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

Abstract

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.

Rola błonowych receptorów melatoniny w zależnym od melatoniny uwalnianiu oksytocyny z układu podwzgórze-część nerwowa przysadki szczura — badania in vitro oraz in vivo

“…10 -9 M) on OT release in vitro could be due to several reasons. It is known that melatonin is released from the pineal gland directly into the cerebrospinal fluid of the third ventricle, where its concentration is much higher than in the blood, and it enters the brain from the ventricles [35]. It is, therefore, possible that a concentration of the hormone in the incubatory medium has to be higher than in the blood, to sufficiently penetrate from the medium into the hypothalamo-neurohypophysial tissue and produce a significant effect on OT secretion in vitro.…”

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…First, compounds synthesised by one region of the brain may require wider CNS distribution and use CSF pathways to achieve this, for example, melatonin and vasopressin [147,152,153]. Melatonin, an antioxidant which also sets the body's circadian rhythm via the suprachiasmatic nucleus (SCN), requires CSF for its distribution from synthesis in the pineal gland to multiple CNS sites.…”

Melatonin — More than Just a Pineal Hormone

“…A correct statement would be that, in mammals and under physiological conditions, circulating melatonin is mainly released from the pineal gland. This organ also secretes melatonin, via the pineal recess, into the third ventricle of the brain [1][2][3]. The chronobiological actions of mammalian melatonin are widely based on its nocturnal release into the blood and the cerebrospinal fluid (CSF).…”