Vinpocetine facilitates the anti-amnesic activity of estrogen-receptor alpha agonist in bilateral ovariectomy-challenged animals

Abstract

The fluctuation in plasma estrogen level influences the cognitive function in the females. The specific estrogen receptor alpha (ERα) agonist, (4,4′,4″-(4-propyl-[1 H] pyrazole-1,3,5-triyl) tris phenol (PPT), is reported to exhibit therapeutic activity similar to that of estrogen replacement therapy. However, the former can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. Moreover, there is no report of cGMP on ERα-mediated phosphorylation of Akt in the experimental condition. Vinpocetine increases the rate of formation of cGMP than cAMP in several tissues. Hence, the present study evaluated the neuroprotective effect of vinpocetine with or without PPT against ovariectomy-induced dementia in experimental rodents. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Vinpocetine (20 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioral tests and increase in body weight in the rodents. Vinpocetine and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the ovariectomized animals. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in all brain regions was attenuated with the monotherapy of either vinpocetine or PPT. Interestingly, the combination of vinpocetine and PPT exhibited better effectiveness than their monotherapy. However, vinpocetine attenuated the PPT-induced increased level of phosphorylated Akt in discrete brain regions and weight of uterus of these rodents. Hence, the combination could be considered as a better alternative candidate with minimal side effects in the management of estrogen insufficiency-induced disorders.