differ from DIP hypertensives by having an impaired nocturnal melatonin secretion. Thus, melatonin may play a role in the circadian rhythm of blood pressure in hypertensive patients.

Aged↗

PubMed2002

Melatonin rhythms in stroke patients.

Very little is known regarding melatonin's circadian rhythm in stroke patients. We compared urinary-sulfatoxymelatonin (6-SMT), its major metabolite, in 11 extensive cortical and seven deep or lacunar stroke patients on day 3 or 4 and day 10 post-stroke. Urinary 6-SMT and creatinine measured every 4 h for 24 h starting at 06:00 h significantly fluctuated during the day in both types of stroke and did not differ between day 3 or 4 and day 10 post-stroke. However, in extensive cortical lesions, a delay in the 6-SMT excretion was observed in the first post-stroke days compared to day 10. We conclude that circadian oscillator is preserved in extensive cortical as well as in deep and lacunar strokes. Extensive cortical stroke might delay the melatonin surge during the first post-stroke days.

Age Factors↗

PubMed2002

Melatonin production in infants.

This study investigated the relationships of the excretion of the melatonin metabolite, 6-sulfatoxymelatonin, to prenatal, natal, and postnatal variables and its possible relation to psychomotor development. nocturnal urinary excretion of 6-sulfatoxymelatonin was studied over a 13-hour period in 355 term infants at 8 weeks of age (n = 320) and 16 weeks of age (n = 96). data on a variety of perinatal factors including pregnancy course, delivery, early postnatal course, birth weight, medical problems, growth (length, weight, and head circumference), and psychomotor development were collected at 1, 3, 6, 9, 12, and 18 months. the relationship between nocturnal 6-sulfatoxymelatonin excretion at 8 and 16 weeks of age and these factors was investigated and analyzed. 6-sulfatoxymelatonin levels at 16 weeks of age were significantly lower in infants with abnormal vs normal development at 3 months of age (7.27 + 1.44 vs 7.97 + 1.06, p = 0.05) as well as at 6 months of age (7.15 + 1.29 vs 7.95 + 1.10, p = 0.04). no other significant relation was evident among growth, perinatal complications, medical problems, and 6-sulfatoxymelatonin excretion at 8 weeks of age and at 16 weeks of age. low melatonin excretion in the first weeks of life correlates with delayed psychomotor achievements at 3 and 6 months of age. this association suggests a causal or predictive link between melatonin and neurodevelopment in infants.

Analysis of Variance↗

PubMed2002

Nuclear exclusion of the androgen receptor by melatonin.

Androgen receptors (AR) play a crucial role in androgen-mediated processes and prostate cancer progression. The pineal hormone melatonin attenuates the androgen-dependent growth of benign and cancer prostate epithelial cells in vitro and may reverse clinical resistance to androgen ablation therapy in patients progressing on gonadotropin releasing hormone (GnRH) analogue. Where along the AR cascade does melatonin act remains to be determined. The effects of melatonin on AR localization, level and activity were assessed using androgen-insensitive prostate carcinoma PC3 cells stably transfected with a wild-type AR-expressing vector (PC3-AR).AR was localized to the PC3-AR cell nucleus in the absence of dihydrotestosterone (DHT). Melatonin caused a robust exclusion of the AR from the cell nucleus to the cytoplasm. The nuclear export inhibitor, leptomycin B prevented this process. The exclusion was selective since melatonin had no such effect on the nuclear localization of estrogen receptors alpha (ERalpha) in these cells. Melatonin also caused nuclear exclusion of the AR in the presence of DHT. In addition, it attenuated androgen induced reporter gene activity in PC3 cells co-transfected with the human AR and AR reporter plasmids. Elevated androgen concentrations counteracted melatonin's effects. Melatonin did not decrease AR level or androgen binding in the cells. The nuclear localization of the AR is a hallmark of its cellular activity. These data point to AR nuclear exclusion as a possible mechanism to attenuate androgen responses in target tissues.

Androgens↗

PubMed2002

Massage therapy by mothers enhances the adjustment of circadian rhythms to the nocturnal period in full-term infants.

The objective of this study was to investigate the effect of massage therapy on phase adjustment of rest-activity and melatonin secretion rhythms to the nocturnal period in full-term infants. Rest-activity cycles of infants (measurement 1, n = 16) were measured by actigraphy before and after 14 days of massage therapy (starting at age 10 [+/-4] d) and subsequently at 6 and 8 weeks of age. 6-Sulphatoxymelatonin excretion was assessed in urine samples at 6, 8, and 12 weeks of age (measurement 2, n = 21). At 8 weeks the controls revealed one peak of activity at approximately 12 midnight (11 p.m.-3 a.m.) and another one at approximately 12 noon (11 a.m.-3 p.m.), whereas in the treated group, a major peak was early in the morning (3 a.m.-7 a.m.) and a secondary peak in the late afternoon (3 p.m.-7 p.m.). At 12 weeks, nocturnal 6-sulphatoxymelatonin excretions were significantly higher in the treated infants (1346.38 +/- 209.40 microg/night vs 823.25 +/- 121.25 microg/night, respectively; <.05). It is concluded that massage therapy by mothers in the perinatal period serves as a strong time cue, enhancing coordination of the developing circadian system with environmental cues.

Adaptation, Physiological↗

PubMed2002

Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells.

OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign human prostate epithelial cells and the androgen-dependent prostate cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma PC3 cells melatonin inhibits cell growth only at high but not low cell density. We have recently found that melatonin causes nuclear exclusion of the AR and attenuates it transcriptional activity in LNCaP cells as well as PC3 cells stably transfected with a wild type AR expressing vector (PC3-AR). The aim of this study was to investigate whether melatonin inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition of AR DNA binding is involved. METHODS: The effects of androgen, melatonin and their combination on the growth of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells were studied. RESULTS: DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding to the androgen responsive element (ARE). Melatonin had no effect on cell growth in the absence of DHT but counteracted the androgen-induced inhibition at low androgen concentrations. Melatonin did not suppress and even slightly enhanced the capacity of AR binding to the ARE in the PC3-AR as well as in LNCaP cells. CONCLUSIONS: Attenuation by melatonin of AR activity in the prostate cancer cells is not due to suppression of AR binding to the ARE, and is presumably caused by its effects on AR protein interaction and intracellular trafficking.

Antioxidants↗