Meihua Deng

Bioavailability of Oral Melatonin in Humans

We administered crystalline melatonin (80 mg) in gelatin capsules to 5 young male volunteers and measured serum and urinary melatonin levels at intervals. Changes in serum melatonin levels were best described by a biexponential equation with an absorption constant (ka) of 1.72 h-1 (half-life = 0.40 h) and an elimination constant (ke1) of 0.87 h-1 (half-life = 0.80 h). Peak serum melatonin levels, ranging from 350 to 10,000 times those occurring physiologically at nighttime, were observed 60-150 min after its administration, remaining stable for approximately 1.5 h. The fraction of ingested melatonin that was absorbed, estimated from the area under the curve describing serum melatonin concentrations as a function of time after melatonin administration (the concentration-time curve), varied by 25-fold among subjects. 3 additional volunteers received three melatonin-containing capsules (80 mg each) at 60-min intervals. This regimen extended the duration of elevated serum melatonin levels to 4-6 h. Melatonin excretion closely paralleled serum melatonin levels until 9 h after the hormones administration, after which urinary levels tended to be higher than those predicted from serum levels. However, the area under the concentration-time curve for serum melatonin correlated well (r = 0.96) with the cumulative melatonin excretion during the initial 15 h after melatonins administration, indicating that either approach can be used to estimate the absorption of orally administered melatonin.

Light intensities required to suppress nocturnal melatonin secretion in albino and pigmented rats

Sprague-Dawley albino rats or Long-Evans pigmented rats were exposed during the dark phase of the daily light:dark cycle to various intensities of a sunlight-stimulating white fluorescent light (0.022, 0.044, 0.110, 0.220, 0.440 or 2.200 microW/cm2) for 30 min; pineal glands and trunk blood samples were then collected and assayed for melatonin by radioimmunoassay. Albino rats exposed to irradiances of 0.110 microW/cm2 or less had pineal melatonin levels that were not significantly different from those of unexposed animals; higher irradiances significantly (P less than 0.001) reduced melatonin levels. In contrast, as little as 0.022 microW/cm2 significantly (P less than 0.02) reduced pineal and serum melatonin levels in the pigmented rats. These results suggest that something other than the simple presence or absence of eye pigmentation is the critical factor in determining the sensitivity of the rats pineal to retinal-mediated photic suppression of melatonin synthesis.

Melatonin concentrations in the sudden infant death syndrome

To examine a possible relationship between pineal function and the sudden infant death syndrome (SIDS), samples of whole blood, ventricular cerebrospinal fluid (CSF) and/or vitreous humor (VH) were obtained at autopsy from 68 infants (45 male, 23 female) whose deaths were attributed to either SIDS (n = 32, 0.5-5.0 months of age; mean +/- S.E.M., 2.6 +/- 0.2 months) or other causes (non-SIDS, n = 36, 0.3-8.0 months of age 4.3 +/- 0.3 months). The melatonin concentrations were measured by radioimmunoassay. A significant correlation was observed for melatonin levels in different body fluids from the same individual. After adjusting for age differences, CSF melatonin levels were significantly lower among the SIDS infants (91 +/- 29 pmol/l; n = 32) than among those dying of other causes (180 +/- 27; n = 35, P less than 0.05). A similar, but non-significant trend was also noted in blood (97 +/- 23, n = 30 vs. 144 +/- 22 pmol/l, n = 33) and vitreous humor (68 +/- 21, n = 10 vs. 81 +/- 17 pmol/l, n = 15). These differences do not appear to be explainable in terms of the interval between death and autopsy, gender, premortem infection or therapeutic measures instituted prior to death. Diminished melatonin production may be characteristic of SIDS and could represent an impairment in the maturation of physiologic circadian organization.

Regulation of APP Processing by First Messengers

Brain amyloid deposits are invariant neuropathological hallmarks of Alzheimer’s disease (AD) and Down’s syndrome, and are sometimes also found in lesser amounts in brains of non-demented aged human subjects. Alzheimer disease-type brain amyloid consists of aggregated amyloid s- (As) peptides which are self-aggregating molecules of 39–43 residues in length. As is derived, by proteolytic processing, from a larger amyloid s-protein precursor (APP). The hydrophobic C-terminal region of the amyloidogenic As domain is located within the single transmembrane domain of APP, and its N-terminus extends 28 residues into the ectodomain (for review, see Selkoe, 1994). The APP gene is expressed at remarkably high levels in brain but is also expressed in many peripheral tissues. The biological function of APP is unclear and it is possible that individual proteolytic derivatives of APP have distinct biological consequences. For instance, accumulating evidence suggests that the full-length protein and its secreted N-terminal derivatives can promote cell adhesion (Schubert et al., 1989), stimulate neunte outgrowth (Milward et al., 1992), and protect cultured neurons from excitotoxic damage (Mattson et al., 1993). In contrast, As and its aggregates can be cytotoxic and induce cell death in cultured neurons (Yankner et al., 1990; Loo et al., 1993). Moreover, As inhibits the normal function of a potassium channel which appears to be impaired in fibroblasts obtained from AD patients (Etcheberrigaray et al., 1994). These initial data support the concept that large portions of the N-terminal ectodomain have trophic functions whereas the As domain can be cytotoxic. The biochemical mechanisms involved in the regulation of local brain tissue concentrations of particular proteolytic APP derivatives may thus play an important role in determining the actual functions of APP.

The Responses of Melatonin Rhythms to Environmental Lighting

Two very powerful generalizations characterize present conceptions of normal pineal function (1–3): In almost all species examined thus far in laboratory situations, the pineal secretes more melatonin at nighttime than during the day, and melatonin secretion is suppressed when the animals are placed in a lighted environment. Since nighttime for humans coincides with the daily dark period, investigators have often tacitly assumed that the second generalization explains the first, — that is, that the circadian increases in melatonin secretion occurs nocturnally because the absence of light terminates the retina-mediated suppression of pineal sympathetic activity, thereby increasing the organ’s stimulation by norepinephrine.

Modulation of APP Processing by Neurotransmission

Brain amyloid deposits are invariant neuropathological hallmarks of Alzheimer’s disease (AD) and Down’s syndrome, and are sometimes also found in lesser amounts in brains of neuropsychologically normal, aged human subjects. AD-type brain amyloid consists of aggregated As peptides which are 39–43 amino acid residues in length. As is derived, by proteolytic processing, from a larger amyloid s-protein precursor (APP), which is a transmembrane glycoprotein that contains a single membrane spanning domain, a large N-terminal ectodomain and a short cytoplasmic C-terminal tail. The As domain is located within the ectodomain and extends with its hydrophobic C-terminal region 11-15 residues into the membrane. APP exists in various forms generated by alternative splicing of mRNA derived from a single gene on chromosome 21 (for review, see Kosik, 1992). APP is highly conserved and expressed at high levels in brain and, at lower levels, in many peripheral tissues. The biological function of APP is unclear but accumulating evidence suggests roles in cell adhesion (Schubert et al., 1989), in neurite outgrowth (Milward et al., 1992), as well as excitoprotective functions via the regulation of intracellular calcium concentrations (Mattson et al., 1993). Mature APP is rapidly degraded by various alternative proteolytic processing pathways. Proteolytic derivatives are secreted into the extracellular space and are found at high concentrations in human cerebrospinal fluid. Secreted APP derivatives include the large N-terminal ectodomain, termed APPs (Esch et al., 1990; Sisodia et al., 1990) and ~4KDa As-peptides (Haass et al., 1992; Shoji et al., 1992) that potentially can aggregate into amyloid. In addition to the secretory processing pathways, full-length APP can be internalized from the cell surface and targeted to the endosomal-lysosomal system (Haass et al., 1992), where multiple cleavage products are generated. Some of these contain the intact sA4 domain and thus are also potentially amyloidogenic (Golde et al., 1992; Estus et al., 1992). As is neurotoxic in some experimental systems (Yankner et al., 1990) and may induce apoptosis (Loo et al., 1993). Thus, APP processing pathways yielding either As or APPs are likely to have distinct cellular consequences: processing events that generate As may be toxic and are potentially amyloidogenic, whereas APP processing to yield APPs generate trophic and precludes APP’s role as an amyloidogenic molecule. It thus becomes important to understand the cellular mechanisms involved in the regulation of APP processing pathways.