N-nitrosomelatonin as a chronobiotic

BAIDANOFF FM; PLANO SA; DOCTOROVICH F; SUÁREZ SA; GOLOMBEK DA; CHIESA JJ

Tunuyan

Simposio; XII Latin American Symposium on Chronobiology; 2013

Virtually almost all physiological processes in mammals are synchronized to the daily light:dark cycle by a circadian clock located in the hypothalamic suprachiasmatic nucleus. Signal transduction of light-induced circadian phase changes is mediated through the neuronal nitric oxide synthase. We have employed a novel nitric oxide- donor, N-nitrosomelatonin, to enhance photic synchronization of locomotor activity rhythms in hamsters. The intraperitoneal administration of this drug before a sub- saturating light pulse at circadian time 18, generated a two-fold increase of photically-induced advances This potentiation was also obtained even when inhibiting suprachiasmatic nitric oxide synthase activity. However, N- nitrosomelatonin had no effect on light-induced phase delays at circadian time 14 or on resynchronization to a 6-hour delay. The light pulse-enhancing effects were correlated with an increased suprachiasmatic immunoreactivity of cFOS, an immediate-early gene expressed in response to light. Moreover, in vivo nitric oxide release by N-nitrosomelatonin was verified by measuring nitrate and nitrite levels in suprachiasmatic nuclei homogenates. The drug proved to be efficient in an experimental jet-lag protocol, by accelerating resynchronization to an abrupt 6-h advance in the light:dark cycle. In summary, we demonstrated the chronobiotic properties of N-nitrosomelatonin, emphasizing the importance of nitric oxide- mediated transduction for circadian phase advances.