Abstract
The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.
Highlights
In mammals, the master circadian clock resides in the hypothalamic suprachiasmatic nuclei (SCN), which is able to adjust its parameters with a variety of environmental signals
In a previous study we demonstrated that inhibition of PDE5 by sildenafil increases a 50-lux light-induced phase advance but has no effect when administered by itself in the absence of a LP, and accelerates circadian reentrainment to a 6-h advance of the LD cycle [17]
Our results suggest a possible role for PDEs in modulating the sensitivity of the circadian system to photic stimulation
Summary
The master circadian clock resides in the hypothalamic suprachiasmatic nuclei (SCN), which is able to adjust its parameters with a variety of environmental signals. The light-dark (LD) cycle is the principal synchronizer of the biological clock [1,2]; photic information reaches the SCN through the retinohypothalamic tract (RHT) by means of a glutamatergic signal, resulting in phase shifts of biological rhythms [3,4,5,6]. Responses to light during the subjective night are mediated through a common signaling pathway involving glutamate, Ca2+, CaMKII and neuronal nitric oxide synthase (nNOS), which couple photic stimulation to the transcriptional activation of clock genes [9,10]. The activation of a cGMP-dependent pathway — including the activation of guanylyl cyclase (GC)— and the activation of a cGMP dependent protein kinase (PKG) is involved in phase advances [12,13,14]. Pharmacological manipulation of cGMP by inhibition of its degradation pathway (i.e., by blocking cGMP-phosphodiesterase (PDE) should affect photic entrainment and resynchronization
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