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.
Behav Brain Res. 2020 Sep 1;393:112789. doi: 10.1016/j.bbr.2020.112789. Epub 2020 Jun 25.
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.
血浆雌激素水平的波动会影响女性的认知功能。特定的雌激素受体α（ERα）激动剂，（4,4',4″-(4-丙基-[1 H]吡唑-1,3,5-三基)三苯酚（PPT），据报道具有与雌激素替代疗法相似的治疗活性。然而，前者也会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。此外，在实验条件下，没有关于 cGMP 对 ERα 介导的 Akt 磷酸化的报道。长春西汀在几种组织中比 cAMP 更能增加 cGMP 的形成率。因此，本研究评估了长春西汀与 PPT 联合或不联合治疗对实验啮齿动物去卵巢引起的痴呆的神经保护作用。在实验方案的第 1 天（D-1）通过双侧卵巢切除术诱导雌性大鼠雌激素不足的状态。长春西汀（20mg/kg）和 PPT 可减轻行为测试中去卵巢引起的认知功能障碍，并增加啮齿动物的体重。长春西汀和 PPT 增加了去卵巢动物海马体、前额叶皮层和杏仁核中的胆碱能功能和 cGMP/cAMP 比值。此外，去卵巢引起的所有脑区 ERα 磷酸化程度降低，均被长春西汀或 PPT 的单一治疗所减弱。有趣的是，长春西汀和 PPT 的联合治疗比单一治疗更有效。然而，长春西汀减弱了 PPT 诱导的这些啮齿动物离散脑区中磷酸化 Akt 水平的升高和子宫重量的增加。因此，该联合治疗可被视为治疗雌激素不足引起的疾病的一种更好的替代候选药物，副作用最小。
