Sildenafil promotes the anti-amnesic activity of estrogen receptor alpha agonist in animals with estrogen insufficiency

Abstract

The cognitive function in the females is observed to modulate with the fluctuation in plasma estrogen level. The specific estrogen receptor alpha (ERα) agonist, (4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT), exerts similar therapeutic activity to that of estrogen replacement therapy. It can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. However, there is no report of cGMP on the ERα-mediated phosphorylation of Akt in the experimental condition. Sildenafil increases the level of cGMP in most of the tissues including brain. Hence, the present study evaluated the therapeutic effect of Sildenafil with or without PPT in rats with experimentally-induced estrogen insufficiency. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Sildenafil (1.0 and 10.0 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioural tests and increase in body weight in the rodents. Sildenafil and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the animals. Further, the ovariectomy-induced decrease in the extent of phosphorylation of ERα in all the brain regions was attenuated with the monotherapy of either Sildenafil or PPT. Interestingly, the combination of Sildenafil and PPT exhibited better therapeutic effectiveness than their monotherapy. However, Sildenafil attenuated the PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in the discrete brain regions and the weight of uterus of these rodents. Hence, it can be assumed that the combination could be a better therapeutic alternative with minimal side effect in the management of estrogen insufficiency-induced disorders.