Plasma, Cerebrospinal Fluid, and Brain Distribution of 14C‐Melatonin in Rat: A Biochemical and Autoradiographic Study
TL;DR: Chromatographic analysis indicated that the radioactivity from biological samples taken at various times following the injection of label was mainly associated with 14C‐MT, which was found in cortex, thalamic nuclei, medial geniculate nucleus, anterior pretectal area, paraventricular nucleus of the hypothalamus, choroid plexuses, and bulb‐pons.
Abstract: The distribution of 14C-Melatonin (14C-MT) after systemic injection was studied in the plasma, cerebrospinal fluid (CSF), and brain of rats. Chromatographic analysis (thin-layer chromatography and high-performance liquid chromatography) indicated that the radioactivity from biological samples taken at various times following the injection of label was mainly associated with 14C-MT. Computer analysis of plasma 14C-MT kinetics showed a three-compartment system with half-lives of 0.21 +/- 0.05, 5.97 +/- 1.11, and 47.52 +/- 8.86 min. The volume of distribution and the clearance were 1,736 +/- 349 ml.kg-1 and 25.1 +/- 1.7 ml.min-1.kg-1 respectively. The entry of 14C-MT into the CSF was rapid and reached a maximum at 5 min. The decay followed a two-compartment system with half-lives of 16.5 +/- 2.9 and 47.3 +/- 8.6 min. The CSF/plasma concentration ratio was 0.38 at the steady state (30 min). At 2 min the level of 14C-MT in the brain was 3.8 higher than in the CSF. Representative autoradiograms revealed an heterogeneous localization of 14C-MT in the grey matter. The highest regional values, as evaluated by the permeability area product technique, were found in cortex, thalamic nuclei, medial geniculate nucleus, anterior pretectal area, paraventricular nucleus of the hypothalamus, choroid plexuses, and bulb-pons. Thirty minutesmore » later 14C-MT was still detected in most of the brain regions analyzed. These results point to a low but rapid penetration of circulating MT into the brain and the CSF. The heterogeneous distribution and the partial retention of 14C-MT in the brain are compatible with the hypothesis of a central action of this hormone mediated via binding sites.« less
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TL;DR: The recent recognition of BAT in normal adult humans suggests a potential target for stimulation of energy expenditure by BAT to help mitigate increased body fat storage.
Abstract: The innervation of brown adipose tissue (BAT) by the sympathetic nervous system (SNS) is incontrovertible and, with its activation, functions as the principal, if not exclusive, stimulator of BAT thermogenesis. The parasympathetic innervation of BAT only appears in two minor BAT depots, but not in the major interscapular BAT (IBAT) depot. BAT thermogenesis is triggered by the release of norepinephrine from its sympathetic nerve terminals, stimulating β3-adrenoceptors that turns on a cascade of intracellular events ending in activation of uncoupling protein-1 (UCP-1). BAT also has sensory innervation that may function to monitor BAT lipolysis, a response necessary for activation of UCP-1 by fatty acids, or perhaps responding in a feedback manner to BAT temperature changes. The central sympathetic outflow circuits ultimately terminating in BAT have been revealed by injecting the retrograde viral transneuronal tract tracer, pseudorabies virus, into the tissue; moreover, there is a high degree of colocalization of melanocortin 4-receptor mRNA on these neurons across the neural axis. The necessary and sufficient central BAT SNS outflow sites that are activated by various thermogenic stimuli are not precisely known. In a chronic decerebration procedure, IBAT UCP-1 gene expression can be triggered by fourth ventricular injections of melanotan II, the melanocortin 3/4 receptor agonist, suggesting that there is sufficient hindbrain neural circuitry to generate thermogenic responses with this stimulation. The recent recognition of BAT in normal adult humans suggests a potential target for stimulation of energy expenditure by BAT to help mitigate increased body fat storage.
399 citations
TL;DR: Maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth, and unique ways of action turn melatonin into a biological time-domain-acting molecule.
Abstract: Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.
318 citations
TL;DR: Evidence is given for bidirectional communication between brain and WAT occurring via the sympathetic nervous system (SNS) and sensory innervation of this tissue and a possible neural negative feedback loop to regulate lipolysis.
247 citations
TL;DR: Results indicate that melatonin through its receptor can modulate the survival of newborn neurons in the adult hippocampus, making it the first known exogenously applicable substance with such specificity.
208 citations
Cites background from "Plasma, Cerebrospinal Fluid, and Br..."
...…melatonin (rapid half-life of 3.04–5.97 min, a slower half-life of 36–47.52 min and the slowest half-life of 24 h), and the bioavailability of melatonin up to 48 h after its administration (Anton-Tay et al, 1988; Vitte et al, 1988) as well as the melatonin levels in plasma (Supplementary Table 1)....
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TL;DR: Functional evidence for the role of the SNS innervation in lipid mobilization in human WAT is convincing, with some controversy regarding the level of sympathetic nerve activity in human obesity.
200 citations
Cites background from "Plasma, Cerebrospinal Fluid, and Br..."
..., median and dorsal raphe, raphe obscurus, and pontine reticular nuclei) in laboratory rats (71), areas that...
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References
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TL;DR: It is shown here how the response of the immune system to repeated exposure to high-energy radiation affects its ability to discriminate between healthy and diseased tissue.
11,002 citations
TL;DR: Iodo[14C]antipyrine appears, therefore, to be a satisfactory nonvolatile tracer for the measurement of local cerebral blood flow.
Abstract: The autoradiographic diffusible tracer technique for the measurement of local cerebral blood flow was originally designed for use with the radioactive, inert gas 131I-labeled trifluoroiodomethane and is applicable only with tracers that exhibit unrestricted diffusion through the blood-brain barrier. Because of the technical problems associated with the use of gaseous tracers, a suitable nonvolatile tracer has been sought. [14C] Antipyrine has been used previously and found to be unsuitable because of limitations in its diffusion through the blood-brain barrier. An analogue of [14C]antipyrine, iodo [14C]antipyrine, exhibits higher partition coefficients than [14C]antipyrine between nonpolar solvents and water and might, therefore, be expected to diffuse more freely through the barrier. Its use as the tracer in the local blood flow technique leads to values considerably above those obtained with [14C]antipyrine in the rat and cat and essentially the same as those obtained with the gas trifluoro[131I]iodomethane in the cat. Iodo[14C]antipyrine appears, therefore, to be a satisfactory nonvolatile tracer for the measurement of local cerebral blood flow.
1,032 citations
TL;DR: In seasonally breeding mammals that use changes in the photoperiod to time their reproductive cycles, temporal signals to the reproductive system are controlled by the daily rhythm in melatonin production.
Abstract: There is a daily rhythm in the production of the pineal hormone melatonin in all mammalian species. Production is stimulated by darkness and inhibited by light. This provides a signal reflecting the changing environmental lighting cycle. In seasonally breeding mammals that use changes in the photoperiod to time their reproductive cycles, temporal signals to the reproductive system are controlled by the daily rhythm in melatonin production.
611 citations
TL;DR: The hypothesis that at least part of the increase in monovalent cation active transport produced by insulin is related to enhanced Na-K-ATPase activity is supported and the latter phenomenon is dependent on some components or properties of the intact cell.
Abstract: The effects of insulin on monovalent cation transport and on Na-K-ATPase activity from intact cells, tissue homogenates, and purified enzyme of the avian salt gland were studied. Monovalent cation active transport, measured by ouabain-inhibitable 86Rb+ uptake, was significantly increased (21.9 +/- 7.3% SE) in tissue slices exposed to insulin (100 mU/ml) for 15 min. A small but significant (12.2 +/- 1.9%) increase in Na-K-ATPase activity was similarly observed after salt gland tissue slices were exposed to insulin. This increase in enzymatic activity did not occur when broken-cell homogenates were exposed to insulin. Purified preparations of Na-K-ATPase showed no insulin enhancement of activity either in the presence of optimal or less than fully activating Na+ and ATP concentrations. Na-K-ATPase activity was the same in detergent-activated homogenates of both control and insulin-treated slices, consistent with insulin activation of existing enzyme sites. These data support the hypothesis that at least part of the increase in monovalent cation active transport produced by insulin is related to enhanced Na-K-ATPase activity and indicate that the latter phenomenon is dependent on some components or properties of the intact cell.
577 citations