Lithium chloride enhances survival of NZB/W lupus mice: influence of melatonin and timing of treatment.

Daily administration of 4 mg 6LiCl to groups (15 mice/group) of female NZB/W mice starting at 8 weeks of age led to long-term survival (44 weeks of age) of 73% of the mice when injections were performed between 08:00 and 10:00 h and 67% of mice when injections were performed between 17:00 and 19:00 h. Untreated controls were dead by 34 weeks of age and the differences between untreated and treated groups was significant (P < or = 10(-4)). In contrast daily administration of melatonin (100 micrograms/mouse) did not significantly enhance survival when injections were performed between 17:00 and 19:00 h but did enhance survival when given between 08:00 and 10:00 h (P < or = 10(-3)). Differences between the two melatonin groups was also significant (P < or = 0.05). Mice treated with Li plus melatonin exhibited survival curves identical to mice treated with Li alone. Therefore, the Li effect was dominant and survival was not altered by melatonin. Cessation of treatment in long-term survivors at 44 weeks of age led to the rapid death of 80% of the mice previously treated between 17:00 and 19:00 h (Li, Li + melatonin). In contrast, only 40% of the long-term survivors in the other groups had died by 66 weeks of age (22 weeks post-treatment). Thus the p.m. groups were less protected from disease reactivation than were the a.m. groups. Neither Li, melatonin, nor Li+melatonin influenced anti-gp70 or anti-ssDNA levels in serum, but Li treatment maintained renal function as determined by proteinuria scores. These findings indicate that the effectiveness of Li is probably not related to melatonin metabolism and immunomodulating influences, but the influence of other neuroendocrine variables cannot be eliminated.