Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation.
ABSTRACT Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.
- SourceAvailable from: Ege Can Serefoglu[show abstract] [hide abstract]
ABSTRACT: Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The use of on-demand PDE5 inhibitors for the treatment of erectile dysfunction (ED) has recently obtained approval for chronic daily dosing for the same indication. There are published data supporting the use of PDE5 inhibitors for the treatment of lower urinary tract symptoms (LUTS) caused by BPH. Additional reports suggest befeit by these agents in patients with chronic heart failure, pulmonary hypertension, essential hypertension, and for the treatment of ischemia. Various central nervous system disorders have been described as targets by for PDE5 inhibitors. Sildenafil may have a potential therapeutic indication as a cognitive enhancer in age-related cerebral conditions. There is preclinical evidence for further investigation of the use of PDE5A inhibitors to improve recovery of cerebral function in humans after stroke by enhancing angiogenesis, neurogenesis and improving neurologic function. Sildenafil delays intestinal ulceration by an increase in the secretion of mucus/fluid and a decrease in hypermotility, and has a protective effect in reducing gastric damage. Larger scale, well designed clinical trials are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5 inhibitors in the future treatment of both urologic and non-urologic diseases. In this review, potential applications of PDE5 inhibitors on urologic, cardiovascular, gastrointestinal, and central nervous system disorders will be updated.Current pharmaceutical design 06/2012; · 4.41 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We review here that oxytocin (OT) is released into blood and within distinct brain regions in response to stressful and social stimuli, and has been shown to have an antidepressant-like effect in animal studies. Clinical reports suggest OT to be a promising drug for psychiatric diseases such as depression, anxiety disorders, schizophrenia, and autism. OT may also have therapeutic potential in the treatment of major depressive disorders, even though OT administered into blood does not readily cross the blood–brain barrier. Physiological functions such as sexual activity and mating induce the release of OT in the central nervous system. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. This drug has antidepressant-like effects through activation of an OT signaling pathway. These results suggest that sildenafil may have promise as a potential antidepressant.The Journal of Physiological Sciences 62(6). · 1.09 Impact Factor