Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces.

Historically, the direct release of pineal melatonin into the capillary bed within the gland has been accepted as the primary route of secretion. Herein, we propose that the major route of melatonin delivery to the brain is after its direct release into the cerebrospinal fluid (CSF) of the third ventricle (3V). Melatonin concentrations in the CSF are not only much higher than in the blood, also, there is a rapid nocturnal rise at darkness onset and precipitous decline of melatonin levels at the time of lights on. Because melatonin is a potent free radical scavenger and antioxidant, we surmise that the elevated CSF levels are necessary to combat the massive free radical damage that the brain would normally endure because of its high utilization of oxygen, the parent molecule of many toxic oxygen metabolites, i.e., free radicals. Additionally, the precise rhythm of CSF melatonin provides the master circadian clock, the suprachiasmatic nucleus, with highly accurate chronobiotic information regarding the duration of the dark period. We predict that the discharge of melatonin directly into the 3V is aided by a number of epithalamic structures that have heretofore been overlooked; these include interpinealocyte canaliculi and evaginations of the posterodorsal 3V that directly abut the pineal. Moreover, the presence of tanycytes in the pineal recess and/or a discontinuous ependymal lining in the pineal recess allows melatonin ready access to the CSF. From the ventricles melatonin enters the brain by diffusion and by transport through tanycytes. Melatonin-rich CSF also circulates through the aqueduct and eventually into the subarachnoid space. From the subarachnoid space surrounding the brain, melatonin penetrates into the deepest portions of the neural tissue via the Virchow-Robin perivascular spaces from where it diffuses into the neural parenchyma. Because of the high level of pineal-derived melatonin in the CSF, all portions of the brain are better shielded from oxidative stress resulting from toxic oxygen derivatives.

Clinical relevance of melatonin in ovarian and placental physiology: a review.

Within the last decade, the synthesis of melatonin in and its functions at the level of the peripheral reproductive organs has come into better focus. Melatonin is produced at several reproductive organ sites, e.g., the oocyte, ovarian follicular cells and the placental cytotrophoblasts. Moreover, these cells also contain membrane receptors for this indoleamine. In addition, via the free radical scavenging activity of melatonin and its metabolites, oxidative stress is reduced in all reproductive organ cells ensuring their optimal function. Enhancement of oocyte maturation and preservation of oocyte quality may be major functions of melatonin. Oocyte damage reduces successful fertilization and the development of a healthy fetus. The findings that melatonin protects the oocyte from toxic oxygen species have implications for improving the outcome of in vitro fertilization-embryo transfer procedures, as already shown in two published reports. Some actions of melatonin in the placenta may be context specific. Thus, melatonin is believed to function in the maintenance of optimal placental homeostasis by deferring apoptosis of villous cytotrophoblasts, while protecting syncytiotrophoblasts from oxidative damage. Melatonin reduces oxidative damage in the placenta and may improve hemodynamics and nutrient transfer at the placental-uterine interface. The use of melatonin to treat preeclampsia should also be considered.