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Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice. Am J Physiol Regul Integr Comp Physiol 287: R844-R851, 2004. First published June 24, 2004; 10.1152/ajpregu. 00085.2004.--Rest-activity or cortisol rhythms can be altered in cancer patients, a condition that may impair the benefits from a timed delivery of anticancer treatments. In rodents, the circadian pattern in rest-activity is suppressed by the destruction of the suprachiasmatic nuclei (SCN) in the hypothalamus. We sought whether such ablation would result in a similar alteration of cellular rhythms known to be relevant for anticancer drug chronopharmacology. The SCN of 77 B6D2[F.sub.1] mice synchronized with 12 h of light and 12 h of darkness were destroyed by electrocoagulation [SCN(-)], while 34 animals were sham operated. Activity and body temperature were recorded by telemetry. Blood and organs were sampled at one of six circadian times for determinations of serum corticosterone concentration, blood leukocyte count, reduced glutathione (GSH), and dihydropyrimidine dehydrogenase (DPD) mRNA expression in liver and cell cycle phase distribution of bone marrow cells. Sham-operated mice displayed significant 24-h rhythms in rest-activity and body temperature, whereas such rhythms were found in none and in 15% of the SCN(-) mice. respectively. SCN lesions markedly altered the rhythmic patterns in serum corticosterone and liver GSH, which became nonsinusoidal. Liver DPD mRNA expression and bone marrow cell cycle phase distribution displayed similar 24-h sinusoidal patterns in sham-operated and SCN(-) mice. These results support the existence of another light-dark entrainable pacemaker that can coordinate cellular functions in peripheral organs. They suggest that the delivery of anticancer treatments at an optimal time of day may still be beneficial, despite suppressed rest-activity or cortisol rhythms. circadian coordination; cancer chronotherapeutics; cortisol; cell cycle; dihydropyrimidine dehydrogenase

The final step of melatonin (MLT) synthesis is methylation of N-acetyl-serotonin, with S-adenosyl-methionine as a methyl donor provided by a metabolic pathway involving sulfur-containing amino acids (homocysteine and methionine). Remethylation of homocysteine to methionine requires folate. The present study was undertaken to test the influence of folate deficiency on MLT secretion. Severe folate deficiency was induced in rats by feeding them a synthetic diet containing (per kg diet) 0 mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, erythrocyte folate concentrations were significantly lower and plasma homocysteine levels were greater in folate-deficient rats than in controls. Pineal MLT concentration and urinary excretions of MLT, 6 sulfatoxymelatonin (the main hepatic MLT metabolite) and methoxylated catechol compounds were lower in the folate-deficient group than in the controls, whereas plasma catecholamine concentrations did not differ. Decreases generally were more marked at wk 2 than at wk 4 for the urinary metabolite excretions. These findings indicate that folate deficiency dramatically alters MLT secretion in rats. KEY WORDS:. melatonin * folate * deficiency * rats

Melatonin (MEL) plays an essential role in physiologic functions associated with darkness. We examined the effects of docosahexaenoic acid (DHA)-enriched phospholipids from pig brains (BPL) or hen eggs (EPL), as sources of DHA, on lipid FA composition of pineal membranes and daytime and nighttime concentrations of 6-sulfatoxymelatonin (aMT6) in adult male control and (n-3)-deficient rats fed BPL and EPL diets for 5 wk. In two experiments, at 3 wk of age, rats were divided into subgroups and fed semipurified diets containing either peanut oil [(n-3)-deficient group] or peanut plus rapeseed oil (control group) and two dietary formulas containing either 3.5 g/100 g diet of BPL (Experiment 1) or 5.0 g/100 g diet of EPL (Experiment 2). BPL and EPL diets provided approximately 200 mg of DHA/100 g diet. During the daytime, aMT6 concentrations were not significantly different among groups. Conversely, the (n-3)-deficient rats had significantly lower nighttime aMT6 concentrations than the control rats. BPL and EPL did not affect urinary nighttime aMT6 concentration in the control group, whereas (n-3)-deficient + BPL or EPL groups exhibited significantly higher nighttime aMT6 concentrations than the (n-3)-deficient group (76 and 110%, respectively). The level of DHA was significantly higher in the pineal glands of control rats than in (n-3)-deficient rats. In rats fed EPL and BPL, the level of DHA reached a plateau, between 10 and 11 mg/100 mg total fatty acids in control + BPL or EPL and (n-3)-deficient + BPL or EPL groups. These findings suggest that new DHA-enriched formulas may be used as an efficient alternative source of (n-3) polyunsaturated fatty acids to normalize MEL secretion. KEY WORDS: melatonin; 6-sulfatoxymelatonin; DHA; phospholipids; pineal gland; rats

Abstract Background To evaluate the effect of a dietary supplement containing polyunsaturated fatty acids, in association with Humulus lupulus extract, on the quality of sleep using the Leeds sleep evaluation questionnaire (LSEQ) in subjects with moderate to severe sleep disorders. Methods Randomized placebo-controlled trial, in a Population-based setting. Participants were adult patients 25 to 65 years old with a chronic primary insomnia who volunteered for the study. The tested intervention consisted of two soft gelatine capsules per day, containing either the dietary supplement (active group) or olive oil (placebo group) for a month. Subjects could also volunteer for two ancillary studies on melatonin and actigraphy. Evaluation criteria included i) perception of the quality of sleep at the end of treatment using the LSEQ questionnaire, ii) sleep efficiency measured by one-week actigraphic movement measurement performed before and during the treatment in a subsample of subjects, iii) night melatonin and 6 sulfatoxymelatonin (aMT6S) urine rates in a subsample of subjects. Results The average of Leeds score was similar in both groups (p = 0.95). A marked improvement in the quality of sleep was observed in both placebo (62%) and active (65%) group (p = 0.52). The evolution of urinary melatonin, aMT6S, and of the Mel/aMT6S ratio showed no differences between the two groups. Sleep efficiency, as measured by actigraphy, improved similarly in both groups during the treatment period, from 72% to 76% and 75% in the active and placebo group respectively (p = 0.91). Conclusions The dietary supplement had neither effect on the perceived quality of sleep, nor on the melatonin metabolism and sleep-wake cycle. Trial registration: clinical trials.gov:NCT00484497