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to normal by physiological melatonin administration. The physiological doses of
melatonin employed effectively counteracted the impaired response of lymph node
ODC seen in pinealectomized rats.
It must be thus noted that the pharmacological effect of melatonin on the immune
response may not always be beneficial, particularly in young subjects. In autoim-
mune arthritis developed in mice with type II rat collagen, melatonin administration
(1 mg/kg) induced a more severe arthritis. Accordingly, pinealectomy in two strains
of mice immunized with rat type II collagen reduced severity of the arthritis, as
shown by a slower onset of the disease, a less severe course of the disease (reduced
clinical scores), and reduced serum levels of anti-collagen II antibodies
[143,144]
.
Using a 100-g dose of melatonin, an inflammation-promoting effect could be dem-
onstrated in young rats injected with FCA. In contrast, melatonin administration
(10 or 100 g) to old rats restored the inflammatory response in hind paws of FCA-
injected rats to levels found in young rats
[137]
. Therefore, high levels of melatonin
in young animals may stimulate the immune system and cause exacerbation of both
autoimmune collagen II and mycobacterial arthritis. Indeed, there are data indicating
that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin
and that their synovial macrophages respond to melatonin with increased production
of IL-12 and NO
[145]
. In these patients, inhibition of the antagonism of melatonin
synthesis or effect could be therapeutically desirable.
6.5 Conclusions
Temporal organization is an important feature of biological systems, and its main
function is to facilitate adaptation of the organism to the environment. The daily
variation of biological variables arises from an internal time-keeping system, and the
major action of the environment is to synchronize this internal clock to a period of
exactly 24 hours. The light-dark cycle, food, ambient temperature, scents, and social
cues have been identified as environmental synchronizers or “Zeitgebers” in rats.
This chapter discusses the circadian disruption of hormone release and immune-
related mechanisms in the rat adjuvant arthritis model. The experimental manipula-
tion used perturbed the temporal organization by affecting the shape and amplitude
of the rhythm. Further experiments are needed to assess whether the changes in
amplitude, as well in the timing of 24-hour rhythms discussed herein, can be attrib-
uted to an effect on the SCN or to a masking effect on some output(s) of the clock.
Acknowledgments
Work in the authors' laboratories was supported in part by DGES, Spain; Agencia
Nacional de Promoción Científica y Tecnológica, Argentina; the University of
Buenos Aires and the Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET), Argentina.
