NO-cGMP dependent signal transduction and circadian entrainment

PLANO SA; AGOSTINO PV; GOLOMBEK DA

Valencia

Simposio; II International Symposium on Nitric Oxide-cyclick GMP Signal Transduction in Brain; 2006

The NO/GC/cGMP/PKG pathway is essential for light sincronization of the circadian clock. Phosphodiesterases (PDEs) are key regulators of intracellular cyclic nucleotide concentrations. To study the regulation of cGMP levels in the hamster SCN, we have determined by RT-PCR the presence of PDE5 in this model. In hamsters receiving specific PDE5 inhibitors (sildenafil, vardenafil or taladafil), reentrainment to a 6h phase-advance of the LD cycle took significantly shorter than controls. PDE5 inhibitors also elicited an increase in light-induced phase advances when injected 45 min before light stimulation at CT18. No differences were observed in either reentrainment rates after a delay in the LD cycle, or light-induced phase delays after a light pulse at CT14. We have studied the role of nitric oxide (NO) in the intercellular communication within the dorsal and ventral portions of the SCN. Administration of the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) blocked photic phase advances in a dose-dependent manner and inhibited light-induced cFos-ir, without affecting phase delays. In addition, preliminary results show an inhibition in the non-parametric entrainment to 23.5 h cycle (L:1 D:22.5) in hamsters receiving a single dose of PTIO before light stimulation. These results demonstrate that pharmacological inhibition of PDE5 affects photic entrainment, indicating a potential benefit for circadian disorders which require an increase in light signaling to the clock. These findings could serve as a basis for pharmacological treatment for optimizing circadian adaptation to environmental changes, including transmeridian flight schedules (jet-lag). Also, a role for extracellular NO in the intra-SCN communication A is suggested.