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Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund’s adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund’s complete adjuvant and after 17 daily injections of 10 or 100 µg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 µg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [³H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.

The effect of melatonin injection on Freund's adjuvant-induced changes in levels and 24-hr rhythms of circulating ACTH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and insulin was assessed in rats. Animals received subcutaneous (s.c.) injections of melatonin (30 microg) or vehicle, 1 hr before lights off for 12 days. Ten days after melatonin treatment, they were injected with Freund's complete adjuvant or its vehicle s.c., and after 3 days, rats were killed at six different time intervals throughout a 24-hr cycle to measure the different hormones by radioimmunoassay (RIA). Following Freund's adjuvant injection, an increase in serum ACTH, with maintenance of ACTH diurnal rhythm was found. Acrophases of the ACTH rhythm varied from 13:39 to 17:12 hr and the amplitude of rhythm was augmented after immunization. In immunized rats, melatonin treatment increased the amplitude of serum ACTH rhythm. For GH, a depressive effect of immunization on circulating levels, together with absence of diurnal rhythmicity were found. Immunization augmented circulating PRL, while conserving its diurnal rhythmicity. Melatonin-injected rats showed significant diurnal variations of serum PRL after immunization only. Acrophases of the serum PRL rhythm varied from 19:37 to 22:04 hr. Immunization decreased circulating LH and suppressed its 24-hr rhythmicity pattern. The effect of immunization on LH was counteracted by melatonin injection. Acrophases of serum LH rhythm varied from 00:44 to 03:53 hr. Significant effects of immunization and time of day on circulating insulin were detected; immunization increased serum insulin levels with a shift in acrophase from early afternoon to midnight. The data indicate that several early changes in levels and 24-hr rhythms of circulating ACTH, PRL, and LH in Freund's adjuvant-injected rats were sensitive to treatment with pharmacological amounts of melatonin.

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