Age‐related changes in serum melatonin in mice: higher levels of combined melatonin and 6‐hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues

Abstract

Age-related changes in levels of melatonin and 6-hydroxymelatonin sulfate and effects of dietary melatonin on their levels in different tissues were determined in mice. Levels of melatonin were highest in the serum followed by liver, kidney, cerebral cortex and heart as measured by a quantitative and sensitive enzyme-labeled immunosorbent assay (ELISA). Serum melatonin levels decreased with age, and were reduced by 80% in 27-month old mice relative to 12-month old mice. Levels of 6-hydroxymelatonin sulfate were measured independently in various tissues. Levels of the melatonin metabolite, 6-hydroxymelatonin sulfate were significantly higher than free melatonin in all tissues tested. Levels of 6-hydroxymelatonin sulfate were highest in the cerebral cortex followed by the serum, heart, kidney, and liver. In 12-month old mice 6-hydroxymelatonin sulfate concentration was approximately 1000-fold greater than that of melatonin in the cerebral cortex, it was only 3-fold greater than melatonin levels in the serum. Thus only 0.1% of total melatonin in the brain was present in the free and unconjugated form but the corresponding value for serum was 27.4%. The cerebral cortex had the highest levels of combined melatonin and 6-hydroxymelatonin sulfate than other tissue tested in control mice. There was no significant change in 6-hydroxymelatonin sulfate levels between young and old mice. There was also no age-dependent change in levels of serotonin or cortisol in the serum samples. Dietary supplementation with melatonin resulted in a significant increase in levels of melatonin in the serum and all other tissue samples tested. Thus, any age-related decline of tissue melatonin can be reversed by supplementation with dietary melatonin.

Melatonin Metabolism in the Central Nervous System

“…One should, however, be always aware that concentrations tell little about amounts taken up, since a compound may readily disappear if it is rapidly metabolized. In fact, the same study reported for the cerebral cortex concentrations of the metabolite 6-sulfatoxymelatonin by about 3 orders of magnitude higher than those of melatonin [70].…”

“…Even lower concentrations were measured in the lateral ventricles. In a study comparing melatonin levels in mouse serum and cerebral cortex, the cortical concentrations amounted to 1% or less of those found in serum [70]. Approximately the same ratio was found after administration of exogenous melatonin.…”

“…In earlier publications, rather moderate concentrations were usually found in the brain areas mentioned. In B6C3F1 mice, melatonin was reported to attain levels of about 0.4 pM in the cerebral cortex [70], whereas whole brain concentrations of up to 0.7 M were measured in another, more recent study in Tg2576 mice [85]. Confirmation of these data and clarification would be of utmost importance.…”

Melatonin, Oxidative Stress, and the Aging Brain

“…A proportion of ingested melatonin can access the brain in an unmodified form [55]. On the other hand, the ability of several other potentially beneficial compounds to reach the brain is often limited due to their excessively lipophilic or water-soluble characteristics.…”

“…A key factor in determining this issue may be consideration of levels of free melatonin within the brain. Melatonin is present there at a concentration (around 4 pM) that is only 5% of that found in serum [55]. Therefore -unless it were to be highly concentrated in a localized area -melatonin can make little direct free-radical scavenging contribution in comparison with predominant antioxidant species such as glutathione (present in millimolar amounts) and α-tocopherol (in cells at ca.…”