cGMP modulation by PDE inhibition enhance photic response of the circadian system.

PLANO SA; AGOSTINO PV; DE LA IGLESIA HO; GOLOMBEK DA

Cordoba

Congreso; II Reunion conjunta de Neurociencias; 2010

The circadian clock in mammals is located in the hypothalamic suprachiamatic nuclei (SCN), which are synchronized mainly by the light-dark (LD) cycle. Light pulses (LP) in the late subjective night induce phase advances in circadian rhythms and the expression of clock genes (such as per) by the activation of the NO-GC-cGMP-PKG pathway. Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition increases light-induced (L-I) circadian responses. Vardenafil, Tadalafil or Sildenafil significantly increased L-I phase advances as well as accelerated circadian reentrainment after jet-lag. Sildenafil also increased the phase-shifting effect of saturating LP in male or female hamsters as well as in mice, and was also effective after oral administration. This inhibitor also accelerated reentrainment of temperature circadian rhythms. We also show that the cGMP-dependent pathway converges in L-I clock gene expression in the SCN, since inhibition of PKG significantly decreased L-I Per1 expression in the subjective night. In summary, our results demonstrate the involvement of cGMP and its related signaling pathway on light-induced circadian entrainment, and provide promising tools to design treatments aimed at human circadian disruption.