Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
Neurochem Int. 2020 Jan;132:104609. doi: 10.1016/j.neuint.2019.104609. Epub 2019 Nov 25.
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.
女性的认知功能被观察到随着血浆雌激素水平的波动而变化。特定的雌激素受体α（ERα）激动剂，（4,4',4″-（4-丙基-[1H]吡唑-1,3,5-三基）三苯酚（PPT），具有与雌激素替代疗法相似的治疗活性。它还可以在去卵巢动物的子宫中发挥环磷酸腺苷（cAMP）依赖性致癌活性。然而，在实验条件下，没有关于 cGMP 对 ERα 介导的 Akt 磷酸化的报道。西地那非可增加包括大脑在内的大多数组织中的 cGMP 水平。因此，本研究评估了西地那非联合或不联合 PPT 在实验性雌激素不足的大鼠中的治疗效果。通过在实验开始的第 1 天（D-1）对雌性大鼠进行双侧卵巢切除术，诱导雌激素不足的状态。西地那非（1.0 和 10.0 mg/kg）和 PPT 可减轻行为测试中卵巢切除术引起的认知障碍，并增加啮齿动物的体重。西地那非和 PPT 增加了海马体、前额叶皮层和杏仁核中的胆碱能功能和 cGMP/cAMP 比值。此外，卵巢切除术诱导的所有大脑区域中 ERα 磷酸化程度的降低均被西地那非或 PPT 的单药治疗所减弱。有趣的是，西地那非和 PPT 的联合治疗比它们的单药治疗具有更好的治疗效果。然而，西地那非减弱了 PPT 诱导的离散脑区中磷酸化蛋白激酶-B（Akt）水平的增加以及这些啮齿动物子宫的重量。因此，可以假设联合治疗可能是一种更好的治疗选择，具有最小的副作用，可用于管理雌激素不足引起的疾病。
