Melatonin from Cerebrospinal Fluid but Not from Blood Reaches Sheep Cerebral Tissues Under Physiological Conditions

Abstract

The pineal gland secretes melatonin (MLT) that circulates in the blood and cerebrospinal fluid (CSF). We provide data to support the hypothesis that, in sheep and possibly in humans, only the CSF MLT, and not the blood MLT, can provide most of MLT to the cerebral tissue in high concentrations, particularly in the periventricular area. The MLT content of sheep brain, our chosen animal model, was found in significant concentration gradients oriented from the ventricle (close to the CSF) to the cerebral tissue, with concentrations varying by a factor of 1-125. The highest concentrations were observed close to the ventricle wall, whereas the lowest concentrations were furthest from the ventricles (407.0 ± 71.5 pg/ml compared to 84.7 ± 5.2 pg/ml around the third ventricle). This concentration gradient was measured in brain tissue collected at mid-day and at the end of the night. Nocturnal concentrations were higher than daytime concentrations, reflecting the diurnal variation in the pineal gland. The concentration gradient was not detected when MLT was delivered to the brain via the bloodstream. The diffusion of MLT to cerebral tissues via CSF was supported by in vivo scintigraphy and autoradiography. 2-[(123)I]-MLT infused into the CSF quickly and efficiently diffused into the brain tissues, whereas [(123)I]-iodine (control) was mostly washed away by the CSF flow and [(123)I]-bovine serum albumin remained mostly in the CSF. Taken together, these data support a critical role of CSF in providing the brain with MLT.

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

“…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 is secreted into the third ventricle (3V) CSF, which is in direct contact with the pinealocytes; at night, during peak melatonin synthesis, the CSF concentration is 15-20× that of plasma [110,174]. The hormone is transferred by CSF to the SCN, other hypothalamic regions, the hippocampus, and choroid plexuses, where there are high affinity MT1 receptors [56].…”

“…Lateral ventricle (LV) melatonin concentrations have been reported to be far lower than 3V melatonin concentrations; this observation has been used in part to argue that 3V melatonin is not coming from recirculation via the plasma and choroid plexuses but rather through direct secretion into the pineal recess [159,183]. Indeed, in sheep, brain melatonin concentration close to the third ventricle walls and aqueduct of Sylvius is double that of plasma [110], penetrating 8-10 mm into brain as the concentration gradually falls.…”

Role of AA-NAT and TPH1 in the Ghrelin-Dependent Regulation of Melatonin Secretion in Sheep during Different Seasons: An <em>In Vitro</em> Study

“…These results may also bring us closer to understanding the function of the PG in humans. Between human and sheep PGs, there is anatomical homology of gland vascularization and its distribution in relation to brain ventricles, particularly the position of the PG relative to the third ventricle [50] is comparable, which makes study using ovine PG valuable to carry on.…”

The Timing of Melatonin Administration Is Crucial for Its Antidepressant-Like Effect in Mice

“…Melatonin reaches the CSF directly by the pineal recess [4,5] and from this fluid it is distributed into different brain regions providing the photoperiodic information to the neurons. The nocturnal concentration of melatonin in the CSF is 100-fold higher than in plasma [6]. Recently it was described that the brain tissue is bathed by the melatonin accumulated in the CSF and not by the blood circulating melatonin [6].…”

“…The nocturnal concentration of melatonin in the CSF is 100-fold higher than in plasma [6]. Recently it was described that the brain tissue is bathed by the melatonin accumulated in the CSF and not by the blood circulating melatonin [6]. In the brain, melatonin is also synthesized in extrapineal sites such as the cerebellum and cortex [7,8].…”