N‐nitrosomelatonin enhances photic synchronization of mammalian circadian rhythms

Most 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 phase advances of the clock is mediated through a neuronal nitric oxide synthase‐guanilyl cyclase pathway. We have employed a novel nitric oxide‐donor, N‐nitrosomelatonin, to enhance the photic synchronization of circadian rhythms in hamsters. The intraperitoneal administration of this drug before a sub‐saturating light pulse at circadian time 18 generated a twofold increase of locomotor rhythm phase‐advances, having no effect over saturating light pulses. 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. The photic‐enhancing effects were correlated with an increased suprachiasmatic immunoreactivity of FBJ murine osteosarcoma viral oncogene and period1. Moreover, in vivo nitric oxide release by N‐nitrosomelatonin was verified by measuring nitrate and nitrite levels in suprachiasmatic nuclei homogenates. The compound also accelerated resynchronization to an abrupt 6‐h advance in the light:dark cycle (but not resynchronization to a 6‐h delay). Here, we demonstrate the chronobiotic properties of N‐nitrosomelatonin, emphasizing the importance of nitric oxide‐mediated transduction for circadian phase advances. We demonstrated the chronobiotic effects of a novel nitric oxide donor, N‐nitrosomelatonin (NO‐Mel), which enhanced light‐induced circadian entrainment and gene expression in the suprachiasmatic nuclei, the site of the mammalian biological clock, as well as promoted and accelerated rate of reentrainment to an experimental jetlag protocol. NO‐Mel increased nitrate/nitrite levels in the SCN and we suggest our findings represent a novel strategy for the treatment of human circadian disorders. We demonstrated the chronobiotic effects of a novel nitric oxide donor, N‐nitrosomelatonin (NO‐Mel), which enhanced light‐induced circadian entrainment and gene expression in the suprachiasmatic nuclei, the site of the mammalian biological clock, as well as promoted and accelerated rate of reentrainment to an experimental jetlag protocol. NO‐Mel increased nitrate/nitrite levels in the SCN and we suggest our findings represent a novel strategy for the treatment of human circadian disorders.