Circadian Organization of the Immune Response: Rat Adjuvant Arthritis as a Model - New Insights to Neuroimmune Biology - page 123

endocrine circadian rhythms of plasma prolactin, insulin-like growth factor-1, LH,
and testosterone, and of pituitary prolactin mRNA, was recently reported in male
Long-Evans rats injected with FCA 23 days earlier [110] .
6.4.2 Melatonin as a Circadian Immunoregulatory
Signal in Adjuvant Arthritis
Melatonin was first isolated and identified by Lerner and his associates in 1958 [111] .
It is the major neurohormone secreted by the pineal gland during the dark hours at
night. In addition, melatonin has been demonstrated to be produced by many organs
other than the pineal gland, including the retina [112] , the gastrointestinal tract [113] ,
skin [114] , lymphocytes [115] , the thymus [116] , and bone marrow cells [117] .
Circulating melatonin derives almost exclusively from the pineal gland. Once
formed, melatonin is released into the capillaries, and in higher concentrations
into the cerebrospinal fluid [118] , and is then rapidly distributed to most body tis-
sues [119] . Circulating melatonin is metabolized mainly in the liver, where it is first
hydroxylated by cytochrome P450 monooxygenases and then conjugated with sulfate
to form 6-sulfatoxymelatonin. Melatonin is also metabolized in tissues by oxidative
pyrrole-ring cleavage into kynuramine derivatives. The primary cleavage product is
N 1 -acetyl- N 2 -formyl-5-methoxykynuramine (AFMK), which is deformylated either
by arylamine formamidase or hemoperoxidase to N 1 -acetyl-5-methoxykynuramine.
It has been proposed that AFMK is the primitive and primary active metabolite of
melatonin [120] . The SCN regulates pineal gland function through a polysynaptic
network involving the subparaventricular zone in the hypothalamus. Descending
polysynaptic fibers from these regions project through the medial forebrain bun-
dle and the reticular formation to the intermediolateral horns of the cervical seg-
ments of the spinal cord [121] . Postganglionic sympathetic fibers from the superior
cervical ganglia reach the pineal gland and regulate melatonin biosynthesis through
the presynaptic release of norepinephrine (NE). NE release occurs during the
“night” portion of the circadian pacemaker cycle, provided that this occurs in a
dark environment [122] .
Plasma melatonin exhibits a circadian rhythm with high levels at night and low
levels during the day, attaining peak concentrations of plasma melatonin between
02:00 and 04:00 hours. The timing of melatonin secretion is closely associated with
the timing of sleep, and it also coincides with decreases in core body temperature,
alertness, and performance [123] . Melatonin has the capacity to alter the timing
of circadian rhythms, and functions in concert with light to synchronize circadian
rhythms with the prevailing light-dark cycles. Melatonin has been used therapeuti-
cally in treating various circadian-rhythm sleep disorders, such as the delayed sleep
phase syndrome, shift-work sleep disorder, jet lag, and blindness [124-127] .
Melatonin exerts many physiological effects by acting on membrane and nuclear
receptors, although other actions are receptor-independent (e.g., scavenging of
free radicals or interaction with cytoplasmic proteins). The two melatonin recep-
tors cloned so far (MT 1 and MT 2 ) are membrane receptors that have seven mem-
brane domains and belong to the superfamily of G-protein-coupled receptors [128] .